bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cyclic Di-GMP Riboswitch-Regulated Type IV Pili Contribute to Aggregation of Clostridium difficile
Authors: Bordeleau Eric , Purcell Erin B. , Lafontaine Daniel A. , Fortier Louis-Charles , Tamayo Rita , Burrus Vincent 
Published: December 2014

ABSTRACT

Clostridium difficile
is an anaerobic Gram-positive bacterium that causes intestinal infections with symptoms ranging from mild diarrhea to fulminant colitis. Cyclic diguanosine monophosphate (c-di-GMP) is a bacterial second messenger that typically regulates the switch from motile, free-living to sessile and multicellular behaviors in Gram-negative bacteria. Increased intracellular c-di-GMP concentration in
C. difficile
was recently shown to reduce flagellar motility and to increase cell aggregation. In this work, we investigated the role of the primary type IV pilus (T4P) locus in c-di-GMP-dependent cell aggregation. Inactivation of two T4P genes,
pilA1
(CD3513) and
pilB1
(CD3512), abolished pilus formation and significantly reduced cell aggregation under high c-di-GMP conditions.
pilA1
is preceded by a putative c-di-GMP riboswitch, predicted to be transcriptionally active upon c-di-GMP binding. Consistent with our prediction, high intracellular c-di-GMP concentration increased transcript levels of T4P genes. In addition, single-round
in vitro
transcription assays confirmed that transcription downstream of the predicted transcription terminator was dose dependent and specific to c-di-GMP binding to the riboswitch aptamer. These results support a model in which T4P gene transcription is upregulated by c-di-GMP as a result of its binding to an upstream transcriptionally activating riboswitch, promoting cell aggregation in
C. difficile
.
Identification of a Second Two-Component Signal Transduction System That Controls Fosfomycin Tolerance and Glycerol-3-Phosphate Uptake
Authors: Kurabayashi Kumiko , Hirakawa Yuko , Tanimoto Koichi , Tomita Haruyoshi , Hirakawa Hidetada 
Published: December 2014

ABSTRACT

Particular interest in fosfomycin has resurfaced because it is a highly beneficial antibiotic for the treatment of refractory infectious diseases caused by pathogens that are resistant to other commonly used antibiotics. The biological cost to cells of resistance to fosfomycin because of chromosomal mutation is high. We previously found that a bacterial two-component system, CpxAR, induces fosfomycin tolerance in enterohemorrhagic
Escherichia coli
(EHEC) O157:H7. This mechanism does not rely on irreversible genetic modification and allows EHEC to relieve the fitness burden that results from fosfomycin resistance in the absence of fosfomycin. Here we show that another two-component system, TorSRT, which was originally characterized as a regulatory system for anaerobic respiration utilizing trimethylamine-
N
-oxide (TMAO), also induces fosfomycin tolerance. Activation of the Tor regulatory pathway by overexpression of
torR
, which encodes the response regulator, or addition of TMAO increased fosfomycin tolerance in EHEC. We also show that phosphorylated TorR directly represses the expression of
glpT
, a gene that encodes a symporter of fosfomycin and glycerol-3-phosphate, and activation of the TorR protein results in the reduced uptake of fosfomycin by cells. However, cells in which the Tor pathway was activated had an impaired growth phenotype when cultured with glycerol-3-phosphate as a carbon substrate. These observations suggest that the TorSRT pathway is the second two-component system to reversibly control fosfomycin tolerance and glycerol-3-phosphate uptake in EHEC, and this may be beneficial for bacteria by alleviating the biological cost. We expect that this mechanism could be a potential target to enhance the utility of fosfomycin as chemotherapy against multidrug-resistant pathogens.
Effect of rapid HIV testing on HIV incidence and services in populations at high risk for HIV exposure: an equity-focused systematic review
Authors: Pottie Kevin , Medu Olanrewaju , Welch Vivian , Dahal Govinda P , Tyndall Mark , Rader Tamara , Wells George 
Published: December 2014

ObjectiveTo assess the effects of rapid voluntary counselling and testing (VCT) for HIV on HIV incidence and uptake of HIV/AIDS services in people at high risk for HIV exposure.DesignCochrane systematic review and meta-analysis.Data sourcesWe searched PubMed, EMBASE, AIDSearch, LILACS, Global Health, Medline Africa, PsychInfo, CINAHL, Cochrane CENTRAL, Cochrane HIV/AIDS Group Specialized Register and grey literature from 1 January 2001 to 5 June 2014 without language restriction.Data selectionWe included controlled studies that compared rapid VCT with conventional testing among people at risk for HIV exposure.Data extractionTwo reviewers extracted data. We used Cochrane risk of bias tool and GRADE criteria: risk of bias, inconsistency, indirectness, imprecision and publication bias. For observational studies we used the Newcastle-Ottawa Scale. We used the PRISMA-Equity reporting guideline.ResultsFrom 2441 articles, we included 8 randomised controlled trials and 5 observational studies. Rapid VCT was associated with a threefold increase in HIV-testing uptake (relative risk (RR)=2.95 95% CI 1.69 to 5.16) and a twofold increase in the receipt of test results (RR=2.14, 95% CI 1.08 to 4.24). Women accepted testing more often than men in rapid VCT arm, but no differences in effect for age or socioeconomic status. Observational studies also showed rapid VCT led to higher rates of uptake of testing. Heterogeneity was high. A cluster-randomised trial reported an 11% reduction in HIV incidence in intervention communities (RR=0.89, 95% CI=0.63 to 1.24) over 3 years trial.ConclusionsRapid VCT in health facilities and communities was associated with a large increase in HIV-testing uptake and receipt of results. This has implications for WHO guidelines. The routine use of rapid VCT may also help avoid human rights violations among marginalised populations where testing may occur without informed consent and where existing stigma may create barriers to testing.
Tumor-Associated Hyaluronan Limits Efficacy of Monoclonal Antibody Therapy
Authors: Singha Netai C. , Nekoroski Tara , Zhao Chunmei , Symons Rebecca , Jiang Ping , Frost Gregory I. , Huang Zhongdong , Shepard H. Michael 
Published: December 2014

AbstractDespite tremendous progress in cancer immunotherapy for solid tumors, clinical success of monoclonal antibody (mAb) therapy is often limited by poorly understood mechanisms associated with the tumor microenvironment (TME). Accumulation of hyaluronan (HA), a major component of the TME, occurs in many solid tumor types, and is associated with poor prognosis and treatment resistance in multiple malignancies. In this study, we describe that a physical barrier associated with high levels of HA (HAhigh) in the TME restricts antibody and immune cell access to tumors, suggesting a novel mechanism of in vivo resistance to mAb therapy. We determined that approximately 60% of HER23+ primary breast tumors and approximately 40% of EGFR+ head and neck squamous cell carcinomas are HAhigh, and hypothesized that HAhigh tumors may be refractory to mAb therapy. We found that the pericellular matrix produced by HAhigh tumor cells inhibited both natural killer (NK) immune cell access to tumor cells and antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. Depletion of HA by PEGPH20, a pegylated recombinant human PH20 hyaluronidase, resulted in increased NK cell access to HAhigh tumor cells, and greatly enhanced trastuzumab- or cetuximab-dependent ADCC in vitro. Furthermore, PEGPH20 treatment enhanced trastuzumab and NK cell access to HAhigh tumors, resulting in enhanced trastuzumab- and NK cell–mediated tumor growth inhibition in vivo. These results suggest that HAhigh matrix in vivo may form a barrier inhibiting access of both mAb and NK cells, and that PEGPH20 treatment in combination with anticancer mAbs may be an effective adjunctive therapy for HAhigh tumors. Mol Cancer Ther; 14(2); 523–32. ©2014 AACR.
The Allocation of Attention and Working Memory in Visual Crowding
Authors: Bacigalupo Felix , Luck Steven J. 
Published: December 2014

Abstract
When the distance between a visual target and nearby flankers falls below a critical distance, target discrimination declines precipitously. This is called “crowding.” Many researchers have proposed that selective attention plays a role in crowding. However, although some research has examined the effects of directing attention toward versus away from the targets, no previous research has assessed how attentional allocation varies as a function of target–flanker distance in crowding. Here, we used ERPs to assess the operation of attention during crowding, focusing on the attention-related N2pc component. We used a typical crowding task in which participants were asked to report the category (vowel/consonant) of a lateralized target letter flanked by distractor letters at different distances. We tested the hypothesis that attention fails when the target–flanker distance becomes too small for attention to operate effectively. Consistent with this hypothesis, we found that N2pc amplitude was maximal at intermediate target–flanker distances and decreased substantially when crowding became severe. In addition, we examined the sustained posterior contralateral negativity (SPCN), which reflects the amount of information being maintained in working memory. Unlike the N2pc component, the SPCN increased in amplitude at small target–flanker distances, suggesting that observers stored information about the target and flankers in working memory when attention failed to select the target. Together, the N2pc and SPCN results suggest that attention and working memory play distinctive roles in crowding: Attention operates to minimize interference from the flankers at intermediate target–flanker distances, whereas working memory may be recruited when attention fails to select the target at small target–flanker distances.
Short-term Motor Training, but Not Observational Training, Alters Neurocognitive Mechanisms of Action Processing in Infancy
Authors: Gerson Sarah A. , Bekkering Harold , Hunnius Sabine 
Published: December 2014

Abstract
The role of motor experience in the processing of perceived actions is hotly debated on both behavioral (e.g., action understanding) and neural (e.g., activation of the motor system) levels of interpretation. Whereas some researchers focus on the role of motor experience in the understanding of and motor activity associated with perceived actions, others emphasize the role of visual experience with the perceived actions. The question of whether prior firsthand motor experience is critical to motor system activation during perception of actions performed by others is best addressed through studies with infants who have a limited repertoire of motor actions. In this way, infants can receive motor or visual training with novel actions that are not mere recombinations of previously acquired actions. In this study, 10-month-old infants received active training with a motorically unfamiliar action that resulted in a distinct sound effect. They received observational experience with a second, similarly unfamiliar action. Following training, we assessed infants' neural motor activity via EEG while they listened to the sounds associated with the actions relative to a novel sound. We found a greater decrease in mu power to sounds associated with the motorically learned action than to those associated with the observed action that the infants had never produced. This effect was directly related to individual differences in the degree of motor learning via motor training. These findings indicate a unique effect of active experience on neural correlates of action perception.
Mismatched Training and Test Distributions Can Outperform Matched
Ones
Authors: González Carlos R. , Abu-Mostafa Yaser S. 
Published: December 2014

Abstract
In learning theory, the training and test sets are assumed to be drawn from the same probability distribution. This assumption is also followed in practical situations, where matching the training and test distributions is considered desirable. Contrary to conventional wisdom, we show that mismatched training and test distributions in supervised learning can in fact outperform matched distributions in terms of the bottom line, the out-of-sample performance, independent of the target function in question. This surprising result has theoretical and algorithmic ramifications that we discuss.
Diabetes Educator Mentorship Program
Authors: Beck Joni K. , Traficano Sheryl E. 
Published: December 2014

Purpose The purpose of this article is to describe the Diabetes Educator Mentorship Program, communicate mentors’ experiences and perceptions during the first 3 years following implementation, and provide strategies to encourage mentoring. Conclusions Creation of this collaborative program has fostered successful attainment of additional certified diabetes educators who obtained diabetes self-management education and support (DSMES) practice requirement hours through a voluntary Diabetes Educator Mentorship Program. There is a significant need for additional mentors to meet the growing need for mentoring partnerships. Increasing the number of mentors will provide more opportunities to those seeking to gain DSMES experience and will ultimately expand the number of health professionals available to educate those with diabetes or prediabetes.
Bimaxillary Protrusion in the Caucasian: A Cephalometric Study of the Morphological Features
Authors: Keating P. J. 
Published: December 2014

The skeletal morphology of bimaxillary dental protrusion has been investigated in a comparative cephalometric study. Because this is considered a subset of Class I malocclusions, the null hypothesis is that there should be no significant skeletal differences between this group and a Class I control group. There were 30 Caucasians in each group with no bias for age and sex differences between them. Eighteen radiographic landmarks were identified from which 33 skeletal, dental and soft tissue parameters were computed. The bimaxillary group had an average interincisal angle of 115° versus the controls 135°, and showed the following morphological features which persisted over a 5-year growth period: 1. A shorter posterior cranial base. 2. A longer and more prognathic maxilla. 3. Similar mandibular dimensions and prognathism. 4. A mild Class II skeletal pattern. 5. A smaller upper and posterior face height. 6. Diverging facial planes. 7. A procumbent soft tissue profile with a low lip line. These findings indicate that there is a distinctive difference between the underlying skeletal patterns found in the two groups.
Cephalometric Analysis of Changes Produced by a Modified Herbst Appliance in the Treatment of Class II Division 1 Malocclusion
Authors: Sidhu Maninder S. , Kharbanda O. P. , Sidhu S. S. 
Published: December 2014

This study investigated treatment changes produced by the Herbst appliance in a sample of severe Class II division 1 cases, over a period of 8 months. The sample consisted of 16 girls, of whom eight were treated by the Herbst appliance, whilst eight served as controls. All cases were matched with respect to age, sex, skeletofacial morphology, and length of treatment/observation period. Twenty-two skeletal and 19 dental parameters were recorded on pre- and post-treatment cephalograms. The net treatment effect of Herbst therapy was evaluated, taking into account the growth that occurred in the control sample. The study revealed that during 8 months of Herbst therapy there was a significant increase in mandibular length, along with sagittal repositioning. The skeletal changes in the mandible were mainly responsible for overjet and molar relation correction. A slight, favourable forward rotation of the mandible was identified. Dentoalveolar features included flaring of lower incisors and distalization of upper molars. The appliance did not have any retrusive effect on the maxilla. The modified splint design differed from the original and was cemented rather than bonded.
Overexpression of ERBB4 JM-a CYT-1 and CYT-2 isoforms in transgenic mice reveals isoform-specific roles in mammary gland development and carcinogenesis
Authors: Wali Vikram B , Gilmore-Hebert Maureen , Mamillapalli Ramanaiah , Haskins Jonathan W , Kurppa Kari J , Elenius Klaus , Booth Carmen J , Stern David F 
Published: December 2014

Abstract
Introduction
Human Epidermal Growth Factor Receptor (ERBB4/HER4) belongs to the Epidermal Growth Factor receptor/ERBB family of receptor tyrosine kinases. While ERBB1, ERBB2 and ERBB3 are often overexpressed or activated in breast cancer, and are oncogenic, the role of ERBB4 in breast cancer is uncertain. Some studies suggest a tumor suppressor role of ERBB4, while other reports suggest an oncogenic potential. Alternative splicing of ERBB4 yields four major protein products, these spliced isoforms differ in the extracellular juxtamembrane domain (JM-a versus JM-b) and cytoplasmic domain (CYT-1 versus CYT-2). Two of these isoforms, JM-a CYT-1 and JM-a CYT-2, are expressed in the mammary gland. Failure to account for isoform-specific functions in previous studies may account for conflicting reports on the role of ERBB4 in breast cancer.

Methods
We have produced mouse mammary tumour virus (MMTV) -ERBB4 transgenic mice to evaluate potential developmental and carcinogenic changes associated with full length (FL) JM-a ERBB4 CYT-1 versus ERBB4 CYT-2. Mammary tissue was isolated from transgenic mice and sibling controls at various developmental stages for whole mount analysis, RNA extraction, and immunohistochemistry. To maintain maximal ERBB4 expression, transgenic mice were bred continuously for a year after which mammary glands were isolated and analyzed.

Results
Overexpressing FL CYT-1 isoform resulted in suppression of mammary ductal morphogenesis which was accompanied by decreased number of mammary terminal end buds (TEBs) and Ki-67 positive cells within TEBs, while FL CYT-2 isoform had no effect on ductal growth in pubescent mice. The suppressive ductal phenotype in CYT-1 mice disappeared after mid-pregnancy, and subsequent developmental stages showed no abnormality in mammary gland morphology or function in CYT-1 or CYT-2 transgenic mice. However, sustained expression of FL CYT-1 isoform resulted in formation of neoplastic mammary lesions, suggesting a potential oncogenic function for this isoform.

Conclusions
Together, we present isoform-specific roles of ERBB4 during puberty and early pregnancy, and reveal a novel oncogenic property of CYT-1 ERBB4. The results may be exploited to develop better therapeutic strategies in breast cancer.
TNFα signalling primes chromatin for NF-κB binding and induces rapid and widespread nucleosome repositioning
Authors: Diermeier Sarah , Kolovos Petros , Heizinger Leonhard , Schwartz Uwe , Georgomanolis Theodore , Zirkel Anne , Wedemann Gero , Grosveld Frank , Knoch Tobias A , Merkl Rainer , Cook Peter R , Längst Gernot , Papantonis Argyris 
Published: December 2014

Abstract
Background
The rearrangement of nucleosomes along the DNA fiber profoundly affects gene expression, but little is known about how signalling reshapes the chromatin landscape, in three-dimensional space and over time, to allow establishment of new transcriptional programs.

Results
Using micrococcal nuclease treatment and high-throughput sequencing, we map genome-wide changes in nucleosome positioning in primary human endothelial cells stimulated with tumour necrosis factor alpha (TNFα) - a proinflammatory cytokine that signals through nuclear factor kappa-B (NF-κB). Within 10 min, nucleosomes reposition at regions both proximal and distal to NF-κB binding sites, before the transcription factor quantitatively binds thereon. Similarly, in long TNFα-responsive genes, repositioning precedes transcription by pioneering elongating polymerases and appears to nucleate from intragenic enhancer clusters resembling super-enhancers. By 30 min, widespread repositioning throughout megabase pair-long chromosomal segments, with consequential effects on three-dimensional structure (detected using chromosome conformation capture), is seen.

Conclusions
Whilst nucleosome repositioning is viewed as a local phenomenon, our results point to effects occurring over multiple scales. Here, we present data in support of a TNFα-induced priming mechanism, mostly independent of NF-κB binding and/or elongating RNA polymerases, leading to a plastic network of interactions that affects DNA accessibility over large domains.
Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2
Authors: Love Michael I , Huber Wolfgang , Anders Simon 
Published: December 2014

AbstractIn comparative high-throughput sequencing assays, a fundamental task is the analysis of count data, such as read counts per gene in RNA-seq, for evidence of systematic changes across experimental conditions. Small replicate numbers, discreteness, large dynamic range and the presence of outliers require a suitable statistical approach. We present DESeq2, a method for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates. This enables a more quantitative analysis focused on the strength rather than the mere presence of differential expression. The DESeq2 package is available at http://www.bioconductor.org/packages/release/bioc/html/DESeq2.html.
Cyclosporin A, but not tacrolimus, negatively affects the hepatic extraction fraction of hepatobiliary scintigraphy in liver transplant recipients
Authors: Kaxiras Anastasios , Yamamoto Shinji , Söderdahl Gunnar , Wernerson Annika , Axelsson Rimma , Ericzon Bo-Göran 
Published: December 2014

Abstract

Background
Hepatobiliary scintigraphy using 99mTc-mebrofenin has been used as an investigation to study liver function after liver transplantation (LTx). Hepatic extraction fraction (HEF) is a measurement of the hepatic extraction efficiency and hepatic extraction rate. With the purpose of evaluating a possible diverging effect of cyclosporin A (CSA) and tacrolimus (TAC) on the HEF, we compared the HEF with biochemical and histological parameters in LTx patients receiving either CSA or TAC.

Methods
Thirty-nine adult patients who underwent LTx due to hepatitis C virus (HCV) cirrhosis were evaluated. All patients underwent a 3-month and 1-year follow-up that included hepatobiliary scintigraphy and biochemistry tests. Liver biopsy was performed at 1 year. These clinical parameters were compared between the two groups, TAC (n = 15) and CSA (n = 24).

Results
The average HEF was significantly lower in the CSA group compared to the TAC group both at 3 months and 1 year after LTx. The liver biochemistry tests, average donor and recipient age, average cold ischemia time (CIT), and a clearance were comparable in the two groups. The TAC group had more inflammation than the CSA group. Moreover, three patients who converted from CSA to TAC increased their HEF values.

Conclusions
CSA-treated patients presented a lower HEF value on hepatobiliary scintigraphy in spite of comparable liver function by traditional measurements indicating a decrease on HEF values by CSA.