bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential roles for the Co2+/Ni2+ transporting ATPases, CtpD and CtpJ, in Mycobacterium tuberculosis virulence
Authors: Raimunda Daniel , Long Jarukit E. , Padilla‐Benavides Teresita , Sassetti Christopher M. , Argüello José M.
Published: November 2013

The genome of Mycobacterium tuberculosis encodes two paralogous P1B4‐ATPases, CtpD (Rv1469) and CtpJ (Rv3743). Both proteins showed ATPase activation by Co2+ and Ni2+, and both appear to be required for metal efflux from the cell. However, using a combination of biochemical and genetic studies we found that these proteins play non‐redundant roles in virulence and metal efflux. CtpJ expression is induced by Co2+ and this protein possesses a relatively high turnover rate. A ctpJ deletion mutant accumulated Co2+, indicating that this ATPase controls cytoplasmic metal levels. In contrast, CtpD expression is induced by redox stressors and this protein displays a relatively low turnover rate. A ctpD mutant failed to accumulate metal, suggesting an alternative cellular function. ctpD is cotranscribed with two thioredoxin genes trxA (Rv1470), trxB (Rv1471), and an enoyl‐coA hydratase (Rv1472), indicating a possible role for CtpD in the metallation of these redox‐active proteins. Supporting this, in vitro metal binding assays showed that TrxA binds Co2+ and Ni2+. Mutation of ctpD, but not ctpJ, reduced bacterial fitness in the mouse lung, suggesting that redox maintenance, but not Co2+ accumulation, is important for growth in vivo.
Trichomonas vaginalis flavin reductase 1 and its role in metronidazole resistance
Authors: Leitsch David , Janssen Brian D. , Kolarich Daniel , Johnson Patricia J. , Duchêne Michael
Published: November 2013

The enzyme flavin reductase 1 (FR1) from Trichomonas vaginalis, formerly known as NADPH oxidase, was isolated and identified. Flavin reductase is part of the antioxidative defence in T. vaginalis and indirectly reduces molecular oxygen to hydrogen peroxide via free flavins. Importantly, a reduced or absent flavin reductase activity has been reported in metronidazole‐resistant T. vaginalis, resulting in elevated intracellular oxygen levels and futile cycling of metronidazole. Interestingly, FR1 has no close homologue in any other sequenced genome, but seven full‐length and three truncated isoforms exist in the T. vaginalis genome. However, out of these, only FR1 has an affinity for flavins, i.e. FMN, FAD and riboflavin, which is high enough to be of physiological relevance. Although there are no relevant changes in the gene sequence or any alterations of the predicted FR1‐mRNA structure in any of the strains studied, FR1 is not expressed in highly metronidazole‐resistant strains. Transfection of a metronidazole‐resistant clinical isolate (B7268), which does not express any detectable amounts of FR, with a plasmid bearing a functional FR1 gene nearly completely restored metronidazole sensitivity. Our results indicate that FR1 has a significant role in the emergence of metronidazole resistance in T. vaginalis.
Neuroimmune interactions at different intestinal sites are related to abdominal pain symptoms in children with IBS
Authors: Di Nardo G. , Barbara G. , Cucchiara S. , Cremon C. , Shulman R. J. , Isoldi S. , Zecchi L. , Drago L. , Oliva S. , Saulle R. , Barbaro M. R. , Stronati L.
Published: November 2013

Background

Neuroimmune interactions and inflammation have been proposed as factors involved in sensory‐motor dysfunction and symptom generation in adult irritable bowel syndrome (IBS) patients. In children with IBS and healthy controls, we measured ileocolonic mast cell infiltration and fecal calprotectin and evaluated the relationships between these parameters and abdominal pain symptoms and stooling pattern.

Methods

Irritable bowel syndrome patients diagnosed according to Pediatric Rome III criteria and healthy controls kept a 2‐week pain/stooling diary. Ileocolonic mucosal mast cells (MC) and MC in close proximity to nerve fibers (MC‐NF) were identified immunohistochemically and quantified. Fecal calprotectin concentration was measured.

Key Results

21 IBS patients and 10 controls were enrolled. The MC‐NF count was significantly higher in the ileum (p = 0.01), right colon (p = 0.04), and left colon (p < 0.001) of IBS patients compared with controls. No differences in fecal calprotectin concentration were noted. Abdominal pain intensity score correlated with ileal MC count (rs = 0.47, p = 0.030) and right colon MC‐NF count (rs = 0.52, p = 0.015). In addition, children with IBS with >3 abdominal pain episodes/week had greater ileal (p = 0.002) and right colonic (p = 0.01) MC counts and greater ileal (p = 0.05) and right colonic (p = 0.016) MC‐NF counts than children with less frequent pain. No relationship was found between MC and MC‐NF and fecal calprotectin or stooling pattern.

Conclusions & Inferences

Mast cells‐nerve fibers counts are increased in the ileocolonic mucosa of children with IBS. Mast cells and MC‐NF counts are related to the intensity and frequency of abdominal pain.
Physiological differences explain the co‐existence of different regeneration strategies in Mediterranean ecosystems
Authors: Vilagrosa Alberto , Hernández Encarnación I. , Luis Vanessa C. , Cochard Hervé , Pausas Juli G.
Published: November 2013

Fire and drought are selective driving forces in Mediterranean plants, and thus their ability to resprout or recruit after these disturbances is of paramount importance. The contrast in regeneration niche between resprouters and seeders, and each group's different root characteristics, suggest that they are subjected to different degrees of environmental stress and, consequently, to different evolutionary forces.

We compared leaf traits, xylem traits related to hydraulic efficiency and vulnerability to cavitation, and the physiological response to an imposed drought between seedlings of resprouters and seedlings of seeders. We used 12 species co‐existing in Mediterranean basin ecosystems.

Major differences were found in the xylem architecture and leaf traits, and in the response to drought conditions. Seeders were more efficient at transporting water to leaves but formed, in turn, a safer xylem network. They also presented higher photosynthesis and transpiration rates, and earlier stomatal closure with drought, but good leaf dehydration tolerance.

Seeders and resprouters can be considered two syndromes whose different functional characteristics are related to water availability and drought responses. These characteristics, together with their differences in rooting habits, account for their distinct regeneration niches and, thus, their co‐existence.
Selective expansion of donor‐derived regulatory T cells after allogeneic bone marrow transplantation in a patient with IPEX syndrome
Authors: Horino Satoshi , Sasahara Yoji , Sato Miki , Niizuma Hidetaka , Kumaki Satoru , Abukawa Daiki , Sato Atsushi , Imaizumi Masue , Kanegane Hirokazu , Kamachi Yoshiro , Sasaki Shinya , Terui Kiminori , Ito Etsuro , Kobayashi Ichiro , Ariga Tadashi , Tsuchiya Shigeru , Kure Shigeo
Published: November 2013

IPEX syndrome is a rare and fatal disorder caused by absence of regulatory T cells (Tregs) due to congenital mutations in the Forkhead box protein 3 gene. Here, we report a patient with IPEX syndrome treated with RIC followed by allogeneic BMT from an HLA‐matched sibling donor. We could achieve engraftment and regimen‐related toxicity was well tolerated. Although the patient was in mixed chimera and the ratio of donor cells in whole peripheral blood remained relatively low, selective and sustained expansion of Tregs determined as CD4+CD25+Foxp3+ cells was observed. Improvement in clinical symptoms was correlated with expansion of donor‐derived Tregs and disappearance of anti‐villin autoantibody, which was involved in the pathogenesis of gastrointestinal symptoms in IPEX syndrome. This clinical observation suggests that donor‐derived Tregs have selective growth advantage in patients with IPEX syndrome even in mixed chimera after allogeneic BMT and contribute to the control of clinical symptoms caused by the defect of Tregs.
Photosensitizing medications and photocarcinogenesis
Authors: O'Gorman Susan M. , Murphy Gillian M.
Published: November 2013

Photosensitivity is an exaggerated or abnormal response to ultraviolet (UV) or visible light exposure. Many current medications are known photosensitizers; however, the effects of the sensitization can be subclinical and go unnoticed by the person affected. While some of these drugs are used for short and defined periods, others are used indefinitely for the treatment of chronic disease. The question of whether either of these practices translates into an increased risk of skin cancer is an important one. Numerous medications have real, distinct and well‐elucidated mechanisms that potentiate the development of skin cancer, while with some medications the mechanism for the observed carcinogenesis remains unclear. In this article we will discuss the clinical, mechanistic and epidemiological evidence supporting photochemical genotoxicity and carcinogenesis.
Comparative immunohistochemical assessment of cutaneous cyclooxygenase‐2 enzyme expression in chronological aging and photoaging
Authors: Habib Mohammed Ahmad , Salem Samar Abdallah M. , Hakim Sarah Adel , Shalan Yahia Ahmad Mostafa
Published: November 2013

Background/Purpose

Skin aging can be classified into chronological aging and photoaging. Cyclooxygenase‐2 (COX‐2) may be involved in ultraviolet‐induced inflammation, photocarcinogenesis and the aging process. Studies done focused on assessing COX‐2 expression after acute ultraviolet exposure and in photocarcinogenesis. Comparative assessment of COX‐2 expression in chronological aging and photoaging was not previously studied. We aimed to compare COX‐2 expression in chronological aging and photoaging.

Methods

Sixty participants were included (20 with chronological aging, 20 with photoaging, and 20 non‐skin‐aged contributors as controls). Fitzpatrick skin type and Glogau's photoaging type were assessed. Immunohistochemical evaluation of COX‐2 was done in biopsies from sun‐protected skin in the chronological aging and control groups, and from sun‐exposed skin in the photoaging group.

Results

Comparison between each two groups showed a high statistically significant difference, with the highest percentage of mild, moderate and marked expression in the control, chronological aging and photoaging groups, respectively. A high statistically significant positive correlation was found between grading of solar elastosis in the photoaging group and COX‐2 expression parameters.

Conclusion

COX‐2 expression is significantly higher in chronologically aged and photoaged skin than the normal young skin. This level of expression is significantly higher in photoaging than in chronological aging. COX‐2 expression is positively related with the degree of solar elastosis in photoaging.
Dasya enomotoi sp. nov. (Dasyaceae, Ceramiales), a new large Dasya from Japan
Authors: Yamagishi Yukimasa , Ohta Yusuke , Masuda Michio , Abe Tsuyoshi
Published: November 2013

A new red alga, Dasya enomotoi, is described from Japan. This species is characterized by having a large thallus consisting of an elongated axis and many, radially arranged, polysiphonous branches both of which are heavily corticated and densely covered with numerous, soft monosiphonous filaments. It is distinguished from several similar species by the combination of the following: (i) indistinct pericentral cells in transverse sections except near the apices, (ii) the presence of enlarged, inner cortical cells, (iii) radially arranged adventitious monosiphonous filaments, (iv) three‐celled carpogonial branches, (v) six (sometimes five) tetrasporangia in each fertile segment of the stichidia, and (vi) three tetrasporangial cover cells that are not elongated longitudinally and usually not divided transversely. This species may have been identified as D. villosa Harvey by previous investigators in Japan.
Bayesian Non-Parametric Analysis of Multirater Ordinal Data, with Application to Prioritizing Research Goals for Prevention of Suicide
Authors: Savitsky Terrance D. , Dalal Siddhartha R.
Published: November 2013

Our application data are produced from a scalable, on-line expert elicitation process that incorporates hundreds of participating raters to score the importance of research goals for the prevention of suicide with the purpose of informing policy making. We develop a Bayesian formulation for analysis of ordinal multirater data motivated by our application. Our model employs a non-parametric mixture distribution over rater-indexed parameters for a latent continuous response under a Poisson–Dirichlet process mixing measure that allows inference about distinct rater behavioural and learning typologies from realized clusters.
Histologic and immunohistochemical characterization of thymic epithelial tumours in the dog
Authors: Burgess K. E. , DeRegis C. J. , Brown F. S. , Keating J. H.
Published: November 2013

Thymic epithelial tumour (TET) histologic subclassification has not been well described in the veterinary literature as it has in humans. The objective of this study was to identify and describeTETsubtypes in dogs and to determine the utility of immunohistochemistry (IHC) in differentiating these subtypes. Samples were reviewed and classified according to a modified World Health Organization (WHO) criteria for human tumours of thymic origin. Signallment, presenting signs, treatment and survival data was collected from medical records. Histologic review confirmed the same subtypes as described in humans. Presence of high stage disease, pleomorphism, mitotic figures and capsular invasion was more common in atypical thymomas and thymic carcinomas than in thymomas.IHCwas performed forGLUT‐1,CD5,CD117andCK8/18; however, this was not useful in classifying the tumours.
Singular values of multiple eta-quotients for ramified primes
Authors: Enge Andreas , Schertz Reinhard
Published: November 2013

We determine the conditions under which singular values of multiple $\eta $-quotients of square-free level, not necessarily prime to six, yield class invariants; that is, algebraic numbers in ring class fields of imaginary-quadratic number fields. We show that the singular values lie in subfields of the ring class fields of index ${2}^{{k}^{\prime } - 1} $ when ${k}^{\prime } \geq 2$ primes dividing the level are ramified in the imaginary-quadratic field, which leads to faster computations of elliptic curves with prescribed complex multiplication. The result is generalised to singular values of modular functions on ${ X}_{0}^{+ } (p)$ for $p$ prime and ramified.
Computing characters of groups with central subgroups
Authors: Dabbaghian Vahid , Dixon John D.
Published: November 2013

The so-called Burnside–Dixon–Schneider (BDS) method, currently used as the default method of computing character tables in GAP for groups which are not solvable, is often inefficient in dealing with groups with large centres. If $G$ is a finite group with centre $Z$ and $\lambda $ a linear character of $Z$, then we describe a method of computing the set $\mathrm{Irr} (G, \lambda )$ of irreducible characters $\chi $ of $G$ whose restriction ${\chi }_{Z} $ is a multiple of $\lambda $. This modification of the BDS method involves only $\vert \mathrm{Irr} (G, \lambda )\vert $ conjugacy classes of $G$ and so is relatively fast. A generalization of the method can be applied to computation of small sets of characters of groups with a solvable normal subgroup.

Supplementary materials are available with this article.
T
H
17 Cell Differentiation Is Regulated by the Circadian Clock
Authors: Yu Xiaofei , Rollins Darcy , Ruhn Kelly A. , Stubblefield Jeremy J. , Green Carla B. , Kashiwada Masaki , Rothman Paul B. , Takahashi Joseph S. , Hooper Lora V.
Published: November 2013

Lighting Up Immunity

T
H
17 cells are CD4
+
T helper cells that produce the proinflammatory cytokine interleukin-17. In the intestines, T
H
17 cells protect the host from fungal and bacterial infections, and their proinflammatory function is linked with autoimmune diseases including inflammatory bowel disease.

Yu
et al.

(p.
727
) show that the molecular circadian clock directly regulates the differentiation of T
H
17 cells in the intestine, which suggest that both nutrition and light are important environmental factors that directly regulate the immune response.
The Ears Have It: First Snakes Were Burrowers, Not Swimmers
Authors: Balter Michael
Published: November 2013

Clues to whether snakes first evolved underground or underwater come from the anatomy of their inner ears.
Has Program to Rotate Scientists at NSF Spun Out of Control?
Authors: Mervis Jeffrey
Published: November 2013

NSF relies on a program that brings scientists temporarily to the agency, but there are serious questions about how well it is working.
Malaria as Lifesaving Therapy
Authors: Vogel Gretchen
Published: November 2013

In the pre-antibiotic era, vivax malaria was used to treat patients dying of syphilis, allowing many to make nearly full recoveries.
In the Hot Seat
Authors: Kerr Richard A.
Published: November 2013

Scientists pressed on global warming's link to weather disasters are scrambling to grasp the teachable moment without going beyond their meager understanding.
Identification and Characterization of Intestinal Antigen-Presenting Cells Involved in Uptake and Processing of a Nontoxic Recombinant Chimeric Mucosal Immunogen Based on Cholera Toxin Using Imaging Flow Cytometry
Authors: Zhao Weiwei , Minderman Hans , Russell Michael W.
Published: November 2013

Intragastric immunization with recombinant chimeric immunogen, SBR-CTA2/B, constructed from the saliva-binding region (SBR) ofStreptococcus mutansantigen AgI/II and the A2/B subunits of cholera toxin (CT) induces salivary and circulating antibodies againstS. mutansthat protect against dental caries. We previously found that SBR-CTA2/B activated dendritic cells (DC) in the Peyer's patches (PP) and mesenteric lymph nodes (MLN). To identify the cells involved in the intestinal uptake of SBR-CTA2/B and the initiation of immune responses, mice were immunized intragastrically with fluorescein-labeled SBR-CTA2/B or SBR, and intestinal cells were examined by imaging flow cytometry after fluorescent staining for cell surface markers. SBR-CTA2/B was preferentially taken up by CD103+DC in the PP and by both CD103+and CD11c+DC in intestinal lamina propria (LP), whereas SBR was taken up to a lesser extent by PP CD11c+DC, within 2 to 16 h. By 16 h, CD103+and CD11c+DC containing fluorescein-labeled SBR-CTA2/B were found in MLN and showed upregulation of the chemokine receptor CCR7. Large numbers of SBR-CTA2/B-containing DC were found interacting with CD4+(T helper) cells, which costained for nuclear transcription factors T-bet or RORγt, identifying them as Th1 or Th17 cells. In contrast, SBR-containing CD11c+DC interacted preferentially with GATA3+(Th2) cells. No SBR- or SBR-CTA2/B-containing DC were found interacting with Foxp3+(T regulatory) cells. We conclude that the coupling of SBR to CTA2/B enhances its immunogenicity by promoting uptake by DC in both PP and LP and that these antigen-containing DC migrated to MLN and interacted preferentially with Th1 and Th17 cells to induce active immune responses.
Evaluation of GeneXpert MTB/RIF for Diagnosis of Tuberculous Meningitis
Authors: Nhu Nguyen Thi Quynh , Heemskerk Dorothee , Thu Do Dang Anh , Chau Tran Thi Hong , Mai Nguyen Thi Hoang , Nghia Ho Dang Trung , Loc Pham Phu , Ha Dang Thi Minh , Merson Laura , Thinh Tran Thi Van , Day Jeremy , Chau Nguyen van Vinh , Wolbers Marcel , Farrar Jeremy , Caws Maxine
Published: November 2013

Tuberculous meningitis (TBM) is the most severe form of tuberculosis. Microbiological confirmation is rare, and treatment is often delayed, increasing mortality and morbidity. The GeneXpert MTB/RIF test was evaluated in a large cohort of patients with suspected tuberculous meningitis. Three hundred seventy-nine patients presenting with suspected tuberculous meningitis to the Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam, between 17 April 2011 and 31 December 2012 were included in the study. Cerebrospinal fluid samples were tested by Ziehl-Neelsen smear, mycobacterial growth indicator tube (MGIT) culture, and Xpert MTB/RIF. Rifampin (RIF) resistance results by Xpert were confirmed by an MTBDR-Plus line probe assay and all positive cultures were tested by phenotypic MGIT drug susceptibility testing. Overall, 182/379 included patients (48.0%) were diagnosed with tuberculous meningitis. Sensitivities of Xpert, smear, and MGIT culture among patients diagnosed with TBM were 59.3% (108/182 [95% confidence interval {CI}, 51.8 to 66.5%]), 78.6% (143/182 [95% CI, 71.9 to 84.3%]) and 66.5% (121/182 [95% CI, 59.1 to 73.3%]), respectively. There was one false-positive Xpert MTB/RIF test (99.5% specificity). Four cases of RIF resistance (4/109; 3.7%) were identified by Xpert, of which 3 were confirmed to be multidrug-resistant (MDR) TBM and one was culture negative. Xpert MTB/RIF is a rapid and specific test for the diagnosis of tuberculous meningitis. The addition of a vortexing step to sample processing increased sensitivity for confirmed TBM by 20% (
P
= 0.04). Meticulous examination of a smear from a large volume of cerebrospinal fluid (CSF) remains the most sensitive technique but is not practical in most laboratories. The Xpert MTB/RIF represents a significant advance in the early diagnosis of this devastating condition.
Bacterial Vaginosis Diagnosed by Analysis of First-Void-Urine Specimens
Authors: Datcu Raluca , Gesink Dionne , Mulvad Gert , Montgomery-Andersen Ruth , Rink Elisabeth , Koch Anders , Ahrens Peter , Jensen Jørgen Skov
Published: November 2013

Bacterial vaginosis (BV) is traditionally diagnosed using vaginal samples. The aim of this study was to investigate whether BV can be diagnosed from first-void urine (FVU). Self-collected vaginal smears, vaginal swabs, and FVU were obtained from 176 women. BV was diagnosed by Nugent's criteria. The FVU and vaginal swabs were analyzed by quantitative PCRs (qPCRs) for selected vaginal bacteria (
Atopobium vaginae
,
Prevotella
spp.,
Gardnerella vaginalis
, bacterial vaginosis-associated bacterium 2,
Eggerthella
-like bacterium, “
Leptotrichia amnionii
,”
Megasphaera
type 1), and all had an area under the receiver operating characteristic (ROC) curve of >85%, suggesting good prediction of BV according to the Nugent score. All seven bacteria in FVU were significantly associated with BV in univariate analysis. An accurate diagnosis of BV from urine was obtained in this population by a combination of qPCRs for
Megasphaera
type 1 and
Prevotella
spp. The same two bacteria remained significantly associated with BV in a multivariate model after adjusting for the other five species. There was no statistically significant difference between the sensitivities and specificities of BV diagnosis by molecular methods performed on swabs and FVU samples. A linear regression analysis showed good agreement between bacterial loads from swabs and FVU, but
Prevotella
spp. could be detected in high numbers in a few FVU samples without being present in swabs. This method will allow diagnosis of BV in studies where only urine has been collected and where detection of BV is considered relevant.
Utility of Detection of Telaprevir-Resistant Variants for Prediction of Efficacy of Treatment of Hepatitis C Virus Genotype 1 Infection
Authors: Akuta Norio , Suzuki Fumitaka , Fukushima Taito , Kawamura Yusuke , Sezaki Hitomi , Suzuki Yoshiyuki , Hosaka Tetsuya , Kobayashi Masahiro , Hara Tasuku , Kobayashi Mariko , Saitoh Satoshi , Arase Yasuji , Ikeda Kenji , Kumada Hiromitsu
Published: November 2013

The clinical usefulness of detecting telaprevir-resistant variants is unclear. Two hundred fifty-two Japanese patients infected with hepatitis C virus (HCV) genotype 1b received triple therapy with telaprevir–peginterferon (PEG-IFN)–ribavirin and were evaluated for telaprevir-resistant variants by direct sequencing at baseline and at the time of reelevation of the viral load. An analysis of the entire group indicated that 76% achieved a sustained virological response. Multivariate analysis identified a PEG-IFN dose of <1.3 μg/kg of body weight, an
IL28B
rs8099917 genotype (genotype non-TT), detection of telaprevir-resistant variants of amino acid (aa) 54 at baseline, nonresponse to prior treatment, and a leukocyte count of <5,000/mm
3
as significant pretreatment factors for detection of telaprevir-resistant variants at the time of reelevation of the viral load. In 63 patients who showed nonresponse to prior treatment, a higher proportion of patients with no detected telaprevir-resistant variants at baseline (54%) achieved a sustained virological response than did patients with detected telaprevir-resistant variants at baseline (0%). Furthermore, 2 patients who did not have a sustained virological response from the first course of triple therapy with telaprevir received a second course of triple therapy with telaprevir. These patients achieved a sustained virological response by the second course despite the persistence of very-high-frequency variants (98.1% for V36C) or a history of the emergence of variants (0.2% for R155Q and 0.2% for A156T) by ultradeep sequencing. In conclusion, this study indicates that the presence of telaprevir-resistant variants at the time of reelevation of viral load can be predicted by a combination of host, viral, and treatment factors. The presence of resistant variants at baseline might partly affect treatment efficacy, especially in those with nonresponse to prior treatment.
Ifit2
Deficiency Results in Uncontrolled Neurotropic Coronavirus Replication and Enhanced Encephalitis via Impaired Alpha/Beta Interferon Induction in Macrophages
Authors: Butchi Niranjan B. , Hinton David R. , Stohlman Stephen A. , Kapil Parul , Fensterl Volker , Sen Ganes C. , Bergmann Cornelia C.
Published: November 2013

Type I interferons (IFN-α/β) limit viral dissemination prior to the emergence of adaptive immune responses through the concerted action of interferon-stimulated genes (ISGs). Although IFN-α/β induction by coronaviruses is modest, it effectively limits viral spread within the central nervous system (CNS) and protects against mortality. The protective roles of specific ISGs against the mouse hepatitis virus (MHV) members of the coronaviruses are largely unknown. This study demonstrates a protective role of the ISG
Ifit2
in encephalitis induced by the dual hepato- and neurotropic MHV-A59. Contrasting the mild encephalitis and 100% survival of MHV-A59-infected wild-type (wt) mice, nearly 60% of infected
Ifit2
−/−
mice exhibited severe encephalitis and succumbed between 6 and 8 days postinfection. Increased clinical disease in
Ifit2
−/−
mice coincided with higher viral loads and enhanced viral spread throughout the CNS parenchyma.
Ifit2
−/−
mice also expressed significantly reduced IFN-α/β and downstream ISG mRNAs
Ifit1
,
Isg15
, and
Pkr
, while expression of proinflammatory cytokines and chemokines was only modestly affected in the CNS. Impaired IFN-α/β induction in the absence of
Ifit2
was confirmed by
ex vivo
mRNA analysis of microglia and macrophages, the prominent cell types producing IFN-α/β following MHV CNS infection. Furthermore, both IFN-α/β mRNA and protein production were significantly reduced in MHV-infected
Ifit2
−/−
relative to wt bone marrow-derived macrophages. Collectively, the data implicate Ifit2 as a positive regulator of IFN-α/β expression, rather than direct antiviral mediator, during MHV-induced encephalitis.
Inhibition of Arenavirus by A3, a Pyrimidine Biosynthesis Inhibitor
Authors: Ortiz-Riaño Emilio , Ngo Nhi , Devito Stefanie , Eggink Dirk , Munger Joshua , Shaw Megan L. , de la Torre Juan Carlos , Martínez-Sobrido Luis
Published: November 2013

Arenaviruses merit significant interest as important human pathogens, since several of them cause severe hemorrhagic fever disease that is associated with high morbidity and significant mortality. Currently, there are no FDA-licensed arenavirus vaccines available, and current antiarenaviral therapy is limited to an off-labeled use of the nucleoside analog ribavirin, which has limited prophylactic efficacy. The pyrimidine biosynthesis inhibitor A3, which was identified in a high-throughput screen for compounds that blocked influenza virus replication, exhibits a broad-spectrum antiviral activity against negative- and positive-sense RNA viruses, retroviruses, and DNA viruses. In this study, we evaluated the antiviral activity of A3 against representative Old World (lymphocytic choriomeningitis virus) and New World (Junin virus) arenaviruses in rodent, monkey, and human cell lines. We show that A3 is significantly more efficient than ribavirin in controlling arenavirus multiplication and that the A3 inhibitory effect is in part due to its ability to interfere with viral RNA replication and transcription. We document an additive antiarenavirus effect of A3 and ribavirin, supporting the potential combination therapy of ribavirin and pyrimidine biosynthesis inhibitors for the treatment of arenavirus infections.
The Viral E8^E2C Repressor Limits Productive Replication of Human Papillomavirus 16
Authors: Straub Elke , Dreer Marcel , Fertey Jasmin , Iftner Thomas , Stubenrauch Frank
Published: November 2013

Productive replication of human papillomavirus type 16 (HPV16) occurs only in differentiated keratinocyte cells. In addition to the viral E2 activator protein, HPV16 and related HPV types express transcripts coding for an E8^E2C fusion protein, which limits genome replication in undifferentiated keratinocytes. To address E8^E2C's role in productive replication of HPV16, stable keratinocyte cell lines containing wild-type (wt), E8^E2C knockout (E8−), or E8 KWK mutant (mt) genomes, in which conserved E8 residues were inactivated, were established. Copy numbers of E8− and E8 KWK mt genomes and amounts of early and late viral transcripts were greatly increased compared to those for the wt in undifferentiated keratinocytes, suggesting that HPV16 E8^E2C activities are highly dependent upon the E8 part. Upon differentiation in organotypic cultures, E8 mt genomes displayed higher early viral transcript levels, but no changes in cellular differentiation or virus-induced cellular DNA replication in suprabasal cells were observed. E8 mt genomes were amplified to higher copy numbers and showed increased L1 transcripts compared to wt genomes. Furthermore, the number of cells expressing the viral late protein E4 or L1 or amplifying viral genomes was greatly increased in E8 mt cell lines. In wild-type cells, E8^E2C transcript levels did not decrease by differentiation. Our data indicate that the E8^E2C repressor limits viral transcription and replication throughout the complete life cycle of HPV16.
Human Herpesvirus 8 Interleukin-6 Contributes to Primary Effusion Lymphoma Cell Viability via Suppression of Proapoptotic Cathepsin D, a Cointeraction Partner of Vitamin K Epoxide Reductase Complex Subunit 1 Variant 2
Authors: Chen Daming , Gao Yang , Nicholas John
Published: November 2013

Human herpesvirus 8 (HHV-8) interleukin-6 (vIL-6) promotes cell proliferation and survival and is proangiogenic, implicating it as a contributor to virus-associated Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease. Although predominantly lytically expressed, vIL-6 is also produced at low, functional levels during latency in PEL cells. Unlike other IL-6 cytokines, vIL-6 is secreted very inefficiently and localizes in the endoplasmic reticulum (ER). ER-localized vIL-6 supports PEL cell proliferation and survival, mediated in part through its interaction with the largely uncharacterized ER-resident protein vitamin K epoxide reductase complex subunit 1 variant 2 (VKORC1v2). Here, we report that the ER-transiting and functionally mitogenic secreted proenzyme (pCatD) form of cathepsin D (mature CatD), a proapoptotic lysosomal aspartate protease, is an interaction partner of VKORC1v2 and that vIL-6 promotes this interaction. Depletion of vIL-6 in PEL cells increased levels of the catalytically active, proteolytically cleaved form of CatD, corresponding with decreased PEL cell viability. Ectopic expression of CatD in PEL cells induced apoptosis, suggesting that CatD suppression by vIL-6 is biologically significant. In the context of high-density culture or reactivation of HHV-8 lytic replication in PEL cells, CatD depletion substantially reduced stress-induced apoptosis and increased virus production. In contrast, CatD overexpression, vIL-6 depletion, and peptide-mediated disruption of vIL-6–VKORC1v2 interaction inhibited replication and cell survival. Combined, our data identify pCatD as an interaction partner of VKORC1v2, demonstrate a role of vIL-6 in CatD suppression via VKORC1v2 in PEL cells, and identify a biologically significant mechanism of vIL-6 prosurvival and proreplication activities via VKORC1v2.
Quantitative Modeling of Virus Evolutionary Dynamics and Adaptation in Serial Passages Using Empirically Inferred Fitness Landscapes
Authors: Woo Hyung Jun , Reifman Jaques
Published: November 2013

We describe a stochastic virus evolution model representing genomic diversification and within-host selection during experimental serial passages under cell culture or live-host conditions. The model incorporates realistic descriptions of the virus genotypes in nucleotide and amino acid sequence spaces, as well as their diversification from error-prone replications. It quantitatively considers factors such as target cell number, bottleneck size, passage period, infection and cell death rates, and the replication rate of different genotypes, allowing for systematic examinations of how their changes affect the evolutionary dynamics of viruses during passages. The relative probability for a viral population to achieve adaptation under a new host environment, quantified by the rate with which a target sequence frequency rises above 50%, was found to be most sensitive to factors related to sequence structure (distance from the wild type to the target) and selection strength (host cell number and bottleneck size). For parameter values representative of RNA viruses, the likelihood of observing adaptations during passages became negligible as the required number of mutations rose above two amino acid sites. We modeled the specific adaptation process of influenza A H5N1 viruses in mammalian hosts by simulating the evolutionary dynamics of H5 strains under the fitness landscape inferred from multiple sequence alignments of H3 proteins. In light of comparisons with experimental findings, we observed that the evolutionary dynamics of adaptation is strongly affected not only by the tendency toward increasing fitness values but also by the accessibility of pathways between genotypes constrained by the genetic code.
Diasteroselective conjugate addition of diethylaluminum cyanide to a conjugated N-enoyl system: an alternative synthesis of (S)-pregabalin
Authors: Tovar-Gudiño Erika , Morales-Nava Rosmarbel , Fernández-Zertuche Mario
Published: November 2013

We have explored in this work the conjugate addition of diethylaluminum cyanide (Nagata’s reagent) to an N-enoyl system bearing the (R)-4-phenyl-2-oxazolidinone chiral auxiliary. Since this method provided a practical synthesis of γ-amino acids, we report the conjugate addition of diethylaluminum cyanide as the key step in the synthesis of (S)-pregabalin 1 in a five-step sequence of reactions from commercially available starting materials.
DEFORMED SUPERSYMMETRIC GAUGE THEORIES FROM THE FLUXTRAP BACKGROUND
Authors: ORLANDO DOMENICO , REFFERT SUSANNE
Published: November 2013

The fluxtrap background of string theory provides a transparent and algorithmic way of constructing supersymmetric gauge theories with both mass and Ω-type deformations in various dimensions. In this paper, we review a number of deformed supersymmetric gauge theories in two and four dimensions which can be obtained via the fluxtrap background from string or M-theory. Such theories, the most well-known being Ω-deformed super-Yang–Mills theory in four dimensions, have met with a lot of interest in the recent literature. The string theory treatment offers many new avenues of analysis and applications, such as for example the study of the gravity duals for deformed [Formula: see text] gauge theories.
RICCI LOWER BOUND FOR KÄHLER–RICCI FLOW
Authors: ZHANG ZHOU
Published: November 2013

We provide general discussion on the lower bound of Ricci curvature along Kähler–Ricci flows over closed manifolds. The main result is the non-existence of Ricci lower bound for flows with finite time singularities and non-collapsed global volume. As an application, we give examples showing that positivity of Ricci curvature would not be preserved by Ricci flow in general.
PEGO THEOREM ON LOCALLY COMPACT ABELIAN GROUPS
Authors: GÓRKA PRZEMYSłAW
Published: November 2013

In this paper, we show the version of Pego's theorem on locally compact abelian groups. This theorem, [R. L. Pego, Compactness in L2 and the Fourier transform, Proc. Amer. Math. Soc.95 (1985) 252–254], gives a characterization of precompact sets of L2 in terms of the Fourier transform.
TIGHT WAVELET FRAMES GENERATED BY THE WALSH POLYNOMIALS
Authors: SHAH FIRDOUS AHMAD
Published: November 2013

Tight wavelet frames and their promising features in applications have attracted a great deal of interest and effort in recent years. In this paper, we give an explicit construction of tight wavelet frames generated by the Walsh polynomials on positive half-line ℝ+ using the extension principles. Finally, we derive the wavelet frame decomposition and reconstruction formulas which are similar to those of orthonormal wavelets on positive half-line ℝ+.
ATTRIBUTE REDUCTION OF CONCEPT LATTICE BASED ON IRREDUCIBLE ELEMENTS
Authors: LI TONG-JUN , LI MING-ZHI , GAO YU
Published: November 2013

Attribute reduction of formal context is a crucial reseach issue in formal concept analysis. In this paper, based on the meet-irreducible elements and join-irreducible elements of concept lattice, two kinds of attribute reductions of formal context are proposed, which are called MI-attribute reduction and JI-attribute reduction. Subsequently, we discuss the relationships among them and two existing attribute reductions of formal context, lattice-based attribute reduction and granular reduction. Consequently, we find that the MI-attribute reduction and lattice-based attribute reduction are identical. For JI-attribute reduction, the judgement theorems of JI-consistent attribute sets are obtained. Finally, by using the discernibility attribute sets, a method of computing all JI-attribute reducts of a formal context is presented.
DYNAMIC GRAPH MERGING FOR IMAGE SEGMENTATION
Authors: GU JIANPING , ZHANG LI , CHENG CUN
Published: November 2013

A new algorithm named dynamic graph merging (DGM) for automatic image segmentation is explored. Firstly a novel variational model for multi-section cut is introduced by decomposing the traditional cut into two parts, the harmonic cut and the elastic energy of the boundary. The new energy is called the continuous combined cut. Secondly a new algorithm that removes those edges with higher energy and synchronously merges their starting and ending vertices in an ordered manner is proposed. The continual merging process would iteratively contract the graph, merge those homogeneous vertices into bigger and bigger super-pixels, and fuse the remainder edges into longer and longer boundaries. So we call this algorithm dynamic graph merging. Merging criterions based on the continuous combined cut model are also discussed, which will be used to determine whether a given edge should collapse. Since the merging condition should be highly related to the image content, we present different predicates for structure images and texture images respectively. This algorithm whose efficiency is showed by experiments has a linear time/space complexity, and can efficiently segment gray/color and 2D/3D images.
STUDENTIZED PARTIAL SCORE TESTS FOR VARIANCES IN LONGITUDINAL DATA
Authors: OYET ALWELL J. , OGBONNA CHUKWUDI
Published: November 2013

Koenker9studied a studentized version of Neyman's score statistic and obtained theoretical results which indicated that the studentized version will outperform the score test under a linear model if the data is from a heavy-tailed t-distribution. However, the author failed to examine the size and power performances of the studentized test through a simulation study. Subsequently, Cai, Hurvich and Tsai7after a simulation study in a nonparametric setting, found that even when the data is from a normal population the score test was biased in estimating a pre-assigned level of significance. Thus, he recommended that the studentized score test should be used in all situations. Several authors have, however, shown earlier that when the data is from a normal population, Neyman's partial score test is asymptotically unbiased in estimating a pre-assigned level of significance. As a result in this paper, we obtain the partial score statistic and the studentized version under various models but conduct our simulation studies under the special case considered by Cai et al.7in order to examine the studentized test. We found, in our simulation studies, that when the model of interest is nonparametric with uncorrelated errors, the power of the score test is generally higher than that of the studentized test. The difference in power performances becomes more pronounced under the heavy-tailed t-distribution. In the normal case, both the partial score test and its studentized version performed well in controlling the size of the test. We also found that if the score statistic is constructed based on the underlying distribution of the data, then the score statistic will always outperform the studentized test in both power and size.
A MICROCAPSULE TECHNOLOGY BASED SELF-HEALING SYSTEM FOR CONCRETE STRUCTURES
Authors: DONG BIQIN , HAN NINGXU , ZHANG MING , WANG XIANFENG , CUI HONGZHI , XING FENG
Published: November 2013

In the study, a novel microcapsule technology based self-healing system for concrete structures has been developed. Through situ-polymerization reaction, the microcapsule is formed by urea formaldehyde resin to pack the epoxy material, which is applied to cementitious composite to achieve self-healing effect. The experimental results revealed that the self-healing efficiency of the composite can be accessed from the recovery of the permeability and strength for the cracked cementitious specimens as the healing agent in the microcapsule acting on the cracks directly. Scanning electronic microscope (SEM/EDX) results show that the epoxy resin is released along with the cracking of the cementitious composite and prevent from cracks continued growth. Further studies show that the self-healing efficiency is affected by the pre-loading of composite, particle size of microcapsule, aging duration of healing agent and so on.
Earth's punctuated tectonic evolution: cause and effect
Authors: O’Neill C. , Lenardic A. , Condie K. C.
Published: November 2013

Peaks in the Precambrian preserved crustal record are associated with major volcanic, tectonic and climatic events. These include addition of juvenile continental crust, voluminous high-temperature volcanism, massive mantle depletion, widespread orogeny and mineralization, large apparent polar wander velocity spikes, and subsequent palaeomagnetic intensity increases. These events impinge on the glaciation record, atmospheric and ocean chemistry, and on the rise of oxygen. Here we summarize and assess a number of geodynamic models that have been proposed to explain the observed episodicity in the Precambrian record. We find that episodic behaviour from nonlinear slab-driven models best explains the observed record. Examples of such slab-driven systems include mantle avalanches or episodic subduction. In these cases, rapid descent of slabs into the mantle drives fast plate motions and convergence at the surface. This is accompanied by large-scale upwellings of deep hot mantle, which contribute to voluminous volcanism. Further modelling will determine the relative importance of each mechanism, and reinforce the fundamental contribution of the mantle to the evolution of Earth's surface systems.
Src tyrosine kinase mediates platelet-derived growth factor BB-induced and redox-dependent migration in metanephric mesenchymal cells
Authors: Wagner Brent , Gorin Yves
Published: November 2013

The adult kidney is derived from the interaction between the metanephric blastema and the ureteric bud. Platelet-derived growth factor (PDGF) receptor β is essential for the development of the mature glomerular tuft, as mice deficient for this receptor lack mesangial cells. This study investigated the role of Src tyrosine kinase in PDGF-mediated reactive oxygen species (ROS) generation and migration of metanephric mesenchymal cells (MMCs). Cultured embryonic MMCs from wild-type and PDGF receptor-deficient embryos were established. Migration was determined via wound-healing assay. Unlike PDGF AA, PDGF BB-induced greater migration in MMCs with respect to control. This was abrogated by neutralizing an antibody to PDGF BB. Phosphatidylinositol 3-kinase (PI3K) inhibitors suppressed PDGF BB-induced migration. Conversely, mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) inhibitors had no effect. Src inhibitors inhibited PDGF-induced cell migration, PI3K activity, and Akt phosphorylation. Adenoviral dominant negative Src (AD DN Src) abrogated PDGF BB-induced Akt phosphorylation. Hydrogen peroxide stimulated cell migration. PDGF BB-induced wound closure was inhibited by the antioxidants N-acetyl-l-cysteine, tiron, and the flavoprotein inhibitor diphenyleneiodonium. These cells express the NADPH oxidase homolog Nox4. Inhibiting Nox4 with antisense oligonucleotides or small interfering RNA (siRNA) suppressed PDGF-induced wound closure. Inhibition of Src with siRNA reduced PDGF BB-induced ROS generation as assessed by 2′,7′-dichlorodihydrofluorescein diacetate fluorescence. Furthermore, PDGF BB-stimulated ROS generation and migration were similarly suppressed by Ad DN Src. In MMCs, PDGF BB-induced migration is mediated by PI3K and Src in a redox-dependent manner involving Nox4. Src may be upstream to PI3K and Nox4.
Transepithelial water and urea permeabilities of isolated perfused Munich-Wistar rat inner medullary thin limbs of Henle's loop
Authors: Nawata C. Michele , Evans Kristen K. , Dantzler William H. , Pannabecker Thomas L.
Published: November 2013

To better understand the role that water and urea fluxes play in the urine concentrating mechanism, we determined transepithelial osmotic water permeability ( Pf) and urea permeability ( Purea) in isolated perfused Munich-Wistar rat long-loop descending thin limbs (DTLs) and ascending thin limbs (ATLs). Thin limbs were isolated either from 0.5 to 2.5 mm below the outer medulla (upper inner medulla) or from the terminal 2.5 mm of the inner medulla. Segment types were characterized on the basis of structural features and gene expression levels of the water channel aquaporin 1, which was high in the upper DTL (DTLupper), absent in the lower DTL (DTLlower), and absent in ATLs, and the Cl-1channel ClCK1, which was absent in DTLs and high in ATLs. DTLupperPfwas high (3,204.5 ± 450.3 μm/s), whereas DTLlowershowed very little or no osmotic Pf(207.8 ± 241.3 μm/s). Munich-Wistar rat ATLs have previously been shown to exhibit no Pf. DTLupperPureawas 40.0 ± 7.3 × 10−5cm/s and much higher in DTLlower(203.8 ± 30.3 × 10−5cm/s), upper ATL (203.8 ± 35.7 × 10−5cm/s), and lower ATL (265.1 ± 49.8 × 10−5cm/s). Phloretin (0.25 mM) did not reduce DTLupperPurea, suggesting that Pureais not due to urea transporter UT-A2, which is expressed in short-loop DTLs and short portions of some inner medullary DTLs close to the outer medulla. In summary, Pureais similar in all segments having no osmotic Pfbut is significantly lower in DTLupper, a segment having high osmotic Pf. These data are inconsistent with the passive mechanism as originally proposed.