bluuebunny/crossref_metadata_2025_split huggingface dataset:
Derivative processes for modelling metabolic fluxes
Authors: Žurauskienė Justina , Kirk Paul , Thorne Thomas , Pinney John , Stumpf Michael 
Published: February 2014

Abstract
Motivation: One of the challenging questions in modelling biological systems is to characterize the functional forms of the processes that control and orchestrate molecular and cellular phenotypes. Recently proposed methods for the analysis of metabolic pathways, for example, dynamic flux estimation, can only provide estimates of the underlying fluxes at discrete time points but fail to capture the complete temporal behaviour. To describe the dynamic variation of the fluxes, we additionally require the assumption of specific functional forms that can capture the temporal behaviour. However, it also remains unclear how to address the noise which might be present in experimentally measured metabolite concentrations.
Results: Here we propose a novel approach to modelling metabolic fluxes: derivative processes that are based on multiple-output Gaussian processes (MGPs), which are a flexible non-parametric Bayesian modelling technique. The main advantages that follow from MGPs approach include the natural non-parametric representation of the fluxes and ability to impute the missing data in between the measurements. Our derivative process approach allows us to model changes in metabolite derivative concentrations and to characterize the temporal behaviour of metabolic fluxes from time course data. Because the derivative of a Gaussian process is itself a Gaussian process, we can readily link metabolite concentrations to metabolic fluxes and vice versa. Here we discuss how this can be implemented in an MGP framework and illustrate its application to simple models, including nitrogen metabolism in Escherichia coli.
Availability and implementation: R code is available from the authors upon request.
Contact: j.norkunaite@imperial.ac.uk; m.stumpf@imperial.ac.uk
Supplementary information: Supplementary data are available at Bioinformatics online.
Accurate computational prediction of the transcribed strand of CRISPR non-coding RNAs
Authors: Biswas Ambarish , Fineran Peter C. , Brown Chris M. 
Published: February 2014

Abstract
Motivation: CRISPR RNAs (crRNAs) are a type of small non-coding RNA that form a key part of an acquired immune system in prokaryotes. Specific prediction methods find crRNA-encoding loci in nearly half of sequenced bacterial, and three quarters of archaeal, species. These Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) arrays consist of repeat elements alternating with specific spacers. Generally one strand is transcribed, producing long pre-crRNAs, which are processed to short crRNAs that base pair with invading nucleic acids to facilitate their destruction. No current software for the discovery of CRISPR loci predicts the direction of crRNA transcription.
Results: We have developed an algorithm that accurately predicts the strand of the resulting crRNAs. The method uses as input CRISPR repeat predictions. CRISPRDirection uses parameters that are calculated from the CRISPR repeat predictions and flanking sequences, which are combined by weighted voting. The prediction may use prior coding sequence annotation but this is not required. CRISPRDirection correctly predicted the orientation of 94% of a reference set of arrays.
Availability and implementation: The Perl source code is freely available from http://bioanalysis.otago.ac.nz/CRISPRDirection .
Contact: chris.brown@otago.ac.nz
Supplementary information: Supplementary data are available at Bioinformatics online.
TRIAD IV: Nationwide Survey of Medical Students’ Understanding of Living Wills and DNR Orders
Authors: Mirarchi Ferdinando L. , Ray Matthew , Cooney Timothy 
Published: February 2014

Introduction
Living wills are a form of advance directives that help to protect patient autonomy. They are frequently encountered in the conduct of medicine. Because of their impact on care, it is important to understand the adequacy of current medical school training in the preparation of physicians to interpret these directives.

Methods
Between April and August 2011 of third and fourth year medical students participated in an internet survey involving the interpretation of living wills. The survey presented a standard living will as a “stand-alone,” a standard living will with the addition an emergent clinical scenario and then variations of the standard living will that included a code status designation (“DNR,” “Full Code,” or “Comfort Care”). For each version/ scenario, respondents were asked to assign a code status and choose interventions based on the cases presented.

Results
Four hundred twenty-five students from medical schools throughout the country responded. The majority indicated they had received some form of advance directive training and understood the concept of code status and the term “DNR.” Based on a stand-alone document, 15% of respondents correctly denoted “full code” as the appropriate code status; adding a clinical scenario yielded negligible improvement. When a code designation was added to the living will, correct code status responses ranged from 68% to 93%, whereas correct treatment decisions ranged from 18% to 78%. Previous training in advance directives had no impact on these results.

Conclusion
Our data indicate that the majority of students failed to understand the key elements of a living will; adding a code status designations improved correct responses with the exception of the term DNR. Misunderstanding of advance directives is a nationwide problem and jeopardizes patient safety. Medical School ethics curricula need to be improved to ensure competency with respect to understanding advance directives.
Integrating Data From the UK National Reporting and Learning System With Work Domain Analysis to Understand Patient Safety Incidents in Community Pharmacy
Authors: Phipps Denham L. , Tam W. Vanessa , Ashcroft Darren M. 
Published: February 2014

Objectives
To explore the combined use of a critical incident database and work domain analysis to understand patient safety issues in a health-care setting.

Method
A retrospective review was conducted of incidents reported to the UK National Reporting and Learning System (NRLS) that involved community pharmacy between April 2005 and August 2010. A work domain analysis of community pharmacy was constructed using observational data from 5 community pharmacies, technical documentation, and a focus group with 6 pharmacists. Reports from the NRLS were mapped onto the model generated by the work domain analysis.

Results
Approximately 14,709 incident reports meeting the selection criteria were retrieved from the NRLS. Descriptive statistical analysis of these reports found that almost all of the incidents involved medication and that the most frequently occurring error types were dose/strength errors, incorrect medication, and incorrect formulation. The work domain analysis identified 4 overall purposes for community pharmacy: business viability, health promotion and clinical services, provision of medication, and use of medication. These purposes were served by lower-order characteristics of the work system (such as the functions, processes and objects). The tasks most frequently implicated in the incident reports were those involving medication storage, assembly, or patient medication records.

Conclusions
Combining the insights from different analytical methods improves understanding of patient safety problems. Incident reporting data can be used to identify general patterns, whereas the work domain analysis can generate information about the contextual factors that surround a critical task.
DNA methylation modulates transcription factor occupancy chiefly at sites of high intrinsic cell-type variability
Authors: Maurano T Matthew , Wang Hao , John Sam , Shafer Anthony , Canfield Theresa , Lee Kristen , Stamatoyannopoulos John A 
Published: February 2014

ABSTRACTThe nuclear genome of every cell harbors millions of unoccupied transcription factor (TF) recognition sequences that harbor methylated cytosines. Although DNA methylation is commonly invoked as a repressive mechanism, the extent to which it actively silences specific TF occupancy sites is unknown. To define the role of DNA methylation in modulating TF binding, we quantified the effect of DNA methyltransferase abrogation on the occupancy patterns of a ubiquitous TF capable of autonomous binding to its target sites in chromatin (CTCF). Here we show that the vast majority of unoccupied, methylated CTCF recognition sequences remain unbound upon depletion of DNA methylation. Rather, methylation-regulated binding is restricted to a small fraction of elements that exhibit high intrinsic variability in CTCF occupancy across cell types. Our results suggest that DNA methylation is not a major groundskeeper of genomic transcription factor occupancy landscapes, but rather a specialized mechanism for stabilizing epigenetically labile sites.
e‐Research and learning theory: What do sequence and process mining methods contribute?
Authors: Reimann Peter , Markauskaite Lina , Bannert Maria 
Published: February 2014

AbstractThis paper discusses the fundamental question of how data‐intensive e‐research methods could contribute to the development of learning theories. Using methodological developments in research on self‐regulated learning as an example, it argues that current applications of data‐driven analytical techniques, such as educational data mining and its branch process mining, are deeply grounded in an event‐focused, ontologically flat view of learning phenomena. These techniques provide descriptive accounts of the regularities of events, but have limited power to generate theoretical explanations. Building on the philosophical views of critical realism, the paper argues that educational e‐research needs to adopt more nuanced ways for investigating and theorising learning phenomena that could provide an account of the mechanisms and contexts in which those mechanisms are realised. It proposes that future methodological extensions should include three main aspects: (1) stratified ontological frameworks, (2) multimodal data collection and (3) dynamic analytical methods.
Interleukin levels and their potential association with venous thromboembolism and survival in cancer patients
Authors: Reitter E-M , Ay C , Kaider A , Pirker R , Zielinski C , Zlabinger G , Pabinger I 
Published: February 2014

Summary
Cytokines have been found to be elevated in cancer patients and have been associated with worse prognosis in single tumour entities. We investigated the association of eight different cytokines with venous thromboembolism (VTE) and prognosis in cancer patients. The Vienna Cancer and Thrombosis Study (CATS), a prospective study, includes patients with newly diagnosed tumour or disease progression. Patients with an overt infection are excluded. Study end-points are VTE, death, loss to follow-up or study completion. Interleukin (IL) serum levels were measured using the xMAP technology developed by Luminex. Among 726 included patients, no associations between IL levels and VTE were found, with the exception of a trend for IL-1β and IL-6 in pancreatic cancer. Elevated levels of IL-6 [as continuous variable per double increase hazard ratio (HR) = 1·07, 95% confidence interval (CI) = 1·027–1·114, P = 0·001, IL-8 (HR = 1·12, 95% CI = 1·062–1·170, P &lt; 0·001) and IL-11 (HR = 1·37, 95% CI = 1·103–1·709, P = 0·005] were associated with worse survival. In subgroup analyses based on tumour type, colon carcinoma patients, who had higher IL-6 levels, showed a shorter survival (HR = 2·405, 95% CI = 1·252–4·618, P = 0·008). A significant association of elevated IL-10 levels with a decrease in survival (HR = 1·824, 95% CI = 1·098–3·031, P = 0·020) was seen among patients with lung cancer. No correlation between VTE and IL levels was found, but higher IL-6, IL-8 and IL-11 levels were associated with worse survival in cancer patients. Further, elevated IL-6 levels might be a prognostic marker in colorectal cancer and elevated IL-10 levels in lung cancer patients.
Preferential infiltration of interleukin-4-producing CXCR4+ T cells in the lesional muscle but not skin of patients with dermatomyositis
Authors: Fujiyama T , Ito T , Ogawa N , Suda T , Tokura Y , Hashizume H 
Published: February 2014

Summary
Dermatomyositis (DM) and polymyositis (PM) are collectively termed autoimmune myopathy. To investigate the difference between muscle- and skin-infiltrating T cells and to address their role for myopathy, we characterized T cells that were directly expanded from the tissues. Enrolled into this study were 25 patients with DM and three patients with PM. Muscle and skin biopsied specimens were immersed in cRPMI medium supplemented with interleukin (IL)-2 and anti-CD3/CD28 antibody-conjugated microbeads. The expanded cells were subjected to flow cytometry to examine their phenotypes. We analysed the cytokine concentration in the culture supernatants from the expanded T cells and the frequencies of cytokine-bearing cells by intracellular staining. There was non-biased in-vitro expansion of tissue-infiltrating CD4+ and CD8+ T cells from the muscle and skin specimens. The majority of expanded T cells were chemokine receptor (CCR) type 7– CD45RO+ effecter memory cells with various T cell receptor (TCR) Vβs. The skin-derived but not muscle-derived T cells expressed cutaneous lymphocyte antigen (CLA) and CCR10 and secreted large amounts of IL-17A, suggesting that T helper type 17 (Th17) cells may have a crucial role in the development of skin lesions. Notably, the frequency of IL-4-producing chemokine (C-X-C motif) receptor (CXCR)4+ Th2 cells was significantly higher in the muscle-derived cells and correlated inversely with the serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) levels. stromal-derived factor (SDF)-1/CXCL12, a ligand for CXCR4, was expressed at a high level in the vascular endothelial cells between muscular fasciculi. Our study suggests that T cell populations in the muscle and skin are different, and the Th2 cell infiltrate in the muscle is associated with the low severity of myositis in DM.
Future directions in the study of fingolimod in multiple sclerosis
Authors: Suzumura Akio 
Published: February 2014

AbstractThe efficacy of fingolimod treatment for multiple sclerosis (MS) has been shown, but its exact mechanism remains unclear. Fingolimod is an oral disease‐modifying drug that prevents the entry of autoreactive T cells into the central nervous system (CNS) by inhibiting the egress of T cells from the lymph nodes. It binds sphingosine‐1‐phosphate (S1P) receptors on a variety of cells, including cells in the CNS, where it exerts diverse effects. In addition to its immune mechanisms, recent studies suggested that non‐immune mechanisms might play a role in the efficacy of fingolimod for the treatment of MS. Herein, we explore the underlying mechanisms of fingolimod in MS, which will therefore improve the understanding of its beneficial and adverse effects.
Is leptin a key mediator in the link between immune responses and metabolism in autoimmune diseases of the central nervous system?
Authors: Niino Masaaki 
Published: February 2014

AbstractThe non‐glycosylated protein, leptin, plays a key role in regulating energy intake and energy expenditure. It was also recently shown to be involved in regulating innate and adaptive immune responses. Ehsan et al. reported significantly higher serum leptin levels in patients with multiple sclerosis and neuromyelitis optica, and these levels were correlated with disability in those with progressive multiple sclerosis. Leptin's role as a mediator in the link between the immune responses and metabolic function is clearly important to consider in developing immune therapeutic targets for reducing inflammation and autoimmunity.
Intracellular cyclic adenosine monophosphate regulates the efficiency of intercellular transmission of human T‐lymphotropic virus type I
Authors: Nakamura Tatsufumi , Satoh Katsuya , Nakamura Hideki , Yamasaki Hironori 
Published: February 2014

AbstractObjectiveTo investigate the relationship between the intercellular transmission efficiency of human T‐lymphotropic virus type I (HTLV‐I) and the signaling involved in actin polymerization during cytoskeletal reorganization in a comparative study of HTLV‐I‐infected T‐cell lines derived from an HTLV‐I‐associated myelopathy/tropical spastic paraparesis (HAM/TSP) patient or an HTLV‐I carrier.MethodsHCT‐5 and TL‐Su cells derived from an HAM/TSP patient and an HTLV‐I carrier, respectively, were used as HTLV‐I‐infected T‐cell lines. After co‐cultivation of each HTLV‐I‐infected T‐cell line with H9/K30 luc reporter cells, the relative luc activities were calculated to analyze the efficiency of intercellular transmission of HTLV‐I. The intracellular levels of cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP) were measured in enzyme‐linked immunoassays. The expression of phosphorylated vasodilator‐stimulated phosphoprotein (p‐VASP) was analyzed by western blotting.ResultsTreatment of HCT‐5 cells with latrunculin B, an inhibitor of actin polymerization, significantly suppressed the relative luc activity. Western blotting analysis of HCT‐5 cells treated with the adenylyl cyclase activator forskolin showed upregulation of p‐VASP, with a concomitant and significant increase in the intracellular cAMP concentration. Furthermore, the relative luc activity was significantly decreased. The intracellular cAMP, but not cGMP levels, were significantly lower in HCT‐5 than in TL‐Su. Vasodilator‐stimulated phosphoprotein appeared less phosphorylated in HCT‐5 than in TL‐Su. The relative luc activity was significantly higher in HCT‐5 than in TL‐Su.ConclusionsThe intracellular cAMP concentration regulates the efficiency of intercellular HTLV‐I transmission under the control of p‐VASP expression, suggesting the intercellular transmission potential of HTLV‐I‐infected T cells of HAM/TSP patients is enhanced by downregulated intracellular cAMP levels.
Ecdysone response elements in the distal promoter of the Bombyx Broad‐Complex gene, BmBR‐C
Authors: Nishita Y. 
Published: February 2014

AbstractThe Bombyx mori silkworm's homologue of the Broad‐Complex gene (BmBR‐C) is transcribed from two promoters: a distal promoter (Pdist) and a proximal promoter (Pprox). As determined by a luciferase assay, the transcriptional activity of Pdist, but not Pprox, was activated by ecdysone. Further analyses using reporters driven by sequential deletion Pdist mutants indicated that two regions, ecdysone responsive element (EcRE)‐D and EcRE‐P, −4950 bp and −3480 bp upstream from the distal transcription start site, respectively, were important in the responsiveness of Pdist to 20‐hydroxyecdysone (20E); however, no significant sequence similarities were found between the canonical EcRE and the EcRE‐D or EcRE‐P regions. Electrophoretic mobility shift assays showed that both the EcRE‐D and ‐P sequences specifically bound to Bombyx protein(s). Sequence analyses and competition assays suggested that the protein(s) bound to EcRE‐P might include components other than the ecdysone receptor (EcR), suggesting that BmBR‐C transcription was indirectly activated by ecdysone through the EcRE‐P. Remarkably, protein binding to the mid‐region of the EcRE‐D, EcRE‐Db, was competitively inhibited by an oligonucleotide containing the Drosophila hsp27 EcRE sequence. Furthermore, an anti‐EcR antibody interfered with the formation of the protein‐EcRE‐Db complex. These results indicated that a functional Bombyx ecdysone receptor binds to EcRE‐D and activates the expression of BmBR‐C.
Involvement of the Wnt‐β‐catenin signalling antagonists, sclerostin and dickkopf‐related protein 1, in chronic periodontitis
Authors: Napimoga Marcelo Henrique , Nametala Cynthia , da Silva Fábio Luiz , Miranda Tamires Szeremeske , Bossonaro Jeruza P. , Demasi Ana Paula Dias , Duarte Poliana Mendes 
Published: February 2014

AbstractAimThe regulation of Wnt‐β‐catenin signalling, which is crucial for osteoblast differentiation and for bone resorption, is driven by critical inhibitors such as sclerostin (SOST) and dickkopf‐related protein 1 (DKK1). As such, the aim of this study was to evaluate the involvement of SOST and DKK1 in human chronic periodontitis.Material and MethodsGingival biopsies and serum were sampled from systemically healthy non‐periodontitis (n = 15) and chronic periodontitis subjects (n = 15). The mRNA and protein levels of SOST, DKK1 and TNF‐α in periodontal tissues were measured by qPCR and by enzyme‐linked immunosorbent assay (ELISA) respectively. Serum levels of SOST, DKK1 and TNF‐α were assessed by ELISA.ResultsThe mRNA and protein levels of SOST, DKK1 and TNF‐α were significantly increased in the gingival tissues of the chronic periodontitis when compared to the non‐periodontitis group (p < 0.05). In addition, circulating levels of SOST and TNF‐α, but not DKK1, were higher in the periodontitis group than in the non‐periodontitis group (p < 0.05).ConclusionSOST and DKK1 were upregulated in the periodontal tissues of chronic periodontitis subjects, suggesting a possible role of these molecules on periodontal tissues.
Annual Research Review: Child and adolescent mental health interventions: a review of progress in economic studies across different disorders
Authors: Beecham Jennifer 
Published: February 2014

BackgroundResources for supporting children and adolescents with psychiatric disorders continue to be scarce. Economics research can identify current patterns of expenditure, and help inform allocation of treatment and support resources between competing needs or uses.Scope and methodsThe aim was to identify the costs of supporting children and adolescents, the economic impacts of childhood psychiatric disorders in adulthood and any new evidence on the cost‐effectiveness of interventions. An electronic search of databases (including PubMed, Medline and Psychinfo) identified peer‐reviewed journal articles published between 2005 and 2012.FindingsSixty‐seven papers provided data on support and treatment costs now or in the future, or cost‐effectiveness analyses of services. Half the articles came from the United States. Most articles focussed on autism spectrum disorder (ASD; 23 articles), attention deficit hyperactivity disorder (ADHD; n = 15), conduct disorder (CD; n = 7), and anxiety or depression (n = 8).ConclusionOnly 14 studies used a cost perspective wider than health care; most included education costs (n = 11), but only five included costs to the justice system. The number of studies estimating costs to the family has increased, particularly for children with autism spectrum disorder (ASD). In the United Kingdom, support costs for children and adolescents with conduct disorder (CD) appear to be lower than for those with attention deficit hyperactivity disorder (ADHD), although for the United States, the opposite may be true. Support costs for children and adolescents with ASD may be higher than both CD and ADHD. However, there were many differences between the samples and the methods employed making comparisons between studies difficult. Outcomes in adulthood include negative impacts on (mental) health, quality of life, public sector services, employment status and income. The evidence base is improving for child and adolescent psychiatric disorders, although only one full cost‐effectiveness analysis was identified since the previous review published in 2012. However, we still do not know enough about the economic implications of support and treatment for specific disorders.