bluuebunny/crossref_metadata_2025 huggingface dataset:
Local injection of dsRNA targeting calcitonin receptor-like receptor (CLR) ameliorates
Clostridium difficile
toxin A-induced ileitis
Authors: Bhargava Aditi , Clifton Matthew S. , Mhaske Pallavi , Liao Min , Pothoulakis Charalabos , Leeman Susan E. , Grady Eileen F.
Published: December 2012

Enteritis caused by
Clostridium difficile
toxin (Tx) is a nosocomial disease of increasing clinical concern, but the local mediators of
C. difficile
TxA inflammation are unknown. The potent vasodilator calcitonin gene-related peptide mediates neurogenic inflammation via the calcitonin receptor-like receptor (CLR). Here we examined the ileum-specific effects of reducing CLR on TxA ileitis by local preinjection of double-stranded RNAs. Treatment with CLR dsRNA for 7 d decreased CLR immunoreactivity, whereas treatment with non-CLR dsRNA did not. Subsequent injection of TxA in the same location increased CLR in rats treated with non-CLR dsRNA but not in rats treated with CLR dsRNA, documenting that local injection of dsRNA is effective in preventing the increase in CLR immunoreactivity in response to local TxA. After non-CLR dsRNA pretreatment, TxA induced robust intestinal secretion, myeloperoxidase activity, and histopathologic indications of inflammation including epithelial damage, congestion, neutrophil infiltration, loss of mucin from goblet cells, and increase in mast cell numbers. After CLR dsRNA pretreatment, TxA-induced changes in intestinal secretion and histopathologic inflammation were improved, including normal mucin staining and fewer resident mast cells. Loss of CLR prevented TxA-mediated activation of NF-κB and concomitant increases in pERK1/2 and TNF-α mRNA. Locally produced CLR plays a proinflammatory role in TxA ileitis via MAPK signaling and TNF-α. The results reported here strongly suggest that a local injection of dsRNA targeting CLR could be an effective local therapeutic approach at the inflammation site in the treatment of a growing, clinically relevant hospital-acquired disease,
C. difficile
infection.
Linkage analysis identifies a locus for plasma von Willebrand factor undetected by genome-wide association
Authors: Desch Karl C. , Ozel Ayse B. , Siemieniak David , Kalish Yossi , Shavit Jordan A. , Thornburg Courtney D. , Sharathkumar Anjali A. , McHugh Caitlin P. , Laurie Cathy C. , Crenshaw Andrew , Mirel Daniel B. , Kim Yoonhee , Cropp Cheryl D. , Molloy Anne M. , Kirke Peadar N. , Bailey-Wilson Joan E. , Wilson Alexander F. , Mills James L. , Scott John M. , Brody Lawrence C. , Li Jun Z. , Ginsburg David
Published: December 2012

The plasma glycoprotein von Willebrand factor (VWF) exhibits fivefold antigen level variation across the normal human population determined by both genetic and environmental factors. Low levels of VWF are associated with bleeding and elevated levels with increased risk for thrombosis, myocardial infarction, and stroke. To identify additional genetic determinants of VWF antigen levels and to minimize the impact of age and illness-related environmental factors, we performed genome-wide association analysis in two young and healthy cohorts (n= 1,152 andn= 2,310) and identified signals atABO(P< 7.9E-139) andVWF(P< 5.5E-16), consistent with previous reports. Additionally, linkage analysis based on sibling structure within the cohorts, identified significant signals at chromosome 2q12–2p13 (LOD score 5.3) and at theABOlocus on chromosome 9q34 (LOD score 2.9) that explained 19.2% and 24.5% of the variance in VWF levels, respectively. Given its strong effect, the linkage region on chromosome 2 could harbor a potentially important determinant of bleeding and thrombosis risk. The absence of a chromosome 2 association signal in this or previous association studies suggests a causative gene harboring many genetic variants that are individually rare, but in aggregate common. These results raise the possibility that similar loci could explain a significant portion of the “missing heritability” for other complex genetic traits.
Maternal exposure to bisphenol A and genistein has minimal effect onAvy/aoffspring coat color but favors birth of agouti over nonagouti mice
Authors: Rosenfeld Cheryl S. , Sieli Paizlee T. , Warzak Denise A. , Ellersieck Mark R. , Pennington Kathleen A. , Roberts R. Michael
Published: December 2012

Reports that maternal diet influences coat color in mouse offspring carrying theagoutiAvyallele have received considerable attention because the range, from pseudoagouti (brown) to yellow, predicts adult health outcomes, especially disposition toward obesity and diabetes, in yellower mice. Bisphenol A (BPA), an endocrine-disrupting compound with estrogenic properties, fed toa/adams harboringAvy/aconceptuses has been reported to induce a significant shift toward yellower mice, whereas consumption of either genistein (G) alone or in combination with BPA led to greater numbers of healthy, brown offspring. Groups of C57/B6a/afemales, which are nonagouti, were fed either a phytoestrogen-free control diet or one of six experimental diets: diets 1–3 contained BPA (50 mg, 5 mg, and 50 μg BPA/kg food, respectively); diet 4 contained G (250 mg/kg food); diet 5 contained G plus BPA (250 and 50 mg/kg food, respectively); and diet 6 contained 0.1 μg of ethinyl estradiol (EE)/kg food. Mice were bred toAvy/amales over multiple parities. In all, 2,824 pups from 426 litters were born. None of the diets provided any significant differences in relative numbers of brown, yellow, or intermediate coat colorAvy/aoffspring. However, BPA plus G (P< 0.0001) and EE diets (P= 0.005), but not the four others, decreased the percentage of black (a/a) toAvy/aoffspring from the expected Mendelian ratio of 1:1. Data suggest thatAvy/aconceptuses, which may possess a so-called “thrifty genotype,” are at a competitive advantage overa/aconceptuses in certain uterine environments.
Aldehyde dehydrogenase inhibition as a pathogenic mechanism in Parkinson disease
Authors: Fitzmaurice Arthur G. , Rhodes Shannon L. , Lulla Aaron , Murphy Niall P. , Lam Hoa A. , O’Donnell Kelley C. , Barnhill Lisa , Casida John E. , Cockburn Myles , Sagasti Alvaro , Stahl Mark C. , Maidment Nigel T. , Ritz Beate , Bronstein Jeff M.
Published: December 2012

Parkinson disease (PD) is a neurodegenerative disorder particularly characterized by the loss of dopaminergic neurons in the
substantia nigra
. Pesticide exposure has been associated with PD occurrence, and we previously reported that the fungicide benomyl interferes with several cellular processes potentially relevant to PD pathogenesis. Here we propose that benomyl, via its bioactivated thiocarbamate sulfoxide metabolite, inhibits aldehyde dehydrogenase (ALDH), leading to accumulation of the reactive dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), preferential degeneration of dopaminergic neurons, and development of PD. This hypothesis is supported by multiple lines of evidence. (
i
) We previously showed in mice the metabolism of benomyl to
S
-methyl
N
-butylthiocarbamate sulfoxide, which inhibits ALDH at nanomolar levels. We report here that benomyl exposure in primary mesencephalic neurons (
ii
) inhibits ALDH and (
iii
) alters dopamine homeostasis. It induces selective dopaminergic neuronal damage (
iv
) in vitro in primary mesencephalic cultures and (
v
) in vivo in a zebrafish system. (
vi
) In vitro cell loss was attenuated by reducing DOPAL formation. (
vii
) In our epidemiology study, higher exposure to benomyl was associated with increased PD risk. This ALDH model for PD etiology may help explain the selective vulnerability of dopaminergic neurons in PD and provide a potential mechanism through which environmental toxicants contribute to PD pathogenesis.
Fucosyltransferase 8 as a functional regulator of nonsmall cell lung cancer
Authors: Chen Chien-Yu , Jan Yi-Hua , Juan Yi-Hsiu , Yang Chih-Jen , Huang Ming-Shyan , Yu Chong-Jen , Yang Pan-Chyr , Hsiao Michael , Hsu Tsui-Ling , Wong Chi-Huey
Published: December 2012

The up-regulation of fucosyltransferase 8 (FUT8), the only enzyme catalyzing α1,6-fucosylation in mammals, has been observed in several malignant cancers including liver, ovarian, thyroid, and colorectal cancers. However, the pathological role and the regulatory mechanism of FUT8 in cancers remain largely unknown. In the current study, we report that the expression of FUT8 is up-regulated in nonsmall cell lung cancer (NSCLC) and correlates with tumor metastasis, disease recurrence, and poor survival in patients with NSCLC. Knocking down FUT8 in aggressive lung cancer cell lines significantly inhibits their malignant behaviors including in vitro invasion and cell proliferation, as well as in vivo metastasis and tumor growth. The results of glycoproteomic and microarray analyses show that FUT8 globally modifies surface antigens, receptors, and adhesion molecules and is involved in the regulation of dozens of genes associated with malignancy, suggesting that FUT8 contributes to tumor progression through multiple mechanisms. Moreover, we show that FUT8 is up-regulated during epithelial–mesenchymal transition (EMT), a critical process for malignant transformation of tumor, via the transactivation of β-catenin/lymphoid enhancer-binding factor-1 (LEF-1). These results provide a model to illustrate the relation between FUT8 expression and lung cancer progression and point to a promising direction for the prognosis and therapy of lung cancer.
Coenzyme Q10 prevents peripheral neuropathy and attenuates neuron loss in the
db
−
/db
−
mouse, a type 2 diabetes model
Authors: Shi Tie-Jun Sten , Zhang Ming-Dong , Zeberg Hugo , Nilsson Johanna , Grünler Jacob , Liu Su-Xing , Xiang Qiong , Persson Jonas , Fried Kaj J. , Catrina Sergiu Bogdan , Watanabe Masahiko , Århem Peter , Brismar Kerstin , Hökfelt Tomas G. M.
Published: December 2012

Diabetic peripheral neuropathy (DPN) is the most common complication in both type 1 and type 2 diabetes. Here we studied some phenotypic features of a well-established animal model of type 2 diabetes, the leptin receptor-deficient
db
−
/db
−
mouse, and also the effect of long-term (6 mo) treatment with coenzyme Q10 (CoQ10), an endogenous antioxidant. Diabetic mice at 8 mo of age exhibited loss of sensation, hypoalgesia (an increase in mechanical threshold), and decreases in mechanical hyperalgesia, cold allodynia, and sciatic nerve conduction velocity. All these changes were virtually completely absent after the 6-mo, daily CoQ10 treatment in
db
−
/db
−
mice when started at 7 wk of age. There was a 33% neuronal loss in the lumbar 5 dorsal root ganglia (DRGs) of the
db
−
/db
−
mouse versus controls at 8 mo of age, which was significantly attenuated by CoQ10. There was no difference in neuron number in 5/6-wk-old mice between diabetic and control mice. We observed a strong down-regulation of phospholipase C (PLC) β3 in the DRGs of diabetic mice at 8 mo of age, a key molecule in pain signaling, and this effect was also blocked by the 6-mo CoQ10 treatment. Many of the phenotypic, neurochemical regulations encountered in lumbar DRGs in standard models of peripheral nerve injury were not observed in diabetic mice at 8 mo of age. These results suggest that reactive oxygen species and reduced PLCβ3 expression may contribute to the sensory deficits in the late-stage diabetic
db
−
/db
−
mouse, and that early long-term administration of the antioxidant CoQ10 may represent a promising therapeutic strategy for type 2 diabetes neuropathy.
Recombination regulator PRDM9 influences the instability of its own coding sequence in humans
Authors: Jeffreys Alec J. , Cotton Victoria E. , Neumann Rita , Lam Kwan-Wood Gabriel
Published: December 2012

PRDM9 plays a key role in specifying meiotic recombination hotspot locations in humans and mice via recognition of hotspot sequence motifs by a variable tandem-repeat zinc finger domain in the protein. We now explore germ-line instability of this domain in humans. We show that repeat turnover is driven by mitotic and meiotic mutation pathways, the latter frequently resulting in substantial remodeling of zinc fingers. Turnover dynamics predict frequent allele switches in populations with correspondingly fast changes of the recombination landscape, fully consistent with the known rapid evolution of hotspot locations. We found variation in meiotic instability between men that correlated with
PRDM9
status. One particular “destabilizer” variant caused hyperinstability not only of itself but also of otherwise-stable alleles in heterozygotes. PRDM9 protein thus appears to regulate the instability of its own coding sequence. However, destabilizer variants are strongly self-limiting in populations and probably have little impact on the evolution of the recombination landscape.
at.óow OR l s'aatí át?: Language revitalization, cultural creation, and the tlingit Macbeth
Authors: Pangallo Matteo A.
Published: December 2012

This essay considers a production of Shakespeare’s Macbeth, produced by Alaska’s Perseverance Theatre at the Smithsonian National Museum of the American Indian in March 2007, in which the construction of a new cultural product—a Macbeth translated into the social and linguistic setting of a pre-contact Tlingit society—was claimed as part of a process of language revitalization for the endangered Tlingit language. Perseverance’s Macbeth demonstrated that language recovery might be attainable through importing an iconic text from an hegemonic language and culture and claiming it for the threatened language. At the same time, Perseverance had to confront the possibility that their project could be viewed as a colonizing activity. This inquiry examines several translational tactics the production employed, with the goal of considering the project as one potential methodology for generating linguistic life for an endangered language and reversing language shift. In addition, the study considers how translational comparison at the cultural level demonstrates how the Tlingit Macbeth operated as a two-way force in cultural creation, informing the source as much as the target.
Translating modals between English and Arabic
Authors: alQinai Jamal
Published: December 2012

Although central to many disciplines, modality has not received adequate treatment in the field of contrastive studies of English-Arabic translation. Since there are no neat Arabic counterparts to English modals, the only valid arguments for comparison are, therefore, the semantic-pragmatic ones. The current study investigates the relationship between modality and implicature in English-Arabic translation. The main argument is based on the premise that the speaker’s choice of modal expressions signals both the degree and type of involvement a speaker has in the content of the message, and consequently the interpretation of textual implicatures. The study shows that there are other textual means of expressing modality in Arabic that go beyond the immediate verbal construction. In some contexts, the whole discoursal effect will determine the degree of deontic or epistemic modality. The paper also explores shifts and transitions in translating modal patterns between English and Arabic with a view to assessing their overall effect. The examples cited show that the shift in rendering ST modals often entails an alteration in the possible interpretation of their meanings in the TT. In sensitive contexts, such as religious texts, political treaties and negotiations, business deals and court testimonies, some changes may have grave consequences. Although an analysis of the areas of convergence and divergence may help identify common causes of translation errors, the notion of ‘indeterminacy’ remains paramount in translating texts between these two languages. The paper concludes with a pragmatic strategy for the interpretation of modals in context.
In search of the miracle women: Returning the gaze
Authors: Saraf Babli Moitra
Published: December 2012

In this essay, I elaborate the profile of the language mediator as a specific subject in a given communicative context and present the act of language mediation as a function of that subject. I enter the discussion using an event telecast live by Radiotelevisione Italiana’s (RAI) Vatican channel simultaneously from St. Peter’s and Mother Teresa’s home in Calcutta on the occasion of the Beatification of Mother Teresa by Pope John Paul. In particular, I focus on RAI’s search for the miracolata, a woman who attributed her medical recovery to the miraculous intercession of Mother Teresa. The making of the media event was marked by cultural transactions that in retrospect seem extraordinary. I emphasise how globalization and market forces mediate and reconfigure post-colonial identities and subject positions, and how the comprehension of alterity is central to cross-cultural transactions. I present the narrative of this event and search as a case study, raising issues related to the pragmatics of language and proposing possible resolutions in the form of interventions by the language mediator.
To count or not to count: Scientometrics as a methodological tool for investigating research on translation and interpreting
Authors: Grbić Nadja , Pöllabauer Sonja
Published: December 2012

This paper discusses various different methods and tools of scientometrics, the way in which these can be used in translation and interpreting (T/I) studies and how T/I studies might benefit from such an approach. The authors outline both the potentials and pitfalls of such studies and discuss a number of different subjects of scientometric analysis. The paper also provides examples of scientometric research based on a small corpus of scientometric studies pertaining to T/I studies and pinpoints topics and subjects of research. The authors also explore, in a critical manner, the use (and abuse) of scientometric methods and the relationship between T/I studies and scientometrics. Special attention is paid to the way in which such methods can be combined with other (related) methods of social studies of science such as content analysis or network analysis.
Is it true? Is it new? Does it matter? Towards a paradigm shift in translation and interpreting studies
Authors: Chiaro Delia
Published: December 2012

Despite the widespread emergence of translations and diverse types of language mediation in contemporary society, our knowledge of the processes and operators involved in the "translation industry" is still very sketchy. With most translation scholars working within the liberal arts paradigm, research to date has tended to adopt methodologies pertaining to the humanities while overlooking more practical approaches typical of the more ‘scientific’ disciplines. This paper outlines the necessity for empirical methods that aim at gathering information regarding basic aspects of translation, ranging from typologies of translations to the operators involved in their production as well as aspects regarding end user perception. Such maps and atlases delineating the status quo of translation and interpreting would provide information for fresh insights.
Global analysis of B cell selection using an immunoglobulin light chain–mediated model of autoreactivity
Authors: Andrews Sarah F. , Zhang Qingzhao , Lim Samuel , Li Lie , Lee Jane-Hwei , Zheng Nai-Ying , Huang Min , Taylor William M. , Farris A. Darise , Ni Dongyao , Meng Wenzhao , Luning Prak Eline T. , Wilson Patrick C.
Published: December 2012

The important subtleties of B cell tolerance are best understood in a diverse immunoglobulin (Ig) repertoire context encoding a full spectrum of autoreactivity. To achieve this, we used mice expressing Igκ transgenes that confer varying degrees of autoreactivity within a diverse heavy chain (HC) repertoire. These transgenes, coupled with a biomarker to identify receptor-edited cells and combined with expression cloning of B cell receptors, allowed us to analyze tolerance throughout B cell development. We found that both the nature of the autoantigen and the Ig HC versus light chain (LC) contribution to autoreactivity dictate the developmental stage and mechanism of tolerance. Furthermore, although selection begins in the bone marrow, over one third of primary tolerance occurs in the periphery at the late transitional developmental stage. Notably, we demonstrate that the LC has profound effects on tolerance and can lead to exacerbated autoantibody production.
Hes repressors are essential regulators of hematopoietic stem cell development downstream of Notch signaling
Authors: Guiu Jordi , Shimizu Ritsuko , D’Altri Teresa , Fraser Stuart T. , Hatakeyama Jun , Bresnick Emery H. , Kageyama Ryoichiro , Dzierzak Elaine , Yamamoto Masayuki , Espinosa Lluis , Bigas Anna
Published: December 2012

Previous studies have identified Notch as a key regulator of hematopoietic stem cell (HSC) development, but the underlying downstream mechanisms remain unknown. The Notch target Hes1 is widely expressed in the aortic endothelium and hematopoietic clusters, though Hes1-deficient mice show no overt hematopoietic abnormalities. We now demonstrate that Hes is required for the development of HSC in the mouse embryo, a function previously undetected as the result of functional compensation by de novo expression of Hes5 in the aorta/gonad/mesonephros (AGM) region of Hes1 mutants. Analysis of embryos deficient for Hes1 and Hes5 reveals an intact arterial program with overproduction of nonfunctional hematopoietic precursors and total absence of HSC activity. These alterations were associated with increased expression of the hematopoietic regulators Runx1, c-myb, and the previously identified Notch target Gata2. By analyzing the Gata2 locus, we have identified functional RBPJ-binding sites, which mutation results in loss of Gata2 reporter expression in transgenic embryos, and functional Hes-binding sites, which mutation leads to specific Gata2 up-regulation in the hematopoietic precursors. Together, our findings show that Notch activation in the AGM triggers Gata2 and Hes1 transcription, and next HES-1 protein represses Gata2, creating an incoherent feed-forward loop required to restrict Gata2 expression in the emerging HSCs.
The intramembrane protease SPPL2a promotes B cell development and controls endosomal traffic by cleavage of the invariant chain
Authors: Schneppenheim Janna , Dressel Ralf , Hüttl Susann , Lüllmann-Rauch Renate , Engelke Michael , Dittmann Kai , Wienands Jürgen , Eskelinen Eeva-Liisa , Hermans-Borgmeyer Irm , Fluhrer Regina , Saftig Paul , Schröder Bernd
Published: December 2012

Regulated intramembrane proteolysis is a central cellular process involved in signal transduction and membrane protein turnover. The presenilin homologue signal-peptide-peptidase-like 2a (SPPL2a) has been implicated in the cleavage of type 2 transmembrane proteins. We show that the invariant chain (li, CD74) of the major histocompatability class II complex (MHCII) undergoes intramembrane proteolysis mediated by SPPL2a. B lymphocytes of SPPL2a−/− mice accumulate an N-terminal fragment (NTF) of CD74, which severely impairs membrane traffic within the endocytic system and leads to an altered response to B cell receptor stimulation, reduced BAFF-R surface expression, and accumulation of MHCII in transitional developmental stage T1 B cells. This results in significant loss of B cell subsets beyond the T1 stage and disrupted humoral immune responses, which can be recovered by additional ablation of CD74. Hence, we provide evidence that regulation of CD74-NTF levels by SPPL2a is indispensable for B cell development and function by maintaining trafficking and integrity of MHCII-containing endosomes, highlighting SPPL2a as a promising pharmacological target for depleting and/or modulating B cells.
The intramembrane protease Sppl2a is required for B cell and DC development and survival via cleavage of the invariant chain
Authors: Beisner Daniel R. , Langerak Petra , Parker Albert E. , Dahlberg Carol , Otero Francella J. , Sutton Sue E. , Poirot Laurent , Barnes Whitney , Young Michael A. , Niessen Sherry , Wiltshire Tim , Bodendorf Ursula , Martoglio Bruno , Cravatt Benjamin , Cooke Michael P.
Published: December 2012

B cell development requires tight regulation to allow for the generation of a diverse repertoire while preventing the development of autoreactive cells. We report, using N-ethyl-N-nitrosourea (ENU)–induced mutagenesis, the identification of a mutant mouse (chompB) with a block in early B cell development. The blockade occurs after the transitional 1 (T1) stage and leads to a decrease in mature B cell subsets and deficits in T cell–dependent antibody responses. Additionally, chompB mice have decreases in myeloid dendritic cells (DCs). The mutation was mapped to the intramembrane protease signal peptide peptidase-like 2a (Sppl2a), a gene not previously implicated in immune cell development. Proteomic analysis identified the invariant chain (CD74) as a key substrate of Sppl2a and suggests that regulated intramembrane proteolysis of CD74 by Sppl2a contributes to B cell and DC survival. Moreover, these data suggest that modulation of Sppl2a may be a useful therapeutic strategy for treatment of B cell dependent autoimmune disorders.
B cell survival, surface BCR and BAFFR expression, CD74 metabolism, and CD8− dendritic cells require the intramembrane endopeptidase SPPL2A
Authors: Bergmann Hannes , Yabas Mehmet , Short Alanna , Miosge Lisa , Barthel Nadine , Teh Charis E. , Roots Carla M. , Bull Katherine R. , Jeelall Yogesh , Horikawa Keisuke , Whittle Belinda , Balakishnan Bhavani , Sjollema Geoff , Bertram Edward M. , Mackay Fabienne , Rimmer Andrew J. , Cornall Richard J. , Field Matthew A. , Andrews T. Daniel , Goodnow Christopher C. , Enders Anselm
Published: December 2012

Druggable proteins required for B lymphocyte survival and immune responses are an emerging source of new treatments for autoimmunity and lymphoid malignancy. In this study, we show that mice with an inactivating mutation in the intramembrane protease signal peptide peptidase–like 2A (SPPL2A) unexpectedly exhibit profound humoral immunodeficiency and lack mature B cell subsets, mirroring deficiency of the cytokine B cell–activating factor (BAFF). Accumulation of Sppl2a-deficient B cells was rescued by overexpression of the BAFF-induced survival protein B cell lymphoma 2 (BCL2) but not BAFF and was distinguished by low surface BAFF receptor and IgM and IgD B cell receptors. CD8-negative dendritic cells were also greatly decreased. SPPL2A deficiency blocked the proteolytic processing of CD74 MHC II invariant chain in both cell types, causing dramatic build-up of the p8 product of Cathepsin S and interfering with earlier steps in CD74 endosomal retention and processing. The findings illuminate an important role for the final step in the CD74–MHC II pathway and a new target for protease inhibitor treatment of B cell diseases.
On the distinction between the classes of Dixmier and Connes-Dixmier traces
Authors: Sukochev Fedor , Usachev Alexandr , Zanin Dmitriy
Published: December 2012

We prove that the classes of Dixmier and Connes-Dixmier traces differ even on the Dixmier ideal

M

1
,
∞

\mathcal M_{1,\infty }

. We construct a Marcinkiewicz space

M

ψ

\mathcal M_\psi

and a positive operator

T
∈

M

ψ

T\in \mathcal M_\psi

which is Connes-Dixmier measurable but which is not Dixmier measurable.
Modular assembly of yeast cytochrome oxidase
Authors: McStay Gavin P. , Su Chen Hsien , Tzagoloff Alexander
Published: December 2012

Previous studies of yeast cytochrome oxidase (COX) biogenesis identified Cox1p, one of the three mitochondrially encoded core subunits, in two high–molecular weight complexes combined with regulatory/assembly factors essential for expression of this subunit. In the present study we use pulse-chase labeling experiments in conjunction with isolated mitochondria to identify new Cox1p intermediates and place them in an ordered pathway. Our results indicate that before its assimilation into COX, Cox1p transitions through five intermediates that are differentiated by their compositions of accessory factors and of two of the eight imported subunits. We propose a model of COX biogenesis in which Cox1p and the two other mitochondrial gene products, Cox2p and Cox3p, constitute independent assembly modules, each with its own complement of subunits. Unlike their bacterial counterparts, which are composed only of the individual core subunits, the final sequence in which the mitochondrial modules associate to form the holoenzyme may have been conserved during evolution.
Symptom Validity Test Performance in the Huntington Disease Clinic
Authors: Sieck Barbara C. , Smith Megan M. , Duff Kevin , Paulsen Jane S. , Beglinger Leigh J.
Published: December 2012

Symptom validity tests (SVTs) are often used in neuropsychological assessment; however, recent studies indicate that cognitive impairment/dementia may contribute to failing scores on some effort tests. The purpose of this study was to characterize how individuals with Huntington disease (HD) perform on three SVTs and to examine the relationship between SVT performance and demographic and clinical variables. Results indicate that while the majority of HD patients passed the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Effort Index (EI; 82% of n = 121) and the Test of Memory Malingering (92% of n = 36), failure of these SVTs was associated with poorer cognitive and adaptive functioning, and greater motor impairment. Results showed that less than one-third passed the RBANS Effort Scale (ES; 30% of n = 43) and few clinical and demographic variables were correlated with this SVT performance. Although some SVTs may be better suited to HD, cognitive ability should be considered when evaluating effort in HD.
SRmapper: a fast and sensitive genome-hashing alignment tool
Authors: Gontarz Paul M. , Berger Jennifer , Wong Chung F.
Published: December 2012

Summary: Modern sequencing instruments have the capability to produce millions of short reads every day. The large number of reads produced in conjunction with variations between reads and reference genomic sequences caused both by legitimate differences, such as single-nucleotide polymorphisms and insertions/deletions (indels), and by sequencer errors make alignment a difficult and computationally expensive task, and many reads cannot be aligned. Here, we introduce a new alignment tool, SRmapper, which in tests using real data can align 10s of billions of base pairs from short reads to the human genome per computer processor day. SRmapper tolerates a higher number of mismatches than current programs based on Burrows–Wheeler transform and finds about the same number of alignments in 2–8× less time depending on read length (with higher performance gain for longer read length). The current version of SRmapper aligns both single and pair-end reads in base space fastq format and outputs alignments in Sequence Alignment/Map format. SRmapper uses a probabilistic approach to set a default number of mismatches allowed and determines alignment quality. SRmapper’s memory footprint (∼2.5 GB) is small enough that it can be run on a computer with 4 GB of random access memory for a genome the size of a human. Finally, SRmapper is designed so that its function can be extended to finding small indels as well as long deletions and chromosomal translocations in future versions.

Availability:  http://www.umsl.edu/∼wongch/software.html.

Contact:  wongch@umsl.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
Data exploration, quality control and testing in single-cell qPCR-based gene expression experiments
Authors: McDavid Andrew , Finak Greg , Chattopadyay Pratip K. , Dominguez Maria , Lamoreaux Laurie , Ma Steven S. , Roederer Mario , Gottardo Raphael
Published: December 2012

Motivation: Cell populations are never truly homogeneous; individual cells exist in biochemical states that define functional differences between them. New technology based on microfluidic arrays combined with multiplexed quantitative polymerase chain reactions now enables high-throughput single-cell gene expression measurement, allowing assessment of cellular heterogeneity. However, few analytic tools have been developed specifically for the statistical and analytical challenges of single-cell quantitative polymerase chain reactions data.

Results: We present a statistical framework for the exploration, quality control and analysis of single-cell gene expression data from microfluidic arrays. We assess accuracy and within-sample heterogeneity of single-cell expression and develop quality control criteria to filter unreliable cell measurements. We propose a statistical model accounting for the fact that genes at the single-cell level can be on (and a continuous expression measure is recorded) or dichotomously off (and the recorded expression is zero). Based on this model, we derive a combined likelihood ratio test for differential expression that incorporates both the discrete and continuous components. Using an experiment that examines treatment-specific changes in expression, we show that this combined test is more powerful than either the continuous or dichotomous component in isolation, or a t-test on the zero-inflated data. Although developed for measurements from a specific platform (Fluidigm), these tools are generalizable to other multi-parametric measures over large numbers of events.

Availability: All results presented here were obtained using the SingleCellAssay R package available on GitHub (http://github.com/RGLab/SingleCellAssay).

Contact:  rgottard@fhcrc.org

Supplementary information:  Supplementary data are available at Bioinformatics online.
In silico identification of oncogenic potential of fyn-related kinase in hepatocellular carcinoma
Authors: Chen Jia-Shing , Hung Wei-Shiang , Chan Hsiang-Han , Tsai Shaw-Jenq , Sun H. Sunny
Published: December 2012

Motivation: Cancer development is a complex and heterogeneous process. It is estimated that 5–10% of human genes probably contribute to oncogenesis, whereas current experimentally validated cancer genes only cover 1% of the human genome. Thus hundreds of cancer genes may still remain to be identified. To search for new genes that play roles in carcinogenesis and facilitate cancer research, we developed a systematic workflow to use information saved in a previously established tumor-associated gene (TAG) database.

Results: By exploiting the information of conserved protein domains from the TAG, we identified 183 potential new TAGs. As a proof-of-concept, one predicted oncogene, fyn-related kinase (FRK), which shows an aberrant digital expression pattern in liver cancer cells, was selected for further investigation. Using 68 paired hepatocellular carcinoma samples, we found that FRK was up-regulated in 52% of cases (P < 0.001). Tumorigenic assays performed in Hep3B and HepG2 cell lines revealed a significant correlation between the level of FRK expression and invasiveness, suggesting that FRK is a positive regulator of invasiveness in liver cancer cells.

Conclusion: These findings implied that FRK is a multitalented signal transduction molecule that produces diverse biological responses in different cell types in various microenvironments. In addition, our data demonstrated the accuracy of computational prediction and suggested that other predicted TAGs can be potential targets for future cancer research.

Availability: The TAG database is available online at the Bioinformatics Center website: http://www.binfo.ncku.edu.tw/TAG/.

Contact:  hssun@mail.ncku.edu.tw

Supplementary information:  Supplementary data are available at Bioinformatics online.
Ultranet: efficient solver for the sparse inverse covariance selection problem in gene network modeling
Authors: Järvstråt Linnea , Johansson Mikael , Gullberg Urban , Nilsson Björn
Published: December 2012

Summary: Graphical Gaussian models (GGMs) are a promising approach to identify gene regulatory networks. Such models can be robustly inferred by solving the sparse inverse covariance selection (SICS) problem. With the high dimensionality of genomics data, fast methods capable of solving large instances of SICS are needed.

We developed a novel network modeling tool, Ultranet, that solves the SICS problem with significantly improved efficiency. Ultranet combines a range of mathematical and programmatical techniques, exploits the structure of the SICS problem and enables computation of genome-scale GGMs without compromising analytic accuracy.

Availability and implementation: Ultranet is implemented in C++ and available at www.broadinstitute.org/ultranet.

Contact:  bnilsson@broadinstitute.org or bjorn.nilsson@med.lu.se

Supplementary information:  Supplementary data are available at Bioinformatics online.
OntoMaton: a Bioportal powered ontology widget for Google Spreadsheets
Authors: Maguire Eamonn , González-Beltrán Alejandra , Whetzel Patricia L. , Sansone Susanna-Assunta , Rocca-Serra Philippe
Published: December 2012

Motivation: Data collection in spreadsheets is ubiquitous, but current solutions lack support for collaborative semantic annotation that would promote shared and interdisciplinary annotation practices, supporting geographically distributed players.

Results: OntoMaton is an open source solution that brings ontology lookup and tagging capabilities into a cloud-based collaborative editing environment, harnessing Google Spreadsheets and the NCBO Web services. It is a general purpose, format-agnostic tool that may serve as a component of the ISA software suite. OntoMaton can also be used to assist the ontology development process.

Availability: OntoMaton is freely available from Google widgets under the CPAL open source license; documentation and examples at: https://github.com/ISA-tools/OntoMaton.

Contact:  isatools@googlegroups.com
Disease-gene discovery by integration of 3D gene expression and transcription factor binding affinities
Authors: Piro Rosario M. , Molineris Ivan , Di Cunto Ferdinando , Eils Roland , König Rainer
Published: December 2012

Motivation: The computational evaluation of candidate genes for hereditary disorders is a non-trivial task. Several excellent methods for disease-gene prediction have been developed in the past 2 decades, exploiting widely differing data sources to infer disease-relevant functional relationships between candidate genes and disorders. We have shown recently that spatially mapped, i.e. 3D, gene expression data from the mouse brain can be successfully used to prioritize candidate genes for human Mendelian disorders of the central nervous system.

Results: We improved our previous work 2-fold: (i) we demonstrate that condition-independent transcription factor binding affinities of the candidate genes’ promoters are relevant for disease-gene prediction and can be integrated with our previous approach to significantly enhance its predictive power; and (ii) we define a novel similarity measure—termed Relative Intensity Overlap—for both 3D gene expression patterns and binding affinity profiles that better exploits their disease-relevant information content. Finally, we present novel disease-gene predictions for eight loci associated with different syndromes of unknown molecular basis that are characterized by mental retardation.

Contact:  r.piro@dkfz.de or rmpiro@gmail.com

Supplementary information:  Supplementary data are available at Bioinformatics online.
The Rationality of Being Guided by Rules
Authors: McClennen Edward F.
Published: December 2012

This article addresses a fundamental dilemma facing the claim that it is rational to be guided by rules. Either the practical verdict issued by a rule is the same as that favored by the balance of reasons, in which case the rule is redundant or the verdicts differ, in which case the rule should be abandoned. This article argues that this dilemma can be resolved by revising the account of practical reasoning to accord with the prescriptions of a resolute choice model. Agents in societies in which people resolutely follow, for example, a rule to keep their commitments to return favors fare better than agents in societies that lack a commitment mechanism or in which costs are incurred to enforce it.
The New York Constitution and the Federal System
Authors: Galie Peter
Published: December 2012

This article addresses the establishment of New York Constitution and the American federal system. The New York Constitution demonstrates a framework for governance, distributes and limits powers, and protects individual rights. Constitutional change in the state has led or been reflected in dominant movements in American politics—Jacksonian democracy, Progressive reform, Depression-era activist government. The roots of constitutional government in New York are embedded in the state's colonial history, which is rooted in English constitutional and common law. In New York after 1821, voters could vote directly on whether to approve a constitutional amendment. The constitution of 1846 has been called the “People's Constitution.” Constitutional commissions would come to play an important role in state constitutional reform. State constitutions shape collective public identities and character. The state's constitution is an imperfect document, generally acknowledged in need of reform.
Public Opinion Polling and New York Politics and Governance
Authors: Levy Donald , Koning Ashley
Published: December 2012

This article describes public opinion polling as well as politics and governance in New York. The interaction between the polls, press, politicians, and public creates a constant, continual, and reciprocal interplay along six distinct paths (4P process). The 4P process is a core element of the manner in which modern representative democracy works. This process is developed over time as polling grew to maturity while politicians and the press experimented with its utility and implications and addressed the costs of using polling. Polling has become integral to governing. Furthermore, it examined four cases from the two survey models, comparing and contrasting the different parts of each survey in order to determine the effects of forced-choice questions versus intensity scales. Identifying ambivalence significantly lessened support and opposition for each major issue that New Yorkers faced.
Politics and the News Media in the Empire State
Authors: Muzzio Douglas
Published: December 2012

This article considers politics and the news media in New York. News coverage of election campaigns in New York and throughout the country tends to focus on nonpolicy matters. The news media is widely addressed as a central actor in U.S. politics and government. The news influences how people think about politics. A major change in New York state (and other news) coverage is the altered role of the Associated Press (AP). The cutbacks in newspapers' state coverage reflect the crisis and transformation of U.S. news organizations. The future of the “news media”—specifically the so-called mainstream or traditional media of newspapers, TV, radio—is evolution or death. During the first three months of 2010, Albany proved even more bizarre than it had been over the prior five years, a considerable feat. Albany 2012 seems a different place than it was in 2009–10.
New York State's “Foreign Policy”
Authors: Friedman Kathryn Bryk
Published: December 2012

This article investigates a unique aspect of New York State governance—its engagement in foreign policymaking. It also discusses some of the ways in which state officials collaborate and build relationships with foreign governments and, particularly in the case of Canada, provincial counterparts in economic, political, cultural, and environmental spheres. It is shown that New York State legislators engage in foreign policymaking on issues that directly affect their constituents, although admittedly to a minimal degree when compared to their executive and judicial counterparts. The New York State judiciary has contributed to the growing body of international human rights law. It then turns to local government engagement in foreign policy. New York foreign policy takes place in social, political, cultural, economic, and environmental sectors touching virtually every corner of the globe. It is suggested that New York State has nothing to lose from strengthened engagement on the global stage.
Higher Education in New York State
Authors: Steck Henry
Published: December 2012

This article introduces New York's complex postsecondary sector. It then turns to the question of state financial support, and the broader character of the structure of higher education in New York State. It also discusses the two sectors and argues that the conceptualization of two distinct sectors—one “public” and one “private”—should be framed quite differently. A major goal of the State University of New York (SUNY) and the City University of New York (CUNY) is an assurance that any future tuition increases be used for the campuses and not to help close a state budget gap. The increase in tuition to fill budget gaps produces a paradoxical situation: as tuition rises, student aid provided by the state increases per student. As New York's three major higher education sectors faced the future, they were acutely aware that hard times would continue well into the future.
Selective Bibliography of New York Government and Politics
Authors: Folts James D.
Published: December 2012

This article provides a selective annotated bibliography of sources on various aspects of New York State Government and Politics.
Introduction
Authors: Bradley Ben , Feldman Fred , Johansson Jens
Published: December 2012

This chapter discusses the theme of this book, which is the philosophical aspect of death. The book answers questions about what death is and why it matters that help define the growing interdisciplinary subfield of philosophy of death. It analyzes the views of ancient Greek philosophers including Socrates, Plato, Aristotle, and Epicurus about death; investigates how death is related to various concepts including disintegration of personality, personal identity, and pleasure; and explores the concept of immortality, the wrongness of killing, and the significance of death for animals.
The Evil of Death
Authors: Sider Theodore
Published: December 2012

This chapter examines the evil of death in the context of metaphysics. It explains that fundamental metaphysics is a search for the fundamental reality that underlies ordinary facts, and contends that the relationship between theses of fundamental metaphysics and questions of value is not a straightforward one. The chapter discusses two metaphysical views about the nature of time, four-dimensionalism, and presentism, and suggests that presentism is consistent with the idea that death is evil because it deprives the deceased of the goods of life.
Education and the Poor
Authors: Barrow Lisa , Schanzenbach Diane Whitmore
Published: December 2012

This article presents a basic theoretic framework to explain differences in educational inputs and outcomes. Using several data sets, it documents wide disparities in educational outcomes (educational attainment, test scores, and cognitive skills). As income rises, educational outcomes improve. Highly aggregated measures of school inputs indicate small differences according to income. Average spending per pupil, measured at the school district level, is approximately the same for nonpoor students and for free-lunch students. Average class sizes are also approximately the same across high- and low-poverty schools. The big differences across high- and low-poverty schools are in teacher characteristics, facilities, and school crime rates. Low-poverty schools have more experienced teachers, less teacher turnover, fewer crimes, and more specialized facilities. Parental educational attainment and time spent with children are positively correlated with income. These input differences significantly impact outcome differences. Policies designed to address differences in educational inputs and outcomes are reviewed.