bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modeling the Transcriptional Regulatory Network That Controls the Early Hypoxic Response in Candida albicans
Authors: Sellam Adnane , van het Hoog Marco , Tebbji Faiza , Beaurepaire Cécile , Whiteway Malcolm , Nantel André 
Published: March 2014

ABSTRACT

We determined the changes in transcriptional profiles that occur in the first hour following the transfer of
Candida albicans
to hypoxic growth conditions. The impressive speed of this response is not compatible with current models of fungal adaptation to hypoxia that depend on the depletion of sterol and heme. Functional analysis using Gene Set Enrichment Analysis (GSEA) identified the Sit4 phosphatase, Ccr4 mRNA deacetylase, and Sko1 transcription factor (TF) as potential regulators of the early hypoxic response. Cells mutated in these and other regulators exhibit a delay in their transcriptional responses to hypoxia. Promoter occupancy data for 29 TFs were combined with the transcriptional profiles of 3,111
in vivo
target genes in a Network Component Analysis (NCA) to produce a model of the dynamic and highly interconnected TF network that controls this process. With data from the TF network obtained from a variety of sources, we generated an edge and node model that was capable of separating many of the hypoxia-upregulated and -downregulated genes. Upregulated genes are centered on Tye7, Upc2, and Mrr1, which are associated with many of the gene promoters that exhibit the strongest activations. The connectivity of the model illustrates the high redundancy of this response system and the challenges that lie in determining the individual contributions of specific TFs. Finally, treating cells with an inhibitor of the oxidative phosphorylation chain mimics most of the early hypoxic profile, which suggests that this response may be initiated by a drop in ATP production.
Common Requirement for the Relaxosome of Plasmid R1 in Multiple Activities of the Conjugative Type IV Secretion System
Authors: Lang Silvia , Gruber Christian J. , Raffl Sandra , Reisner Andreas , Zechner Ellen L. 
Published: March 2014

ABSTRACT

Macromolecular transport by bacterial type IV secretion systems involves regulated uptake of (nucleo)protein complexes by the cell envelope-spanning transport channel. A coupling protein receptor is believed to recognize the specific proteins destined for transfer, but the steps initiating their translocation remain unknown. Here, we investigate the contribution of a complex of transfer initiation proteins, the relaxosome, of plasmid R1 to translocation of competing transferable substrates from mobilizable plasmids ColE1 and CloDF13 or the bacteriophage R17. We found that not only does the R1 translocation machinery engage the R1 relaxosome during conjugative self-transfer and during infection by R17 phage but it is also activated by its cognate relaxosome to mediate the export of an alternative plasmid. Transporter activity was optimized by the R1 relaxosome even when this complex itself could not be transferred, i.e., when the N-terminal activation domain (amino acids 1 to 992 [N
1-992
]) of TraI was present without the C-terminal conjugative helicase domain. We propose that the functional dependence of the transfer machinery on the R1 relaxosome for initiating translocation ensures that dissemination of heterologous plasmids does not occur at the expense of self-transfer.
Streptococcus mutans NADH Oxidase Lies at the Intersection of Overlapping Regulons Controlled by Oxygen and NAD
+
Levels
Authors: Baker J. L. , Derr A. M. , Karuppaiah K. , MacGilvray M. E. , Kajfasz J. K. , Faustoferri R. C. , Rivera-Ramos I. , Bitoun J. P. , Lemos J. A. , Wen Z. T. , Quivey R. G. 
Published: March 2014

ABSTRACT

NADH oxidase (Nox, encoded by
nox
) is a flavin-containing enzyme used by the oral pathogen
Streptococcus mutans
to reduce diatomic oxygen to water while oxidizing NADH to NAD
+
. The critical nature of Nox is 2-fold: it serves to regenerate NAD
+
, a carbon cycle metabolite, and to reduce intracellular oxygen, preventing formation of destructive reactive oxygen species (ROS). As oxygen and NAD
+
have been shown to modulate the activity of the global transcription factors Spx and Rex, respectively, Nox is potentially poised at a critical junction of two stress regulons. In this study, microarray data showed that either addition of oxygen or loss of
nox
resulted in altered expression of genes involved in energy metabolism and transport and the upregulation of genes encoding ROS-metabolizing enzymes. Loss of
nox
also resulted in upregulation of several genes encoding transcription factors and signaling molecules, including the redox-sensing regulator gene
rex
. Characterization of the
nox
promoter revealed that
nox
was regulated by oxygen, through SpxA, and by Rex. These data suggest a regulatory loop in which the roles of
nox
in reduction of oxygen and regeneration of NAD
+
affect the activity levels of Spx and Rex, respectively, and their regulons, which control several genes, including
nox
, crucial to growth of
S. mutans
under conditions of oxidative stress.
Turning the tide: national policy approaches to increasing physical activity in seven European countries
Authors: Bull Fiona , Milton Karen , Kahlmeier Sonja , Arlotti Alberto , Juričan Andrea Backović , Belander Olov , Martin Brian , Martin-Diener Eva , Marques Ana , Mota Jorge , Vasankari Tommi , Vlasveld Anita 
Published: March 2014

BackgroundPhysical inactivity is one of the four leading behavioural risk factors for non-communicable disease (NCD). Like tobacco control, increasing levels of health-enhancing physical activity (HEPA) will require a national policy framework providing direction and a clear set of actions. Despite frequent calls, there has been insufficient progress on policy development in the majority of countries around the world. This study sought and summarised national HEPA policy in seven European countries (Finland, Italy, the Netherlands, Norway, Portugal, Slovenia and Switzerland).MethodsData collection used a policy audit tool (PAT), a 27-item instrument structured into four sections.ResultsAll countries reported some legislation or policy across the sectors of education, sport and health. Only some countries reported supportive policy in the transport and environment sectors. Five countries reported a stand-alone HEPA policy and six countries reported national recommendations. HEPA prevalence targets varied in magnitude and specificity and the presence of other relevant goals from different sectors highlighted the opportunity for joint action. Evaluation and the use of scientific evidence were endorsed but described as weak in practice. Only two countries reported a national multisector coordinating committee and most countries reported challenges with partnerships on different levels of policy implementation.ConclusionsBringing together the key components for success within a national HEPA policy framework is not simple. This in-depth policy audit and country comparison highlighted similarities and differences and revealed new opportunities for consideration by other countries. These examples can inform countries within and beyond Europe and guide the development of national HEPA policy within the NCD prevention agenda.
Pharmacy study of natural health product adverse reactions (SONAR): a cross-sectional study using active surveillance in community pharmacies to detect adverse events associated with natural health products and assess causality
Authors: Necyk Candace , Tsuyuki Ross T , Boon Heather , Foster Brian C , LeGatt Don , Cembrowski George , Murty Mano , Barnes Joanne , Charrois Theresa L , Arnason John T , Ware Mark A , Rosychuk Rhonda J , Vohra Sunita 
Published: March 2014

ObjectivesTo investigate the rates and causality of adverse event(s) (AE) associated with natural health product (NHP) use, prescription drug use and concurrent NHP-drug use through active surveillance in community pharmacies.DesignCross-sectional study of screened patients.Setting10 community pharmacies across Alberta and British Columbia, Canada from 14 January to 30 July 2011.ParticipantsThe participating pharmacy staff screened consecutive patients, or agents of patients, who were dropping or picking up prescription medications.Primary outcome measuresPatients were screened to determine the proportions of them using prescription drugs and/or NHPs, as well as their respective AE rates. All AEs reported by the screened patients who took a NHP, consented to, and were available for, a detailed telephone interview (14%) were adjudicated fully to assess for causality.ResultsOver a total of 105 pharmacy weeks and 1118 patients screened, 410 patients reported taking prescription drugs only (36.7%; 95% CI 33.9% to 39.5%), 37 reported taking NHPs only (3.3%; 95% CI 2.4% to 4.5%) and 657 reported taking prescription drugs and NHPs concurrently (58.8%; 95% CI 55.9% to 61.6%). In total, 54 patients reported an AE, representing 1.2% (95% CI 0.51% to 2.9%), 2.7% (95% CI 0.4% to 16.9%) and 7.3% (95% CI 5.6% to 9.6%) of each population, respectively. Compared with patients who reported using prescription drugs, the patients who reported using prescription drugs and NHPs concurrently were 6.4 times more likely to experience an AE (OR; 95% CI 2.52 to 16.17; p<0.001). Combined with data from Ontario, Canada, a national proportion was calculated, which found that 45.4% (95% CI 43.8% to 47.0%) of Canadians who visit community pharmacies take NHPs and prescription drugs concurrently, and of those, 7.4% (95% CI 6.3% to 8.8%) report an AE.ConclusionsA substantial proportion of community pharmacy patients use prescription drugs and NHPs concurrently; these patients are at a greater risk of experiencing an AE. Active surveillance provides a means of detecting such AEs and collecting high-quality data on which causality assessment can be based.
Association of polypharmacy with fall-related fractures in older Taiwanese people: age- and gender-specific analyses
Authors: Pan Hsueh-Hsing , Li Chung-Yi , Chen Tzeng-Ji , Su Tung-Ping , Wang Kwua-Yun 
Published: March 2014

ObjectiveTo elucidate the associations between polypharmacy and age- and gender-specific risks of admission for fall-related fractures.DesignNested case–control study.SettingThis analysis was randomly selected from all elderly beneficiaries in 2007–2008, and represents some 30% of the whole older insurers using Taiwan's National Health Insurance Research Database.ParticipantsWe identified 5933 cases newly admitted for fall-related fractures during 2007–2008, and 29 665 random controls free from fracture.Primary and secondary outcome measuresPolypharmacy was defined as the use of fall-related drugs of four or more categories of medications and prescribed related to fall within a 1-year period. Logistic regression models were employed to estimate the ORs and related 95% CIs. The interaction of polypharmacy with age and sex was assessed separately.ResultsCompared with those who consumed no category of medication, older people who consumed 1, 2, 3 and ≥4 categories of medications were all at significantly increased odds of developing fall-related fractures, with a significant dose–gradient pattern (β=0.7953; p for trend <0.0001). There were significant interactions between polypharmacy and age, but no significant interactions between polypharmacy and gender. The dose–gradient relationship between number of medications category and risk of fall-related fractures was more obvious in women than in men (β=0.1962 vs β=0.1873). Additionally, it was most evident in older people aged 75–84 years (β=0.2338).ConclusionsThis population-based study in Taiwan confirms the link between polypharmacy and increased risk of fall-related fractures in older people; and highlights that elderly women and older people aged 75–84 years will be the targeted participants for further prevention from fall-related fractures caused by polypharmacy.
The impact of funding deadlines on personal workloads, stress and family relationships: a qualitative study of Australian researchers
Authors: Herbert Danielle L , Coveney John , Clarke Philip , Graves Nicholas , Barnett Adrian G 
Published: March 2014

ObjectiveTo examine the impact of applying for funding on personal workloads, stress and family relationships.DesignQualitative study of researchers preparing grant proposals.SettingWeb-based survey on applying for the annual National Health and Medical Research Council (NHMRC) Project Grant scheme.ParticipantsAustralian researchers (n=215).ResultsAlmost all agreed that preparing their proposals always took top priority over other work (97%) and personal (87%) commitments. Almost all researchers agreed that they became stressed by the workload (93%) and restricted their holidays during the grant writing season (88%). Most researchers agreed that they submitted proposals because chance is involved in being successful (75%), due to performance requirements at their institution (60%) and pressure from their colleagues to submit proposals (53%). Almost all researchers supported changes to the current processes to submit proposals (95%) and peer review (90%). Most researchers (59%) provided extensive comments on the impact of writing proposals on their work life and home life. Six major work life themes were: (1) top priority; (2) career development; (3) stress at work; (4) benefits at work; (5) time spent at work and (6) pressure from colleagues. Six major home life themes were: (1) restricting family holidays; (2) time spent on work at home; (3) impact on children; (4) stress at home; (5) impact on family and friends and (6) impact on partner. Additional impacts on the mental health and well-being of researchers were identified.ConclusionsThe process of preparing grant proposals for a single annual deadline is stressful, time consuming and conflicts with family responsibilities. The timing of the funding cycle could be shifted to minimise applicant burden, give Australian researchers more time to work on actual research and to be with their families.
Family carer perspectives of acute hospital care following a diagnosis of motor neuron disease: a qualitative secondary analysis
Authors: O'Brien Mary R , Preston Harriet 
Published: March 2014

ObjectivesThe multifaceted nature of the problems faced by someone with motor neuron disease requires a knowledgeable multidisciplinary team approach. Where available, generally, such services are only provided on an outpatient basis, meaning that hospitalised patients are frequently admitted to non-specialist wards where understanding of their needs is limited. Little is known regarding the inpatient care received by patients. Our objective was to address this by exploring the experience of hospitalisation following a diagnosis of motor neuron disease from the perspective of family carers of those diagnosed with the illness.MethodThis was a qualitative secondary analysis of pre-existing data from two previously published, separately conducted, qualitative studies. The study involved interview data from 18 bereaved carers and 3 current carers of family members diagnosed with motor neuron disease in Northwest England.ResultsThe findings reveal dissatisfaction with the inpatient care received, which impacted negatively not only on patient and carer enthusiasm for future hospital admissions but also on carer bereavement.ConclusionsPatients with motor neuron disease have specialist needs that are not always met during hospital admission, particularly to non-specialist units. The inpatient care provided for these patients must be improved as must the knowledge and understanding of the illness among healthcare professionals who treat them.
Has the economic crisis widened the intraurban socioeconomic inequalities in mortality? The case of Barcelona, Spain
Authors: Maynou Laia , Saez Marc , Lopez-Casasnovas Guillem 
Published: March 2014

BackgroundThere is considerable evidence demonstrating socioeconomic inequalities in mortality, some of which focuses on intraurban inequalities. However, all the studies assume that the spatial variation of inequalities is stable over the time. We challenge this assumption and propose two hypotheses: (i) have spatial variations in socioeconomic inequalities in mortality at an intraurban level changed over time? and (ii) as a result of the economic crisis, has the gap between such disparities widened? In this paper, our objective is to assess the effect of the economic recession on the spatio-temporal variation of socioeconomic inequalities in mortality in Barcelona (Catalonia, Spain).MethodsWe used a spatio-temporal ecological design to analyse mortality inequalities at small area level in Barcelona. Mortality data and socioeconomic indicators correspond to the years 2005 and 2008–2011. We specified spatio-temporal ecological mixed regressions for both men and women using two indicators, neighbourhood and year. We allowed the coefficients of the socioeconomic variables to differ according to the levels and explicitly took into account spatio-temporal adjustment.ResultsFor men and women both absolute and, above all, relative risks for mortality have increased since 2009. In relative terms, this means that the risk of dying has increased much more in the most economically deprived neighbourhoods than in the more affluent ones.ConclusionsAlthough the geographical pattern in relative risks for mortality in neighbourhoods in Barcelona remained very stable between 2005 and 2011, socioeconomic inequalities in mortality at an intraurban level have surged since 2009.
Long-term cardiovascular consequences of Rose angina at age 20–54 years: 29-years’ follow-up of the Tromsø Study
Authors: Graff-Iversen Sidsel , Wilsgaard Tom , Mathiesen Ellisiv B , Njølstad Inger , Løchen Maja-Lisa 
Published: April 2014

BackgroundThe Rose Angina Questionnaire (RAQ) was constructed in the 1960s for assessing the population burden of angina. Studies have found that screening positivity by RAQ conferred an elevated risk of coronary heart disease (CHD). It is, however, not clear to what extent Rose angina represents early CHD in relatively young adults who are free of known CHD. If representing CHD, Rose angina is expected to carry prognostic information in addition to the risk conferred by other risk factors.MethodsThe Tromsø Study is a population-based cohort study in Northern Norway. All men aged 20–54 years (n=8238) and women aged 20–49 years (n=8001), free of known cardiovascular disease (CVD), who participated in a survey 1979–1980, were followed throughout 2010 for incident myocardial infarction (MI), and for incident MI or stroke used as proxy for incident CVD. HRs were estimated using a Cox proportional hazard regression model.ResultsIn age-adjusted analyses, Rose angina predicted MI and CVD in both sexes. The excess risk was substantially accounted for by CVD risk factors, leaving no significantly elevated MI risk above the risk explained by these factors (adjusted HR 1.31; 95% CI 0.95 to 1.80 in men, HR 1.20; 95% CI 0.69 to 2.10 in women). A similar pattern was seen for CVD (adjusted HR 1.16; 95% CI 0.87 to 1.55 in men and 1.30; 95% CI 0.82 to 2.06 in women).ConclusionsRose angina predicted MI and CVD in a 29-years’ follow-up of a relatively young population. Established CVD risk factors were important mediators.
Dietary Flavonoid Intake and Thyroid Cancer Risk in the NIH–AARP Diet and Health Study
Authors: Xiao Qian , Park Yikyung , Hollenbeck Albert R. , Kitahara Cari M. 
Published: April 2014

Abstract
Experimental studies suggested that flavonoids may influence thyroid carcinogenesis, but epidemiologic evidence is sparse. No study has examined different classes of flavonoids in relation to thyroid cancer risk. Using data from the NIH–AARP Diet and Health Study, which enrolled 491,840 U.S. men and women, ages 50 to 71 years at baseline, we prospectively examined the risk of thyroid cancer in relation to dietary intakes of catechins, flavanones, flavonols, anthocyanidins, flavones, isoflavones, and total flavonoids. Dietary intakes were assessed using a food frequency questionnaire. Cancer cases were ascertained by linkage to state cancer registries. Multivariable-adjusted Cox proportional hazard models were used to estimate HRs and 95% confidence intervals (CI). During follow up (mean = 9 years), we identified 586 thyroid cancer cases. Thyroid cancer risk was inversely associated with dietary flavan-3-ols [HRQ5 vs. Q1 (95% CI): 0.70 (0.55, 0.91), PTrend = 0.03], but positively associated with flavanones [HRQ5 vs. Q1 (95% CI): 1.50 (1.14, 1.96), PTrend = 0.004]. Other classes of flavonoids and total flavonoids were not associated with thyroid cancer risk. Similar associations were found for papillary thyroid cancer. Our findings suggest that dietary intake of different classes of dietary flavonoids may have divergent effects on thyroid cancer risk. More studies are needed to clarify a role of flavonoids in thyroid cancer development. Results from our study suggest a potential nutritional etiology of thyroid cancer. Cancer Epidemiol Biomarkers Prev; 23(6); 1102–8. ©2014 AACR.
Molecular Pathways: Preclinical Models and Clinical Trials with Metformin in Breast Cancer
Authors: Thompson Alastair M. 
Published: March 2014

Abstract
Metformin, an oral biguanide widely used to treat diabetes, has considerable potential and is in clinical trials as an experimental preventive or therapeutic agent for a range of cancers. Direct actions targeting cellular pathways, particularly via AMP-activated protein kinase and through inhibiting mitochondrial ATP synthesis, or systemic mechanisms involving insulin and insulin-like growth factors have been much studied in vitro and in preclinical models. Epidemiologic and retrospective studies also provide clinical evidence in support of metformin as an antitumor agent. Preoperative window-of-opportunity trials confirm the safety of metformin in women with primary breast cancer, and demonstrate reduction in tumor cell proliferation and complex pathways of gene suppression or overexpression attributable to metformin. Confirmation of insulin-mediated effects, independent of body mass index, also supports the potential benefit of adjuvant metformin therapy. Neoadjuvant, adjuvant, and advanced disease trials combining metformin with established anticancer agents are under way or proposed. Companion biomarker studies will utilize in vitro and preclinical understanding of the relevant molecular pathways to, in future, refine patient and tumor selection for metformin therapy. Clin Cancer Res; 20(10); 2508–15. ©2014 AACR.