bluuebunny/crossref_metadata_2025_split huggingface dataset:
CodY-Dependent Regulation of Sporulation in Clostridium difficile
Authors: Nawrocki Kathryn L. , Edwards Adrianne N. , Daou Nadine , Bouillaut Laurent , McBride Shonna M. 
Published: June 2016

ABSTRACT

Clostridium difficile
must form a spore to survive outside the gastrointestinal tract. The factors that trigger sporulation in
C. difficile
remain poorly understood. Previous studies have suggested that a link exists between nutritional status and sporulation initiation in
C. difficile
. In this study, we investigated the impact of the global nutritional regulator CodY on sporulation in
C. difficile
strains from the historical 012 ribotype and the current epidemic 027 ribotype. Sporulation frequencies were increased in both backgrounds, demonstrating that CodY represses sporulation in
C. difficile
. The 027
codY
mutant exhibited a greater increase in spore formation than the 012
codY
mutant. To determine the role of CodY in the observed sporulation phenotypes, we examined several factors that are known to influence sporulation in
C. difficile
. Using transcriptional reporter fusions and quantitative reverse transcription-PCR (qRT-PCR) analysis, we found that two loci associated with the initiation of sporulation,
opp
and
sinR
, are regulated by CodY. The data demonstrate that CodY is a repressor of sporulation in
C. difficile
and that the impact of CodY on sporulation and expression of specific genes is significantly influenced by the strain background. These results suggest that the variability of CodY-dependent regulation is an important contributor to virulence and sporulation in current epidemic isolates. This report provides further evidence that nutritional state, virulence, and sporulation are linked in
C. difficile
.

IMPORTANCE
This study sought to examine the relationship between nutrition and sporulation in
C. difficile
by examining the global nutritional regulator CodY. CodY is a known virulence and nutritional regulator of
C. difficile
, but its role in sporulation was unknown. Here, we demonstrate that CodY is a negative regulator of sporulation in two different ribotypes of
C. difficile
. We also demonstrate that CodY regulates known effectors of sporulation, Opp and SinR. These results support the idea that nutrient limitation is a trigger for sporulation in
C. difficile
and that the response to nutrient limitation is coordinated by CodY. Additionally, we demonstrate that CodY has an altered role in sporulation regulation for some strains.
Lingdingyang Bay, Pearl River Estuary (China): geomorphological evolution and hydrodynamics
Authors: Jia Peihong , Xia Zhen , Yin Yong , Xue Qiao 
Published: June 2016

Abstract
The Pearl River is the largest river in southern China; it has eight outlets flowing into the South China Sea, four of which (Humen, Jiaomen, Hongqili and Hengmen) empty via Lingdingyang Bay. Tides, discharge strength and the presence of islands control sediments within these four outlets. Sediments are deposited, and form three shoals and two channels. The shoreline and its seabed topography have changed dramatically with increasing human impact.
In order to understand the geomorphological evolution of Lingdingyang Bay and its hydrodynamics, we integrated data obtained from two marine environment investigations conducted by the Guangzhou Marine Geological Survey (GMGS) in 2003 and in 2012, together with remote sensing multi-temporal images and historical materials, and analysed them using a geographical information system (GIS).
The results obtained show that the outlets are becoming narrower; the surface water area of Lingdingyang Bay is diminishing. Meanwhile, the sediment flux is reducing and becoming finer grained because the currents are being blocked by shoals and islands. Some parts of the bay are becoming deeper (27–37 m in the Chuanbi Channel). Correspondingly, the hydrodynamics in the bay are becoming weaker and sediments easier to deposit. Water exchange between the inner and outer sea is decreasing under the influence of unrestricted anthropogenic activities.
Lingdingyang Bay should be managed and protected continuously based on a scientific framework: otherwise, it will become narrower and, perhaps, even evolving eventually into a river, which may result in serious futures disasters through flooding and tides.
Rendering the 3 + 3 Design to Rest: More Efficient Approaches to Oncology Dose-Finding Trials in the Era of Targeted Therapy
Authors: Nie Lei , Rubin Eric H. , Mehrotra Nitin , Pinheiro José , Fernandes Laura L. , Roy Amit , Bailey Stuart , de Alwis Dinesh P. 
Published: June 2016

Abstract
Selection of the maximum tolerated dose (MTD) as the recommended dose for registration trials based on a dose-escalation trial using variations of an MTD/3 + 3 design often occurs in the development of oncology products. The MTD/3 + 3 approach is not optimal and may result in recommended doses that are unacceptably toxic for many patients and in dose reduction/interruptions that might have an impact on effectiveness. Instead of the MTD/3 + 3 approach, the authors recommend an integrated approach. In this approach, typically an adaptive/Bayesian model provides a general framework to incorporate and make decisions for dose escalation based on nonclinical data, such as animal efficacy and toxicity data; clinical data, including pharmacokinetics/pharmacodynamics data; and dose/exposure–response data for efficacy and safety. To improve dose-ranging trials, model-based estimation, rather than hypothesis testing, should be used to maximize and integrate the information gathered across trials and doses. This approach may improve identification of optimal recommended doses, which can then be confirmed in registration trials. Clin Cancer Res; 22(11); 2623–9. ©2016 AACR.
See all articles in this CCR Focus section, “New Approaches for Optimizing Dosing of Anticancer Agents.”
Plasma 25-Hydroxyvitamin D, Vitamin D Binding Protein, and Risk of Colorectal Cancer in the Nurses' Health Study
Authors: Song Mingyang , Konijeti Gauree Gupta , Yuan Chen , Ananthakrishnan Ashwin N. , Ogino Shuji , Fuchs Charles S. , Giovannucci Edward L. , Ng Kimmie , Chan Andrew T. 
Published: June 2016

AbstractTotal circulating 25-hydroxyvitamin D [25(OH)D)] has been associated with lower risk of colorectal cancer. The physiologic mechanism, however, may be more directly related to the free or bioavailable fraction of 25(OH)D, which is influenced by levels of vitamin D binding protein (VDBP). We assessed the association of prediagnosis total, free, and bioavailable 25(OH)D and VDBP with colorectal cancer risk among predominantly white women in the Nurses' Health Study (NHS) who provided a blood specimen in 1989–1990. We documented 378 cases of colorectal cancer through 2011 and matched them to 689 controls according to age and time of blood draw. We genotyped two common polymorphisms in the gene coding VDBP and calculated free and bioavailable 25(OH)D levels based on total 25(OH)D, VDBP, albumin, and their estimated genotype-specific binding affinities. Total 25(OH)D was associated with lower colorectal cancer risk (P for trend = 0.01). Compared with women in the lowest quintile of total 25(OH)D, those in the highest quintile had a multivariable-adjusted odds ratio (OR) for colorectal cancer of 0.54 [95% confidence interval (CI), 0.33–0.87]. Comparing extreme quintiles, we did not find any significant association with risk of colorectal cancer for VDBP (OR, 0.98; 95% CI, 0.65–1.47), free 25(OH)D (OR, 0.71; 95% CI, 0.46–1.10), or bioavailable 25(OH)D (OR, 0.92; 95% CI, 0.60–1.42). In conclusion, prediagnosis levels of total, but not free or bioavailable 25(OH)D, were associated with lower colorectal cancer risk. Although our findings support an inverse association of vitamin D with colorectal cancer, this association does not appear to be due to the unbound or bioavailable fraction of circulating vitamin D. Cancer Prev Res; 9(8); 664–72. ©2016 AACR.
Infarct Size Following Treatment With Second‐ Versus Third‐Generation P2Y
12
Antagonists in Patients With Multivessel Coronary Disease at ST‐Segment Elevation Myocardial Infarction in the CvLPRIT Study
Authors: Khan Jamal N. , Greenwood John P. , Nazir Sheraz A. , Lai Florence Y. , Dalby Miles , Curzen Nick , Hetherington Simon , Kelly Damian J. , Blackman Daniel , Peebles Charles , Wong Joyce , Flather Marcus , Swanton Howard , Gershlick Anthony H. , McCann Gerry P. 
Published: June 2016

Background

Third‐generation P2Y
12
antagonists (prasugrel and ticagrelor) are recommended in guidelines on ST‐segment elevation myocardial infarction. Mechanisms translating their more potent antiplatelet activity into improved clinical outcomes versus the second‐generation P2Y
12
antagonist clopidogrel are unclear. The aim of this post hoc analysis of the Complete Versus Lesion‐Only PRImary PCI Trial‐CMR (CvLPRIT‐CMR) substudy was to assess whether prasugrel and ticagrelor were associated with reduced infarct size compared with clopidogrel in patients undergoing primary percutaneous coronary intervention.

Methods and Results

Cv
LPRIT
‐
CMR
was a multicenter, prospective, randomized, open‐label, blinded end point trial in 203 ST‐segment elevation myocardial infarction patients with multivessel disease undergoing primary percutaneous coronary intervention with either infarct‐related artery–only or complete revascularization. P2Y
12
inhibitors were administered according to local guidelines. The primary end point of infarct size on cardiovascular magnetic resonance was not significantly different between the randomized groups. P2Y
12
antagonist administration was not randomized. Patients receiving clopidogrel (n=70) compared with those treated with either prasugrel or ticagrelor (n=133) were older (67.8±12 versus 61.5±10 years,
P
<0.001), more frequently had hypertension (49% versus 29%,
P
=0.007), and tended to have longer symptom‐to‐revascularization time (234 versus 177 minutes,
P
=0.05). Infarct size (median 16.1% [quartiles 1–3, 10.5–27.7%] versus 12.1% [quartiles 1–3, 4.8–20.7%] of left ventricular mass,
P
=0.013) and microvascular obstruction incidence (65.7% versus 48.9%,
P
=0.022) were significantly greater in patients receiving clopidogrel. Infarct size remained significantly different after adjustment for important covariates using both generalized linear models (
P
=0.048) and propensity score matching (
P
=0.025).

Conclusions

In this analysis of Cv
LPRIT
‐
CMR
, third‐generation P2Y
12
antagonists were associated with smaller infarct size and lower microvascular obstruction incidence versus the second‐generation P2Y
12
antagonist clopidogrel for ST‐segment elevation myocardial infarction.

Clinical Trial Registration

URL
:
http://www.isrctn.com/ISRCTN70913605
.
On Breaking Up Time, or, Perennialism as Philosophy of History
Authors: Gilbert Bennett 
Published: June 2016

Abstract
Current and recent philosophy of history contemplates a deep change in fundamental notions of the presence of the past. This is called breaking up time. The chief value for this change is enhancing the moral reach of historical research and writing. However, the materialist view of reality that most historians hold cannot support this approach. The origin of the notion in the thought of Walter Benjamin is suggested. I propose a neo-idealist approach called perennialism, centered on recurrent moral dilemmas and choices. This suggests a view of the relations of moral thought and ontology placed in the diachronic context that historians study.
Autoantibodies to domain 1 of beta 2 glycoprotein I determined using a novel chemiluminescence immunoassay demonstrate association with thrombosis in patients with antiphospholipid syndrome
Authors: Mahler M , Albesa R , Zohoury N , Bertolaccini M L , Ateka-Barrutia O , Rodriguez-Garcia J L , Norman G L , Khamashta M 
Published: June 2016

Introduction Antibodies to the domain 1 of beta 2 glycoprotein I (β2GPI–D1) have been suggested as a risk marker for thrombosis in patients with the antiphospholipid syndrome (APS). This cross-sectional study aimed to analyze the clinical utility of a novel chemiluminescence assay for the detection of anti-β2GPI–D1 antibodies. Patients and methods Sera collected from patients with primary or secondary APS ( n = 106; 72 with and 34 without history of thrombosis) and controls ( n = 272) were tested for anti-β2GPI–D1 IgG by chemiluminescence assay (QUANTA Flash) and by two anti-β2GPI IgG assays (QUANTA Lite and QUANTA Flash β2GPI IgG). Results Anti-β2GPI–D1 IgG titers were significantly higher in patients with thrombosis ( P = 0.0032) than those without. At the cut-off of 20 units, which yielded a 99.5% specificity, 24 of 72 (34.9%) patients with thrombosis and four of 34 (11.8%) without thrombosis were anti-β2GPI–D1 IgG positive (odds ratio, OR = 4.0). By further optimizing the cut-off specifically for correlation with thrombosis, 20.8% of the patients with thrombosis and 2.9% of the patients without thrombosis were positive (OR = 8.7). The ORs were significantly lower for antibodies to the full-length β2GPI by either the chemiluminescence assay or ELISA. Using the anti-β2GPI chemiluminescence assay, the OR was 2.3 (recommended cut-off of 20 CU) or 4.1 (optimal cut-off 164.6 CU). Using the anti-β2GPI ELISA, the OR was 2.7 (recommended cut-off of 20 units) or 3.7 (optimal cut-off 7.6 units). Conclusion These data indicate that anti-β2GPI–D1 IgG are present more frequently and in higher titers in APS patients with thrombotic complications than in those without.The novel β2GPI–D1 chemiluminescence assay appears to be superior to full-length β2GPI assays for the risk assessment of thrombotic events in APS patients.
Clinical and serological associations of autoantibodies to the Ku70/Ku80 heterodimer determined by a novel chemiluminescent immunoassay
Authors: Mahler M , Swart A , Wu J , Szmyrka-Kaczmarek M , Senécal J-L , Troyanov Y , Hanly J G , Fritzler M J 
Published: June 2016

Background Autoantibodies targeting Ku, an abundant nuclear protein with DNA helicase activity, have been reported in patients with systemic autoimmune rheumatic diseases. Little is known about the clinical associations of anti-Ku antibodies, especially when novel diagnostic technologies are used. The objective of the present study was to analyse the prevalence of anti-Ku antibodies in different medical conditions using a novel chemiluminescent immunoassay. Patients and methods Serum samples from adult patients with systemic lupus erythematosus (SLE, n=305), systemic sclerosis (SSc, n=70) and autoimmune myositis patients (AIM, n=109) were the primary focus of the study. Results were compared with disease controls (rheumatoid arthritis, RA, n=30; infectious diseases, n=17) and healthy individuals ( n=167). In addition, samples submitted for routine autoantibody testing from patients referred to a rheumatology clinic ( n=1078) were studied. All samples were tested for anti-Ku antibodies by QUANTA Flash Ku chemiluminescent immunoassay (research use only, Inova Diagnostics, San Diego, USA) using full length recombinant human Ku. SLE patient samples were also tested for other autoantibodies. Clinical data of anti-Ku antibody positive patients (high titres) were obtained by retrospective chart review. Results and findings In the disease cohorts, 30/305 (9.8%) SLE, 3/70 (4.3%) systemic sclerosis and 4/109 (3.7%) autoimmune myositis (AIM) patients were positive, respectively. The four positive AIM patients had an overlap myositis syndrome that included two patients with SLE. The three systemic sclerosis (SSc) positive samples had diagnoses of SSc/SLE overlap, diffuse cutaneous SSc, and early edematous phase SSc. In the control cohorts, 2/170 (1.2%) healthy individuals (all low titre), 0/30 (0.0%) (RA) and 0/17 (0.0%) infectious disease patients were positive. The area under the curve values were: 0.75 for SLE vs. controls, 0.68 for SSc vs. controls and 0.37 for AIM vs. controls. In the rheumatology clinic referral cohort, 12/1078 (1.1%) were positive for anti-Ku antibodies, nine showing low and three high titres. The diagnoses of the three high positive anti-Ku positive patients were: probable SLE, mixed connective tissue disease (MCTD) and ANA positive RA. Conclusion Anti-Ku antibodies detected by chemiluminescent immunoassay are most prevalent in SLE. When found in AIM and SSc, they were associated with overlap syndrome and early SSc.
B-cell subsets, signaling and their roles in secretion of autoantibodies
Authors: Iwata S , Tanaka Y 
Published: June 2016

B cells play a pivotal role in the pathogenesis of autoimmune diseases. In patients with systemic lupus erythematosus (SLE), the percentages of plasmablasts and IgD−CD27− double-negative memory B cells in peripheral blood are significantly increased, while IgD+CD27+ IgM memory B cells are significantly decreased compared to healthy donors. The phenotypic change is significantly associated with disease activity and concentration of autoantibodies. Treatment of B-cell depletion using rituximab results in the reconstitution of peripheral B cells in SLE patients with subsequent improvement in disease activity. Numerous studies have described abnormalities in B-cell receptor (BCR)-mediated signaling in B cells of SLE patients. Since differences in BCR signaling are considered to dictate the survival or death of naïve and memory B cells, aberrant BCR signal can lead to abnormality of B-cell subsets in SLE patients. Although Syk and Btk function as key molecules in BCR signaling, their pathological role in SLE remains unclear. We found that Syk and Btk do not only transduce activation signal through BCR, but also mediate crosstalk between BCR and Toll-like receptor (TLR) as well as BCR and JAK-STAT pathways in human B cells in vitro. In addition, pronounced Syk and Btk phosphorylation was observed in B cells of patients with active SLE compared to those of healthy individuals. The results suggest the involvement of Syk and Btk activation in abnormalities of BCR-mediated signaling and B-cell phenotypes during the pathological process of SLE and that Syk, Btk and JAK are potential therapeutic targets in SLE.
Transforming India Post: Crossing the Crossroads
Authors: Janakiraman M. 
Published: June 2016

“India Post has the potential and the resilience to effect a turn around. In the next five years, India Post should work in a technology driven and commercially competitive environment, accompanied by a paradigm shift in the mindset, to be consumer conscious and render quality service.” - Shri. Dayanidhi Maran, Honorable Minister for Communications and Information Technology, Government of India.
Offshore Outsourcing of Business Processes: Understanding IPR Implications
Authors: Goyal Preeti , Sahay Arun 
Published: June 2016

Business process outsourcing is a multi billion-dollar industry today. Intellectual property becomes important in such arrangements; as such projects may require resources and information to be shared between the client and the service provider. Underlying the availability and application of these resources such as personnel, hardware and software are intellectual property issues, more specifically patents, copyrights, trademarks and trade secrets. These intellectual properties have the potential of providing firms with sustained competitive advantage which, in turn, affect the firm performance of the business. Given the importance of IPR implications and the growing BPO industry, the paper attempts to develop a framework for understanding IPR implications for offshore outsourcing of business processes. The framework can be used by both the client and service provider for development and sharing of IPRs to their mutual advantage.
Regional Science City, Lucknow
Authors: Aithal Rajesh K. 
Published: June 2016

The footfalls at the Regional Science City, Lucknow had been stagnant for the last few years. The centre's main focus till now had been predominantly on school children. But to get the targeted growth in number of visitors, they had to start focusing on attracting general visitors. The case revolves around the challenges faced by the management in increasing the number of visitors to the centre. Questions on the best possible means of local promotions to attract more visitors to the facility are raised. The case tries to sensitise the discussants to the issues and problems faced by a not-for-profit organization. The case also raises the larger questions of application of marketing concepts to non-profits and educational context.
Marketing of Innovative New Products in Emerging Markets: A Trust Based Framework
Authors: Mukherjee Jaydeep 
Published: June 2016

There are instances of products with proven performance as well as marketing successes in one market, which do not succeed in emerging markets. Commonly used marketing techniques are not adequate in planning consumer adoption and ensuring successful commercial launch. The consumer faces some degree of irresolvable uncertainty and risk for any new product adoption decision, especially in the emerging markets where institutional consumer protection mechanisms are relatively ineffective. Thus the resolution of the uncertainty and risk is fundamental to the adoption in emerging markets. Literature suggests that one such psychological mechanism is use of “trust”, which has been explored in this paper. The current research explores how the consumers make adoption decision for innovative new product under condition of risk, uncertainty and ineffective institutional mechanisms of consumer protection. The research evidence suggests the adoption decision may be modeled as that trust based decision making process and it may provide useful choice criteria for decisions on alternative product offers. The trust based innovative new product adoption process suggests that the disposition to trust and direct experience of the consumers are primary drivers for adoption decision. For innovative products, the product performance seems to be more significant decision making criteria as compared to the marketer intention.
Circulating microRNAs as biomarkers in progressive multiple sclerosis
Authors: Vistbakka Julia , Elovaara Irina , Lehtimäki Terho , Hagman Sanna 
Published: June 2016

Background: In multiple sclerosis (MS), microRNA (miRNA) dysregulation is mostly reported in different immune cells, but less information is available on circulating miRNAs that exert strong biomarker potential due to their exceptional stability in body fluids. Objective: The aim of this study was to profile expression of circulating miRNAs in primary progressive multiple sclerosis (PPMS) and secondary progressive multiple sclerosis (SPMS) and assess their association with neurological worsening. Methods: The expressions of 84 different miRNAs were profiled in serum of 83 subjects (62 MS and 21 controls) using miScript miRNA techniques. First, they were screened on 18 PPMS and 10 controls; thereafter, 10 most aberrantly expressed miRNAs were validated on a larger cohort. Results: In comparison with controls, upregulation of miR-191-5p was found in both progressive MS subtypes, while miR-376c-3p was overexpressed only in PPMS. Additionally, upregulation of miR-128-3p and miR-24-3p was detected in PPMS when compared to controls and SPMS. Progression index correlated with miR-128-3p in PPMS and miR-375 in SPMS. Conclusion: We detected overexpression of four miRNAs that have not been previously associated with progressive forms of MS. The increased expression of circulating miR-191-5p seems to be associated with progressive forms of MS, while miR-128-3p seems to be associated mostly with PPMS.