bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome-Wide Analysis of Phosphorylated PhoP Binding to Chromosomal DNA Reveals Several Novel Features of the PhoPR-Mediated Phosphate Limitation Response in Bacillus subtilis
Authors: Salzberg Letal I. , Botella Eric , Hokamp Karsten , Antelmann Haike , Maaß Sandra , Becher Dörte , Noone David , Devine Kevin M. 
Published: February 2015

ABSTRACT

The PhoPR two-component signal transduction system controls one of three responses activated by
Bacillus subtilis
to adapt to phosphate-limiting conditions (PHO response). The response involves the production of enzymes and transporters that scavenge for phosphate in the environment and assimilate it into the cell. However, in
B. subtilis
and some other
Firmicutes
bacteria, cell wall metabolism is also part of the PHO response due to the high phosphate content of the teichoic acids attached either to peptidoglycan (wall teichoic acid) or to the cytoplasmic membrane (lipoteichoic acid). Prompted by our observation that the phosphorylated WalR (WalR∼P) response regulator binds to more chromosomal loci than are revealed by transcriptome analysis, we established the PhoP∼P bindome in phosphate-limited cells. Here, we show that PhoP∼P binds to the chromosome at 25 loci: 12 are within the promoters of previously identified PhoPR regulon genes, while 13 are newly identified. We extend the role of PhoPR in cell wall metabolism showing that PhoP∼P binds to the promoters of four cell wall-associated operons (
ggaAB
,
yqgS
,
wapA
, and
dacA
), although none show PhoPR-dependent expression under the conditions of this study. We also show that positive autoregulation of
phoPR
expression and full induction of the PHO response upon phosphate limitation require PhoP∼P binding to the 3′ end of the
phoPR
operon.

IMPORTANCE
The PhoPR two-component system controls one of three responses mounted by
B. subtilis
to adapt to phosphate limitation (PHO response). Here, establishment of the phosphorylated PhoP (PhoP∼P) bindome enhances our understanding of the PHO response in two important ways. First, PhoPR plays a more extensive role in adaptation to phosphate-limiting conditions than was deduced from transcriptome analyses. Among 13 newly identified binding sites, 4 are cell wall associated (
ggaAB
,
yqgS
,
wapA
, and
dacA
), revealing that PhoPR has an extended involvement in cell wall metabolism. Second, amplification of the PHO response must occur by a novel mechanism since positive autoregulation of
phoPR
expression requires PhoP∼P binding to the 3′ end of the operon.
Role of RNA Secondary Structure and Processing in Stability of the
nifH1
Transcript in the Cyanobacterium Anabaena variabilis
Authors: Pratte Brenda S. , Ungerer Justin , Thiel Teresa 
Published: February 2015

ABSTRACT

In the cyanobacterium
Anabaena variabilis
ATCC 29413, aerobic nitrogen fixation occurs in micro-oxic cells called heterocysts. Synthesis of nitrogenase in heterocysts requires expression of the large
nif1
gene cluster, which is primarily under the control of the promoter for the first gene,
nifB1
. Strong expression of
nifH1
requires the
nifB1
promoter but is also controlled by RNA processing, which leads to increased
nifH1
transcript stability. The processing of the primary
nifH1
transcript occurs at the base of a predicted stem-loop structure that is conserved in many heterocystous cyanobacteria. Mutations that changed the predicted secondary structure or changed the sequence of the stem-loop had detrimental effects on the amount of
nifH1
transcript, with mutations that altered or destabilized the structure having the strongest effect. Just upstream from the transcriptional processing site for
nifH1
was the promoter for a small antisense RNA,
sava4870.1
. This RNA was more strongly expressed in cells grown in the presence of fixed nitrogen and was downregulated in cells 24 h after nitrogen step down. A mutant strain lacking the promoter for
sava4870.1
showed delayed nitrogen fixation; however, that phenotype might have resulted from an effect of the mutation on the processing of the
nifH1
transcript. The
nifH1
transcript was the most abundant and most stable
nif1
transcript, while
nifD1
and
nifK1
, just downstream of
nifH1
, were present in much smaller amounts and were less stable. The
nifD1
and
nifK1
transcripts were also processed at sites just upstream of
nifD1
and
nifK1
.

IMPORTANCE
In the filamentous cyanobacterium
Anabaena variabilis
, the
nif1
cluster, encoding the primary Mo nitrogenase, functions under aerobic growth conditions in specialized cells called heterocysts that develop in response to starvation for fixed nitrogen. The large cluster comprising more than a dozen
nif1
genes is transcribed primarily from the promoter for the first gene,
nifB1
; however, this does not explain the large amount of transcript for the structural genes
nifH1
,
nifD1
, and
nifK1
, which are also under the control of the distant
nifB1
promoter. Here, we demonstrate the importance of a predicted stem-loop structure upstream of
nifH1
that controls the abundance of
nifH1
transcript through transcript processing and stabilization and show that
nifD1
and
nifK1
transcripts are also controlled by transcript processing.
Patients’ experiences of the choice of GP practice pilot, 2012/2013: a mixed methods evaluation
Authors: Tan Stefanie , Erens Bob , Wright Michael , Mays Nicholas 
Published: February 2015

ObjectivesTo investigate patients’ experiences of the choice of general practitioner (GP) practice pilot.DesignMixed-method, cross-sectional study.SettingPatients in the UK National Health Service (NHS) register with a general practice responsible for their primary medical care and practices set geographic boundaries. In 2012/2013, 43 volunteer general practices in four English NHS primary care trusts (PCTs) piloted a scheme allowing patients living outside practice boundaries to register as an out of area patient or be seen as a day patient.ParticipantsAnalysis of routine data for 1108 out of area registered patients and 250 day patients; postal survey of out of area registered (315/886, 36%) and day (64/188, 34%) patients over 18 years of age, with a UK mailing address; comparison with General Practice Patient Survey (GPPS); semistructured interviews with 24 pilot patients.ResultsPilot patients were younger and more likely to be working than non-pilot patients at the same practices and reported generally more or at least as positive experiences than patients registered at the same practices, practices in the same PCT and nationally, despite belonging to subgroups of the population who typically report poorer than average experiences. Out of area patients who joined a pilot practice did so: after moving house and not wanting to change practice (26.2%); for convenience (32.6%); as newcomers to an area who selected a practice although they lived outside its boundary (23.6%); because of dissatisfaction with their previous practice (13.9%). Day patients attended primarily on grounds of convenience (68.8%); 51.6% of the day patient visits were for acute infections, most commonly upper respiratory infections (20.4%). Sixty-six per cent of day patients received a prescription during their visit.ConclusionsThough the 12-month pilot was too brief to identify all costs and benefits, the scheme provided a positive experience for participating patients and practices.
Zonal T2* and T1Gdassessment of knee joint cartilage in various histological grades of cartilage degeneration: an observational in vitro study
Authors: Bittersohl Bernd , Hosalkar Harish S , Miese Falk R , Schibensky Jonas , König Dietmar P , Herten Monika , Antoch Gerald , Krauspe Rüdiger , Zilkens Christoph 
Published: February 2015

ObjectivesAccurate assessment of cartilage status is increasingly becoming important to clinicians for offering joint preservation surgeries versus joint replacements. The goal of this study was to evaluate the validity of three-dimensional (3D), gradient-echo (GRE)-based T2* and T1Gdmapping for the assessment of various histological severities of degeneration in knee joint cartilage with potential implications for clinical management.MethodsMRI and histological assessment were conducted in 36 ex vivo lateral femoral condyle specimens. The MRI protocol included a 3D GRE multiecho data image combination sequence in order to assess the T2* decay, a 3D double-echo steady-state sequence for assessment of cartilage morphology, and a dual flip angle 3D GRE sequence with volumetric interpolated breathhold examination for the T1Gdassessment. The histological sample analysis was performed according to the Mankin system. The data were then analysed statistically and correlated.ResultsWe observed a significant decrease in the T2* and T1Gdvalues with increasing grades of cartilage degeneration (p<0.001) and a moderate correlation between T2* (r=0.514)/T1Gd(r=0.556) and the histological grading of cartilage degeneration (p<0.001). In addition, we noted a zonal variation in the T2* and T1Gdvalues reflecting characteristic zonal differences in the biochemical composition of hyaline cartilage.ConclusionsThis study outlines the potential of GRE-based T2* and T1Gdmapping to identify various grades of cartilage damage. Early changes in specific zones may assist clinicians in identifying methods of early intervention involving the targeted joint preservation approach versus moving forward with unicompartmental, bicompartmental or tricompartmental joint replacement procedures.Trial registration numberDRKS00000729.
Effectiveness of a multifactorial intervention on preventing development of frailty in pre-frail older people: study protocol for a randomised controlled trial
Authors: Fairhall Nicola , Kurrle Susan E , Sherrington Catherine , Lord Stephen R , Lockwood Keri , John Beatrice , Monaghan Noeline , Howard Kirsten , Cameron Ian D 
Published: February 2015

IntroductionFrailty is a major concern due to its costly and widespread consequences, yet evidence of effective interventions to delay or reduce frailty is lacking. Our previous study found that a multifactorial intervention was feasible and effective in reducing frailty in older people who were already frail. Identifying and treating people in the pre-frail state may be an effective means to prevent or delay frailty. This study describes a randomised controlled trial that aims to evaluate the effectiveness of a multifactorial intervention on development of frailty in older people who are pre-frail.Methods and analysisA single centre randomised controlled trial with concealed allocation, assessor blinding and intention-to-treat analysis. Two hundred and thirty people aged above 70 who meet the Cardiovascular Health Study frailty criteria for pre-frailty, reside in the community and are without severe cognitive impairment will be recruited. Participants will be randomised to receive a multifactorial intervention or usual care. The intervention group will receive a 12-month interdisciplinary intervention targeting identified characteristics of frailty and problems identified during geriatric assessment. Participants will be followed for a 12-month period. Primary outcome measures will be degree of frailty measured by the number of Cardiovascular Health Study frailty criteria present, and mobility measured with the Short Physical Performance Battery. Secondary outcomes will include measures of mobility, mood and use of health and community services.Ethics and disseminationThe study was approved by the Northern Sydney Local Health District Health Research Ethics Committee (1207-213M). The findings will be disseminated through scientific and professional conferences, and in peer-reviewed journals.Trial registration numberAustralian New Zealand Clinical Trials Registry: ACTRN12613000043730.
Promoting vision and hearing aids use in an intensive care unit
Authors: Zhou Qiaoling , Faure Walker Nicholas 
Published: February 2015

AbstractVision and hearing impairments have long been recognised as modifiable risk factors for delirium.[1,2,3] Delirium in critically ill patients is a frequent complication (reported as high as 60% to 80% of intensive care patients), and is associated with a three-fold increase in mortality and prolonged hospital stay.[1] Guidelines by the UK Clinical Pharmacy Association recommend minimising risk factors to prevent delirium, rather than to treat it with pharmacological agents which may themselves cause delirium.[4] To address risk factors is a measure of multi-system management, such as sleep-wake cycle correction, orientation and use of vision and hearing aids, etc.[5]We designed an audit to survey the prevalence and availability of vision and hearing aids use in the intensive care unit (ICU) of one university hospital. The baseline data demonstrated a high level of prevalence and low level of availability of vision /hearing aid use.We implemented changes to the ICU Innovian assessment system, which serves to remind nursing staff performing daily checks on delirium reduction measures. This has improved practice in promoting vision and hearing aids use in ICU as shown by re-audit at six month. Further amendments to the Innovian risk assessments have increased the rate of assessment to 100% and vision aid use to near 100%.
Training veterinarians and agricultural advisers on a novel tool for tail biting prevention
Authors: vom Brocke A. L. , Madey D. P. , Gauly M. , Schrader L. , Dippel S. 
Published: February 2015

IntroductionMany health and welfare problems in modern livestock production are multifactorial problems which require innovative solutions, such as novel risk assessment and management tools. However, the best way to distribute such novel ‐ and usually complex ‐ tools to the key applicants still has to be discussed.Materials and methodsThis paper shares experiences from distributing a novel tail biting prevention tool (‘SchwIP’) to 115 farm advisers and 19 veterinarians in 23 one‐day workshops. Participants gave written and oral feedback at the end of the workshops, which was later analysed together with the number of farms they had visited after the workshops. Workshop groups were categorised into groups showing (a) HIGH, (b) INTermediate or (c) LOW levels of antagonism against SchwIP or parts of it during workshop discussions.ResultsGroup types did not significantly differ in their evaluation of knowledge transfer. However, HIGH group members evaluated the on‐farm usability of the tool significantly lower in the workshop feedback and tended to visit fewer farms.ConclusionsAs antagonistic discussion can influence workshop output, future workshop leaders should strive for basic communication training as well as some group leadership experience before setting up and leading workshops.
Influence of dog appeasing pheromone (DAP) on dogs housed in a long‐term kennelling facility
Authors: Grigg E. K. , Piehler M. 
Published: February 2015

IntroductionKennel facilities are commonly acknowledged as a stressful environment for many domestic dogs (Canis familiaris). One therapeutic measure used to reduce anxiety in dogs is dog appeasing pheromone (DAP), which has been found effective in reducing stress‐related behaviours in a number of contexts.Aims and ObjectivesA pilot study was conducted to assess whether DAP would reduce frequency of stress‐related behaviours in a group of eight dogs housed for teaching purposes in a long‐term kennelling facility.Materials and MethodsUsing video analysis, proportion of time spent in stress‐related behaviours for six dogs fitted with DAP collars, versus two control dogs (without collars), was compared for the time before and during DAP exposure.ResultsNo significant differences were found either in the proportion of time spent in stress‐related behaviours in the baseline versus treatment periods or between the collared and control dogs in the change in proportion of time they spent in any of the focal behaviours in the baseline versus treatment periods.ConclusionsPossible reasons for these findings include an actual lack of effect of DAP on dogs housed in this long‐term kennelling facility, an apparent lack of effect due to small sample size in this pilot study and high behavioural variation among individual dogs. Despite lack of a demonstrated effect of the DAP collars on these dogs, attention brought by this study to the behavioural issues seen in some of the dogs did have a positive impact, as it contributed to the development of an active, coordinated behavioural wellness and enrichment programme for the colony.
Chemostratigraphy and magnetic susceptibility of the Late Devonian Frasnian–Famennian transition in western Canada and southern China: implications for carbon and nutrient cycling and mass extinction
Authors: Whalen Michael T. , Śliwiński Maciej G. , Payne Joshua H. , Day James E. , Chen Daizhao , Da Silva Anne-Christine 
Published: February 2015

Abstract

We investigate the Late Devonian Frasnian–Famennian extinction interval in western Alberta and south China to shed light on the palaeoecological and palaeoceanographic conditions that characterize this biotic crisis. Both the Lower and Upper Kellwasser events are documented in western Canada. Only the Upper Kellwasser event has been evaluated in south China. Our multiproxy geochemical approach reveals that these events are characterized by positive δ
13
C and δ
15
N excursions and increasing magnetic susceptibility (Canada/China) and increases in detrital (Al, Si, Ti, Zr), productivity (Cu, Ni, Zn) and redox (Mo, U, V) elemental proxies (Canada). We interpret these trends as part of a systemic palaeoecological shift associated with the development of widespread terrestrial forests and their alteration of chemical–mechanical weathering patterns. Increase in detrital proxies is thus interpreted as resulting from pedogenically driven weathering on the continents that nutrified epeiric and continental margin seas. High biological productivity led to eutrophication and development of suboxic to anoxic conditions during both events and probably euxinic conditions during the Upper Kellwasser event in western Canada. Positive δ
13
C excursions are the telltale signature of excessive carbon burial, while redox proxies and δ
15
N records indicate suboxic–anoxic denitrifying conditions.
The role of local societies in early modern geotourism: a case study of the Chester Society of Natural Science and the Woolhope Naturalists’ Field Club
Authors: Burek Cynthia V. , Hose Thomas A. 
Published: February 2015

Abstract
Local voluntary natural science societies played an important role in the development of early modern geotourism. This chapter explores the development of field, especially geological, excursions and their popularity in two local natural science societies – The Chester Society of Natural Science and the Woolhope Naturalists’ Field Club – from the 1850s to the 1950s. Both societies were established in the borderlands between England and Wales and had a strong emphasis on local and regional scientific studies. They exemplify broader trends in public engagement in the natural sciences and associated fieldwork consequent upon the British socio-political environment. Further, they draw out comparisons between the attitudes of society to excursions and scientific fieldwork, as well as involvement by social status and gender.
Improving Coverage of Test Cases Generated by Symbolic PathFinder for Programs with Loops
Authors: Kersten Rody , Person Suzette , Rungta Neha , Tkachuk Oksana 
Published: February 2015

Symbolic execution is a program analysis technique that is used for many purposes, one of which is test case generation. For loop-free programs, this generates a test set that achieves path coverage. Program loops, however, imply exponential growth of the number of paths in the best case and non-termination in the worst case. In practice, the number of loop unwindings needs to be bounded for analysis.
We consider symbolic execution in the context of the tool Symbolic Pathfinder. This tool extends the Java Pathfinder model-checker and relies on its bounded state-space exploration for termination. We present an implementation of k-bounded loop un- winding, which increases the amount of user-control over the symbolic execution of loops.
Bounded unwinding can be viewed as a naive way to prune paths through loops. When using symbolic execution for test case generation, branch coverage will likely be lost when paths are naively pruned. In order to improve coverage of branches within a loop body, we present a technique that semi-automatically concretizes variables used in a loop. The basic technique is limited and we therefore present annotations to manually steer symbolic execution towards certain branches, as well as ideas on how the technique can be extended to be more widely applicable.
Adapting a Drug Screening Platform to Discover Associations of Molecular Targeted Radiosensitizers with Genomic Biomarkers
Authors: Liu Qi , Wang Meng , Kern Ashley M. , Khaled Saman , Han Jing , Yeap Beow Y. , Hong Theodore S. , Settleman Jeff , Benes Cyril H. , Held Kathryn D. , Efstathiou Jason A. , Willers Henning 
Published: February 2015

Abstract
Large collections of annotated cancer cell lines are powerful tools for precisely matching targeted drugs with genomic alterations that can be tested as biomarkers in the clinic. Whether these screening platforms, which utilize short-term cell survival to assess drug responses, can be applied to precision radiation medicine is not established. To this end, 32 cancer cell lines were screened using 18 targeted therapeutic agents with known or putative radiosensitizing properties (227 combinations). The cell number remaining after drug exposure with or without radiation was assessed by nonclonogenic assays. We derived short-term radiosensitization factors (SRF2Gy) and calculated clonogenic survival assay–based dose enhancement factors (DEFSF0.1). Radiosensitization was characterized by SRF2Gy values of mostly ∼1.05 to 1.2 and significantly correlated with drug-induced changes in apoptosis and senescence frequencies. SRF2Gy was significantly correlated with DEFSF0.1, with a respective sensitivity and specificity of 91.7% and 81.5% for a 3-day endpoint, and 82.8% and 84.2% for a robotic 5-day assay. KRAS mutations (codons 12/13) were found to be a biomarker of radiosensitization by midostaurin in lung cancer, which was pronounced under conditions that enriched for stem cell–like cells. In conclusion, although short-term proliferation/survival assays cannot replace the gold-standard clonogenic survival assay for measuring cellular radiosensitivity, they capture with high accuracy the relative change in radiosensitivity that is caused by a radiosensitzing targeted agent.
Implications: This study supports a paradigm shift regarding the utility of short-term assays for precision radiation medicine, which should facilitate the identification of genomic biomarkers to guide the testing of novel drug/radiation combinations. Mol Cancer Res; 13(4); 713–20. ©2015 AACR.
Where Demons Fear to Tread
Authors: Johnson Adam J. 
Published: February 2015

This essay consolidates, organizes, and contributes to the reflections of theologians throughout the history of the church concerning the inestimable benefits received by the un-fallen angels from Christ’s atoning death and resurrection, that we might better understand how the blood of Christ reconciles all things in heaven to God (Col. 1:20). Specifically, I explore five different ways in which the un-fallen angels are affected by the saving work of Christ, both in terms of salvation from the effects of sin, and salvation as the fulfillment of their being, while briefly considering the implications thereof for the church.