bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification and Characterization of Serotype-Specific Variation in Group A Streptococcus Pilus Expression
Authors: Calfee Gregory , Danger Jessica L. , Jain Ira , Miller Eric W. , Sarkar Poulomee , Tjaden Brian , Kreikemeyer Bernd , Sumby Paul
Published: November 2017

Isolates of a given bacterial pathogen often display phenotypic variation, and this can negatively impact public health, for example, by reducing the efficacy of preventative measures. Here, we identify that the human pathogen group AStreptococcus(GAS;Streptococcus pyogenes) expresses pili on its cell surface in a serotype-specific manner. Specifically, we show that serotype M3 GAS isolates, which are nonrandomly associated with causing particularly severe and lethal invasive infections, produce negligible amounts of pili relative to serotype M1 and M49 isolates. Performance of an interserotype transcriptome comparison (serotype M1 versus serotype M3) was instrumental in this discovery. We also identified that the transcriptional regulator Nra positively regulates pilus expression in M3 GAS isolates and that the low level of pilus expression of these isolates correlates with a low level ofnratranscription. Finally, we discovered that the phenotypic consequences of low levels of pilus expression by M3 GAS isolates are a reduced ability to adhere to host cells and an increased ability to survive and proliferate in human blood. We propose that an enhanced ability to survive in human blood, in part due to reduced pilus expression, is a contributing factor in the association of serotype M3 isolates with highly invasive infections. In conclusion, our data show that GAS isolates express pili in a serotype-dependent manner and may inform vaccine development, given that pilus proteins are being discussed as possible GAS vaccine antigens.
Polyphosphate Kinase Antagonizes Virulence Gene Expression in Francisella tularensis
Authors: Rohlfing Amy E. , Ramsey Kathryn M. , Dove Simon L.
Published: November 2017

The alarmone ppGpp is a critical regulator of virulence gene expression in
Francisella tularensis
. In this intracellular pathogen, ppGpp is thought to work in concert with the putative DNA-binding protein PigR and the SspA protein family members MglA and SspA to control a common set of genes. MglA and SspA form a complex that interacts with RNA polymerase (RNAP), and PigR functions by interacting with the RNAP-associated MglA-SspA complex. Prior work suggested that ppGpp indirectly exerts its regulatory effects in
F. tularensis
by promoting the accumulation of polyphosphate in the cell, which in turn was required for formation of the MglA-SspA complex. Here we show that in
Escherichia coli
, neither polyphosphate nor ppGpp is required for formation of the MglA-SspA complex but that ppGpp promotes the interaction between PigR and the MglA-SspA complex. Moreover, we show that polyphosphate kinase, the enzyme responsible for the synthesis of polyphosphate, antagonizes virulence gene expression in
F. tularensis
, a finding that is inconsistent with the notion that polyphosphate accumulation promotes virulence gene expression in this organism. Our findings identify polyphosphate kinase as a novel negative regulator of virulence gene expression in
F. tularensis
and support a model in which ppGpp exerts its positive regulatory effects by promoting the interaction between PigR and the MglA-SspA complex.

IMPORTANCE
In
Francisella tularensis
, MglA and SspA form a complex that associates with RNA polymerase to positively control the expression of key virulence genes. The MglA-SspA complex works together with the putative DNA-binding protein PigR and the alarmone ppGpp. PigR functions by interacting directly with the MglA-SspA complex, but how ppGpp exerts its effects was unclear. Prior work indicated that ppGpp acts by promoting the accumulation of polyphosphate, which is required for MglA and SspA to interact. Here we show that formation of the MglA-SspA complex does not require polyphosphate. Furthermore, we find that polyphosphate antagonizes the expression of virulence genes in
F. tularensis
. Thus, ppGpp does not promote virulence gene expression in this organism through an effect on polyphosphate.
Early-onset group BStreptococcus(EOGBS) infection subsequent to cessation of screening-based intrapartum prophylaxis: findings of an observational study in West London, UK
Authors: Gopal Rao Guduru , Townsend Jane , Stevenson Daniel , Nartey Grace , Hiles Stephen , Bassett Paul , Lamagni Theresa , Nicholl Richard
Published: November 2017

Objectives

To describe the impact on early-onset group BStreptococcus(EOGBS) infection rates following reversion from screening-based to risk-based intrapartum antimicrobial prophylaxis (IAP) for prevention.

Setting

Maternity services provided by secondary healthcare organisation in North West London.

Participants

All women who gave birth in the healthcare organisation between April 2016 and March 2017. There were no exclusions.

Design

Observational study comparing EOGBS rates in the postscreening period (2016–2017) with prescreening (2009–2013) and screening periods (2014–2015).

Methods

Local guidelines for risk-based IAP were reintroduced in April 2016. Compliance with guidelines was audited. Gestational age, mode of delivery, maternal demographics and EOGBS rates in three time periods were compared using Poisson regression analysis. EOGBS was defined through GBS being cultured from blood, cerebrospinal fluid or other sterile fluids within 6 days of birth.

Primary outcome

EOGBS rates/1000 live births in prescreening, screening and postscreening periods

Results

Incremental changes in maternity population were observed throughout the study period (2009 onwards), in particular the ethnic profile of mothers. Of the 5033 live births in postscreening period, 9 babies developed EOGBS infection. Only one of the mothers of affected babies had a risk factor indicating use of IAP. Comparison of postscreening period with screening period showed a fivefold increase in EOGBS rates after adjustment for ethnicity (1.79 vs 0.33/1000 live births; risk ratio =5.67, p=0.009). There was no significant difference between prescreening and postscreening periods with rates of infection reverting to their prescreening level.

Conclusions

This study provides further evidence of efficacy of screening-based IAP compared with risk-based IAP in prevention of EOGBS in newborns in an area of high incidence.
Identification of nuclear localization signals in the human homeoprotein MSX1
Authors: Shibata Akio , Machida Junichiro , Yamaguchi Seishi , Kimura Masashi , Tatematsu Tadashi , Miyachi Hitoshi , Nakayama Atsuo , Shimozato Kazuo , Tokita Yoshihito
Published: November 2017

MSX1 is one of the homeoproteins with the homeodomain (HD) sequence, which regulates proliferation and differentiation of mesenchymal cells. In this study, we investigated the nuclear localization signal (NLS) in the MSX1 HD by deletion and amino acid substitution analyses. The web-based tool NLStradamus predicted 2 putative basic motifs in the N- and C-termini of the MSX1 HD. Green fluorescent protein (GFP) chimera studies revealed that NLS1 (161RKHKTNRKPR170) and NLS2 (216NRRAKAKR223) were independently insufficient for robust nuclear localization. However, they can work cooperatively to promote nuclear localization of MSX1, as was shown by the 2 tandem NLS motifs partially restoring functional NLS, leading to a significant nuclear accumulation of the GFP chimera. These results demonstrate a unique NLS motif in MSX1, which consists of an essential single core motif in helix-I, with weak potency, and an auxiliary subdomain in helix-III, which alone does not have nuclear localization potency. Additionally, other peptide sequences, other than predicted 2 motifs in the spacer, may be necessary for complete nuclear localization in MSX1 HD.
Evaluating spatial and temporal variability in growth and mortality for recreational fisheries with limited catch data
Authors: Li Yan , Wagner Tyler , Jiao Yan , Lorantas Robert , Murphy Cheryl A.
Published: November 2017

Understanding the spatial and temporal variability in life-history traits among populations is essential for the management of recreational fisheries. However, valuable freshwater recreational fish species often suffer from a lack of catch information. In this study, we demonstrated the use of an approach to estimate the spatial and temporal variability in growth and mortality in the absence of catch data and apply the method to riverine smallmouth bass (Micropterus dolomieu) populations in Pennsylvania, USA. Our approach included a growth analysis and a length-based analysis that estimates mortality. Using a hierarchical Bayesian approach, we examined spatial variability in growth and mortality by assuming parameters vary spatially but remain constant over time and temporal variability by assuming parameters vary spatially and temporally. The estimated growth and mortality of smallmouth bass showed substantial variability over time and across rivers. We explored the relationships of the estimated growth and mortality with spring water temperature and spring flow. Growth rate was likely to be positively correlated with these two factors, while young mortality was likely to be positively correlated with spring flow. The spatially and temporally varying growth and mortality suggest that smallmouth bass populations across rivers may respond differently to management plans and disturbance such as environmental contamination and land-use change. The analytical approach can be extended to other freshwater recreational species that also lack of catch data. The approach could also be useful in developing population assessments with erroneous catch data or be used as a model sensitivity scenario to verify traditional models even when catch data are available.
Limited evidence of fungicide-driven triazole-resistant Aspergillus fumigatus in Hamilton, Canada
Authors: Ashu Eta Ebasi , Kim Ga Young , Roy-Gayos Patrick , Dong Kelly , Forsythe Adrian , Giglio Victoria , Korfanty Gregory , Yamamura Deborah , Xu Jianping
Published: November 2017

Aspergillus fumigatus is a ubiquitous opportunistic fungal pathogen that can cause aspergillosis in humans. Over the last decade there have been increasing global reports of treatment failure due to triazole resistance. An emerging hypothesis states that agricultural triazole fungicide use causes clinical triazole resistance. Here we test this hypothesis in Hamilton, Ontario, Canada, by examining a total of 195 agricultural, urban, and clinical isolates using 9 highly polymorphic microsatellite markers. For each isolate, the in vitro susceptibilities to itraconazole and voriconazole, 2 triazole drugs commonly used in the management of patients, were also determined. Our analyses suggested frequent gene flow among the agricultural, urban environmental, and clinical populations of A. fumigatus and found evidence for widespread sexual recombination within and among the different populations. Interestingly, all 195 isolates analyzed in this study were susceptible to both triazoles tested. However, compared with the urban population, agricultural and clinical populations showed significantly reduced susceptibility to itraconazole and voriconazole, consistent with ecological niche-specific selective pressures on A. fumigatus populations in Hamilton. Frequent gene flow and genetic recombination among these populations suggest greater attention should be paid to monitor A. fumigatus populations in Hamilton and other similar jurisdictions.
Development and Application of the Power Plant Real-Time Temperature and Stress Monitoring System
Authors: Duda Piotr
Published: November 2017

The paper presents a method of temperature and stress estimation in pressure components of conventional or nuclear power plants. The proposed algorithm can be applied without the information concerning the thermal boundary condition on the component inner surfaces and it is fast enough to be applied in an online mode. The solution is possible thanks to “measured” temperature histories determined in easily accessible points located on the component outer surface. The presented model has been recently verified analytically, numerically, and experimentally. The proposed algorithm was used to calculate the transient temperature and stress distribution in the outlet header of a steam reheater and the results indicate that the component lower part is loaded the most, but allowable stresses are not exceeded. If the presented heating process was shortened, the calculated stresses would exceed the allowable values. Monitoring the boiler thermal and strength operating conditions makes it possible to identify dangerous loads of the power boiler pressure elements during transient-state operations. The presented method for controlling thermal and pressure-related stresses is suitable for nuclear power plants because it does not require drilling holes for sensors in the pressure element walls.
Cross-Checking Multiple Data Sources Using Multiway Join in MapReduce
Authors: Afrati Foto , Momani Zaid , Stasinopoulos Nikos
Published: November 2017

As data sources accumulate information and data size escalates it becomes more and more difficult to maintain the correctness and validity of these datasets. Therefore, tools must emerge to facilitate this daunting task. Fact checking usually involves a large number of data sources that talk about the same thing but we are not sure which holds the correct information or which has any information at all about the query we care for. A join among all or some data sources can guide us through a fact-checking process. However, when we want to perform this join on a distributed computational environment such as MapReduce, it is not obvious how to distribute efficiently the records in the data sources to the reduce tasks in order to join any subset of them in a single MapReduce job. To this end, we propose an efficient approach using the multiway join to cross-check these data sources in a single round.
Investigation of Antimicrobial, Antioxidant, and DNA Binding Studies of Bioactive Cu(II), Zn(II), Co(II), and Ni(II) Complexes of Pyrimidine Derivative Schiff Base Ligand
Authors: Saleem Shahul Hameed Sukkur , Sankarganesh Murugesan , Jose Paul Raj Adwin , Sakthikumar Karunganathan , Mitu Liviu , Raja Jeyaraj Dhaveethu
Published: November 2017

A new pyrimidine based Schiff base ligand (HL) and its four complexes of type [MLOAc]·nH2O (Cu(II), 1; Zn(II), 2; Co(II), 3; and Ni(II), 4) have been synthesized and characterized by elemental analysis, MS, 1H-NMR, FT-IR, UV-visible, and ESR techniques. The electronic and ESR spectral data suggested that complexes 1–4 possess square planar geometry. Antimicrobial activities of HL and complexes 1–4 were tested against four bacteria (Staphylococcus aureus, Staphylococcus pneumonia, Salmonella enterica typhi, and Haemophilus influenzae) and two fungal strains (Aspergillus flavus and Aspergillus niger). These results show that complexes 1–4 have good antimicrobial activity compared to HL. The DNA cleavage activity of HL and complexes 1–4 was monitored by the agarose gel electrophoresis method. The antioxidant property of the prepared compounds was assessed by using 2,2′-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging method. DNA binding properties of HL and complexes 1–4 have been investigated by electronic absorption technique and viscometric measurements.
3D Temperature Distribution Model Based on Thermal Infrared Image
Authors: Jia Tong , Wang HongYu , Chen DongYue , Hou MingYa , Wu ChengDong , Tu Mo , Jiang Yuli , Zhang Shuai
Published: November 2017

This paper aims to study the construction of 3D temperature distribution reconstruction system based on binocular vision technology. Initially, a traditional calibration method cannot be directly used, because the thermal infrared camera is only sensitive to temperature. Therefore, the thermal infrared camera is calibrated separately. Belief propagation algorithm is also investigated and its smooth model is improved in terms of stereo matching to optimize mismatching rate. Finally, the 3D temperature distribution model is built based on the matching of 3D point cloud and 2D thermal infrared information. Experimental results show that the method can accurately construct the 3D temperature distribution model and has strong robustness.
Clinical Factors Predictive for Intracranial Hemorrhage in Mild Head Injury
Authors: Yuksen Chaiyaporn , Sittichanbuncha Yuwares , Patumanond Jayanton , Muengtaweepongsa Sombat , Aramvanitch Kasamon , Supamas Amornrat , Sawanyawisuth Kittisak
Published: November 2017

Patients with mild head injuries, a GCS of 13–15, are at risk for intracranial hemorrhage. Clinical decision is needed to weigh between risks of intracranial hemorrhage and costs of the CT scan of the brain particularly those who are equivocal. This study aimed to find predictors for intracranial hemorrhage in patients with mild head injuries with a moderate risk of intracranial hemorrhage. We defined moderate risk of mild head injury as a GCS score of 13–15 accompanied by at least one symptom such as headache, vomiting, or amnesia or with alcohol intoxication. There were 153 patients who met the study criteria. Eighteen of the patients (11.76%) had intracranial hemorrhage. There were four independent factors associated with intracranial hemorrhage: history of hypertension, headache, loss of consciousness, and baseline GCS. The sensitivity for the presence of intracranial hemorrhage was 100% with the cutoff point for the GCS of 13. In conclusion, the independent factors associated with intracranial hemorrhage in patients with mild head injury who were determined to be at moderate risk for the condition included history of hypertension, headache, loss of consciousness, and baseline GCS score.
Strongly Unforgeable Certificateless Signature Resisting Attacks from Malicious-But-Passive KGC
Authors: Yang Wenjie , Weng Jian , Luo Weiqi , Yang Anjia
Published: November 2017

In digital signature, strong unforgeability requires that an attacker cannot forge a new signature on any previously signed/new messages, which is attractive in both theory and practice. Recently, a strongly unforgeable certificateless signature (CLS) scheme without random oracles was presented. In this paper, we firstly show that the scheme fails to achieve strong unforgeability by forging a new signature on a previously signed message under its adversarial model. Then, we point out that the scheme is also vulnerable to the malicious-but-passive key generation center (MKGC) attacks. Finally, we propose an improved strongly unforgeable CLS scheme in the standard model. The improved scheme not only meets the requirement of strong unforgeability but also withstands the MKGC attacks. To the best of our knowledge, we are the first to prove a CLS scheme to be strongly unforgeable against the MKGC attacks without using random oracles.
The Glucocorticoid Receptor Is a Key Player for Prostate Cancer Cell Survival and a Target for Improved Antiandrogen Therapy
Authors: Puhr Martin , Hoefer Julia , Eigentler Andrea , Ploner Christian , Handle Florian , Schaefer Georg , Kroon Jan , Leo Angela , Heidegger Isabel , Eder Iris , Culig Zoran , Van der Pluijm Gabri , Klocker Helmut
Published: November 2017

Purpose: The major obstacle in the management of advanced prostate cancer is the occurrence of resistance to endocrine therapy. Although the androgen receptor (AR) has been linked to therapy failure, the underlying escape mechanisms have not been fully clarified. Being closely related to the AR, the glucocorticoid receptor (GR) has been suggested to play a role in enzalutamide and docetaxel resistance. Given that glucocorticoids are frequently applied to prostate cancer patients, it is essential to unravel the exact role of the GR in prostate cancer progression.

Experimental Design: Assessment of GR expression and functional significance in tissues from 177 prostate cancer patients, including 14 lymph node metastases, as well as in several human prostate cancer models, including androgen-dependent, androgen-independent, and long-term antiandrogen-treated cell lines.

Results: Although GR expression is reduced in primary prostate cancer tissue, it is restored in metastatic lesions. Relapse patients with high GR experience shortened progression-free survival. GR is significantly increased upon long-term abiraterone or enzalutamide treatment in the majority of preclinical models, thus identifying GR upregulation as an underlying mechanism for cells to bypass AR blockade. Importantly, GR inhibition by RNAi or chemical blockade results in impaired proliferation and 3D-spheroid formation in all tested cell lines.

Conclusions: GR upregulation seems to be a common mechanism during antiandrogen treatment and supports the notion that targeting the GR pathway combined with antiandrogen medication may further improve prostate cancer therapy. Clin Cancer Res; 24(4); 927–38. ©2017 AACR.
The Canadian Path from Discovery to Implementation of Personalized Medicine Approaches
Authors: Richer Étienne , Syme Rachel , Robbins Stephen M. , Lasko Paul
Published: November 2017

Personalized (or precision) medicine approaches are currently being introduced in healthcare delivery following the development of new technologies and of novel ways to integrate and analyze various data sources. This editorial describes the efforts invested since 2012 by the Canadian Institutes of Health Research (CIHR) to foster the development and implementation of personalized medicine in Canada. Success stories from past investments as well as future developments are presented from a Canadian perspective.
Leviathan, or the Rudder of Public Health
Authors: Horgan Denis , Ricciardi Walter
Published: November 2017

In the world of modern health, despite the fact that we've been blessed with amazing advances of late - the advent of personalised medicine is just one example - “change” for most citizens seems slow. There are clear discrepancies in availability of the best care for all, the divisions in access from country to country, wealthy to poor, are large. There are even discrepancies between regions of the larger countries, where access often varies alarmingly. Too many Member States (with their competence for healthcare) appear to be clinging stubbornly to the concept of “one-size-fits-all” in healthcare and often stifle advances possible through personalised medicine. Meanwhile, the legislative arena encompassing health has grown big and unwieldy in many respects. And bigger is not always better. The health advances spoken of above, an increased knowledge on the part of patients, the emergence of Big Data and more, are quickly changing the face of healthcare in Europe. But healthcare thinking across the EU isn't changing fast enough. The new technologies will certainly speak for themselves, but only if allowed to do so. Acknowledging that, this article highlights a positive reform agenda, while explaining that new avenues need to be explored.
A Healthy Sense of Trust
Authors: Horgan Denis
Published: November 2017

In the fast-moving arena of modern healthcare with its cutting-edge science it is already, and will become more, vital that stakeholders collaborate openly and effectively. Transparency, especially on drug pricing, is of paramount importance. There is also a need to ensure that regulations and legislation covering, for example the new, smaller clinical trials required to make personalised medicine work effectively, and the huge practical and ethical issues surrounding Big Data and data protection, are common, understood and enforced across the EU. With more integration, collaboration, dialogue and increased trust among each and every one in the field, stakeholders can help mould the right frameworks, in the right place, at the right time. Once achieved, this will allow us all to work more quickly and more effectively towards creating a healthier - and thus wealthier - European Union.
Personalised Medicine - Bringing Innovation to the Healthcare System
Authors: Horgan Denis , Baker Mary , Riegman Peter , Bernini Chiara
Published: November 2017

Healthcare innovation has never been more prevalent than it is today. But these innovations are only very slowly being embedded into Europe's healthcare systems. There is a huge capacity here in the EU to improve the health and quality of life of all citizens, but the extent to which it is happening is far from optimal. What is ringing out like a bell is that there is a clear need for better focus from policy makers, as this article explains. A policy bridge is required and a conscious decision among the powers-that-be in Europe needs to find a way to harmonise multiple strands of activity and responsibility in the health arena. The end goal will be for the EU to more effectively integrate the incredible advances in science into healthcare systems, for the benefit of all patients.
Precision Medicine: From “Omics” to Economics towards Data-Driven Healthcare - Time for European Transformation
Authors: Lacombe Denis , Liu Lifang , Meunier Françoise , Golfinopoulos Vassilis
Published: November 2017

There is room for improvement for optimally bringing the latest science to the patient while taking into account patient priorities such as quality of life. Too often, regulatory agencies, governments, and funding agencies do not stimulate the integration of research into care and vice versa. Re-engineering the drug development process is a priority, and healthcare systems are long due for transformation. On one hand, patients need efficient access to treatments, but despite precision oncology approaches, efficiently shared screening platforms for sorting patients based on the biology of their tumour for trial access are lacking and, on the other hand, the true value of cancer care is poorly addressed as central questions such as dose, scheduling, duration, and combination are not or sub-optimally addressed by registration trials. Solid evidence on those parameters could potentially lead to a rational and wiser use of anti-cancer treatments. Together, optimally targeting patient population and robust comparative effectiveness data could lead to more affordable and economically sound approaches. The drug development process and healthcare models need to be interconnected through redesigned systems taking into account the full math from drug development into affordable care.
Translational Education
Authors: Horgan Denis , Schneider Daniel , Pravettoni Gabriella , Paradiso Angelo , Denis Louis , Chomienne Christine
Published: November 2017

The issue of translational education of healthcare professionals is a major one. It is clear that a great degree of upskilling is already required and, to keep pace with the science, this must be ongoing. Stakeholders need to achieve this together - with agreed-on standards across the board so that no patient is denied a suitable, virtually tailor-made treatment due to a lack of knowledge or understanding on behalf of the healthcare professional treating and diagnosing him or her. A key partner in tackling this is the healthcare community, and one way to achieve the goal is through increased EU-wide investment in translational education and training of healthcare professionals.
For the Many, Not the Few: Patient Empowerment
Authors: Horgan Denis , Henning Geoffrey , Banks Ian , van der Wal Tom , Hasurdjiev Stanimir , Pelouchova Jana
Published: November 2017

Today's patients are more knowledgable than ever before and should be placed at the centre of their own healthcare decisions. Empowering the patient is, and always will be, a fundamental pillar of personalised medicine. Front-line healthcare professionals cannot treat a patient properly without taking into account his or her perceptions of value. They cannot treat a patient properly without taking into account that patient's lifestyle and, of course, they cannot treat a patient properly without creating equal access across the EU to the best possible treatments available. The authors of this article examine ways to enhance the empowerment of Europe's patients.
Type 1 Diabetes: Disease Stratification
Authors: Insel Richard , Dutta Sanjoy , Hedrick Joseph
Published: November 2017

Type 1 diabetes, a disorder characterized by immune-mediated loss of functional pancreatic beta cells, is a disease continuum with specific presymptomatic stages with defined risk of progression to symptomatic disease. Prognostic biomarkers have been developed for disease staging and for stratification of subjects that address the heterogeneity in rate of disease progression. Using biomarkers for stratification of subjects at different stages of type 1 diabetes will enable smaller and shorter intervention clinical trials with greater effect size. Addressing the heterogeneity of the disease will allow precision medicine-based approaches to prevention and interception of presymptomatic stages of disease and treatment and cure of symptomatic disease.
The Role of Multigene Assays in Addressing Treatment Heterogeneity for Breast Cancer
Authors: Aapro Matti
Published: November 2017

Breast cancer has a complex biology with heterogeneous treatment approaches that have changed significantly over the last two decades. The MAGIC survey provides valuable insight into worldwide treatment recommendations for early breast cancer patients and the clinical and pathologic criteria used for these decisions. The overall findings indicate that there is substantial heterogeneity in how patients are treated and a substantial uncertainty in treatment recommendations for a large proportion of patients, highlighting an unmet need for broadly available markers, such as multigene assays, that can help to make more informed treatment decisions by predicting a patient's likelihood of benefit from adjuvant chemotherapy.
EU Health Policy, Coherence, Stakeholder Diversity and Their Impact on the EMA
Authors: Horgan Denis , Kent Alastair
Published: November 2017

Innovation is a major pillar in bringing new, targeted medicines to patients. In the health arena, this means the translation of knowledge into what we can call “value.” The latter covers the value to patients but must also take into account value to healthcare systems, society and, of course, manufacturers. The EU has recognised that innovations in healthcare can contribute to the health and well-being of citizens and patients through access to new products, services and treatments with added value. It is also aware that in order to stimulate development, there is a need to facilitate the translation of scientific advances into innovative medicinal products that meet regulatory standards, accelerate patients' access to new therapies and are affordable to Member States' health systems. Early dialogue between technology developers, regulators, health technology assessment and, where relevant, pricing bodies will promote innovation and quicker access to medicines at affordable prices, for the benefit of patients. But while uncertainties in healthcare policy still exist, a request by the European Ombudsman to the European Medicines Agency to provide more information about its early dialogue procedures questions the above “early dialogue” principal. It raises the issue of what the EU aims to do with its health regulation in bringing innovation to the patient. Is this added uncertainty about the hereto trusted role of the EMA a welcome development? Not necessarily.
Supporting Innovation through Regulation and Science: Ireland as an Innovation Hub for Health Products
Authors: O'Dwyer Laurence , Nolan Lorraine , Fisher Caitriona
Published: November 2017

New technologies and our ever-increasing knowledge provide an exciting potential to develop innovative health products that can address challenges such as chronic diseases and ultimately improve outcomes for patients. Ireland has a strategic focus on supporting innovation and offers an ideal environment for health product innovation. This is due to the expertise and experience that is available within the life sciences sector and an established national infrastructure which supports the translation of research into health products in a collaborative manner. The Health Products Regulatory Authority (HPRA) is committed to supporting innovation for health products. Anyone developing an innovative health product can obtain regulatory guidance via the HPRA's Innovation Office. Scientific advice and a product classification service are also available. The HPRA is actively engaging with innovators through an outreach programme to discuss how regulation can support innovation and to raise awareness of available supports. In order to facilitate the appropriate regulation of innovative therapies, the HPRA is performing horizon scanning to identify innovations at an early stage of development, so that proactive action can be taken to put in place any additional regulatory tools or develop any expertise required to regulate such products and provide safe and timely access for patients.
Efficacy of Long-Term Oral Vitamin B12 Supplementation after Total Gastrectomy: Results from a Prospective Study
Authors: Moleiro Joana , Mão de Ferro Susana , Ferreira Sara , Serrano Miguel , Silveira Margarida , Dias Pereira António
Published: November 2017

Background/Objectives: Vitamin B12 (VB12) deficiency is a common complication after total gastrectomy which may be associated with megaloblastic anemia and potentially irreversible neurologic symptoms. Intramuscular supplementation of VB12 has been considered the standard treatment, although it is associated with high costs and patient discomfort. Patients/Methods: We performed a prospective uncontrolled study (ACTRN12614000107628) in order to evaluate the clinical and laboratory efficacy of long-term oral VB12 supplementation in patients submitted to total gastrectomy. All patients received daily oral VB12 (1 mg/day) and were evaluated every 3 months (clinical and laboratory evaluation: hemoglobin, VB12, total iron, ferritin, and folate). Results: A total of 26 patients were included with a mean age of 64 years (29-79). Patients were included with a mean period of 65 months (3-309) after total gastrectomy. At inclusion time, 17/26 patients were under intramuscular VB12, and 9 had not started supplementation yet. There were normal serum VB12 levels in 25/26 patients (mean VB12 serum levels: 657 pg/mL). The mean follow-up period was 20 (8.5-28) months. During follow-up, all patients had normal VB12 levels and there was no need for intramuscular supplementation. The patient with low VB12 levels had an increase to adequate levels, which remained stable. There were no differences with statistical significance among VB12 levels at 6 (867 pg/mL), 12 (1,008 pg/mL), 18 (1,018 pg/mL), and 24 (1,061 pg/mL) months. Iron and folate supplementation was necessary in 21 and 7 patients, respectively. Conclusions: Oral VB12 supplementation is effective and safe in patients who underwent total gastrectomy and should be considered the preferential form of supplementation.
A Novel Dedicated Route Protection Scheme for Survivability of Link Failure in Elastic Optical Networks
Authors: Iyer Sridhar , Singh Shree Prakash
Published: November 2017

The spectrally efficient transportation of the high bit rate(s) data is achievable by the Elastic optical networks (EONs). However, in the EONs, owing to the failure occurrence even in an individual simple element, different service(s) maybe interrupted. Hence, it is imperative that the schemes for survivability be developed so that the issues due to the possible failure(s) can be overcome. In the current work, in view of survivability of the link failure(s) in the EONs, we propose the Spectrum Continuity and Contiguity Established DRP (SCC-E-DRP) algorithm which is a novel dedicated route protection (DRP) scheme that attempts to avoid the problem of trap topology during its exploration for a pair of link disjoint path. Further, to evaluate the link disjoint paths, we resort to the use of the SCC Established Shortest Route (SCC-E-SR) algorithm which is a modified Dijkstra’s algorithm based scheme that selects the path(s) pair(s) based on the end-toend SCC. We conduct extensive simulations considering realistic network topologies, and compare the performance of the SCCE-DRP scheme with the existing techniques. The obtained results show that, compared to the existing schemes, the SCC-E-DRP scheme achieves better results in terms of blocking probability.
Stable Oxidative Cytosine Modifications Accumulate in Cardiac Mesenchymal Cells From Type2 Diabetes Patients
Authors: Spallotta Francesco , Cencioni Chiara , Atlante Sandra , Garella Davide , Cocco Mattia , Mori Mattia , Mastrocola Raffaella , Kuenne Carsten , Guenther Stefan , Nanni Simona , Azzimato Valerio , Zukunft Sven , Kornberger Angela , Sürün Duran , Schnütgen Frank , von Melchner Harald , Di Stilo Antonella , Aragno Manuela , Braspenning Maarten , van Criekinge Wim , De Blasio Miles J. , Ritchie Rebecca H. , Zaccagnini Germana , Martelli Fabio , Farsetti Antonella , Fleming Ingrid , Braun Thomas , Beiras-Fernandez Andres , Botta Bruno , Collino Massimo , Bertinaria Massimo , Zeiher Andreas M. , Gaetano Carlo
Published: November 2017

Rationale:

Human cardiac mesenchymal cells (CMSCs) are a therapeutically relevant primary cell population. Diabetes mellitus compromises CMSC function as consequence of metabolic alterations and incorporation of stable epigenetic changes.

Objective:

To investigate the role of α-ketoglutarate (αKG) in the epimetabolic control of DNA demethylation in CMSCs.

Methods and Results:

Quantitative global analysis, methylated and hydroxymethylated DNA sequencing, and gene-specific GC methylation detection revealed an accumulation of 5-methylcytosine, 5-hydroxymethylcytosine, and 5-formylcytosine in the genomic DNA of human CMSCs isolated from diabetic donors. Whole heart genomic DNA analysis revealed iterative oxidative cytosine modification accumulation in mice exposed to high-fat diet (HFD), injected with streptozotocin, or both in combination (streptozotocin/HFD). In this context, untargeted and targeted metabolomics indicated an intracellular reduction of αKG synthesis in diabetic CMSCs and in the whole heart of HFD mice. This observation was paralleled by a compromised TDG (thymine DNA glycosylase) and TET1 (ten–eleven translocation protein 1) association and function with TET1 relocating out of the nucleus. Molecular dynamics and mutational analyses showed that αKG binds TDG on Arg275 providing an enzymatic allosteric activation. As a consequence, the enzyme significantly increased its capacity to remove G/T nucleotide mismatches or 5-formylcytosine. Accordingly, an exogenous source of αKG restored the DNA demethylation cycle by promoting TDG function, TET1 nuclear localization, and TET/TDG association. TDG inactivation by CRISPR/Cas9 knockout or TET/TDG siRNA knockdown induced 5-formylcytosine accumulation, thus partially mimicking the diabetic epigenetic landscape in cells of nondiabetic origin. The novel compound (S)-2-[(2,6-dichlorobenzoyl)amino]succinic acid (AA6), identified as an inhibitor of αKG dehydrogenase, increased the αKG level in diabetic CMSCs and in the heart of HFD and streptozotocin mice eliciting, in HFD, DNA demethylation, glucose uptake, and insulin response.

Conclusions:

Restoring the epimetabolic control of DNA demethylation cycle promises beneficial effects on cells compromised by environmental metabolic changes.
Vik Muniz's Pictures of Garbage and the Aesthetics of Poverty
Authors: Schmidt Christopher
Published: November 2017

This essay focuses on Brazilian–American artist Vik Muniz's 2008 Pictures of Garbage and the pendant 2010 documentary on their making, Waste Land, directed by Lucy Walker. Muniz enlists a group of Brazilian garbage pickers as subjects and participants in the construction of their own portraits, using garbage picked from a landfill outside of Rio de Janeiro. The use of garbage as a material draws attention to global patterns of exploitation that produce both the waste itself and the poverty of the garbage pickers. However, this essay argues that Muniz's social aims are undermined by formal incoherences within the portraits and their subsequent recommodification on the global art market. Using Michael Fried's theories, the essay identifies a tension in Pictures of Garbage between the theatricality of the subjects' poses, drawn from canonical European paintings, and the absorptive qualities of the garbage itself. This dissonance reflects Muniz's own split position as a cosmopolitan global artist compelled to represent Brazilian identity through associations with base materiality.
Colophon as a Marginal Witness
Authors: Mereb Faride
Published: November 2017

“Graphic design” was not a proper term until the beginning of the twentieth century. This led to confusion in credits/authorship for book covers, typography, which was exacerbated by the fact that printers, in addition to being in charge of the production process of books, were also making decisions regarding their finishings. Venezuela presents an interesting chapter in the history of publishing in the world given the hybrid character of publishing in the country in which traditional national artists, illustrators, and publicists comprised a mix of European and North American immigrants. The lack of current bibliographic material inspired me, as a researcher, to make a timeline of the political and graphic history of the country through its colophons. Colophons, which appear at the end of books and thus are often ignored, are nonetheless providers of essential information—witnesses of our progress in authorship and as a society.
A Grammar of Religious “Truth”: Pragmatic Considerations on the Nature of Religious Truth
Authors: Albinus Lars
Published: November 2017

This article explores various ways in which the concept of truth is actually used across discursive boundaries separating common sense, science, mathematics, and religion. Although my overall approach is pragmatic, I argue that we also need to take some semantic restrictions into consideration. The main objective of the article is the issue of translating concepts of truth in various linguistic and cultural contexts without losing sight of the particular network of connotations. I come to the conclusion that with regard to a religious discourse, a translatable concept of truth typically enters the grammatical place of the subject rather than the predicate. From this position the discursive constraints of authority, authenticity and expressivity are held in check by an internal predetermination of the implied possibility of falsehood. Most of all, however, the article focuses on non-propositional aspects of a religious expression of truth, in which case the very distinction between true and false becomes patently irrelevant.
Cooperation, Competence and Coherence: The Role of Regional Ocean Governance in the South West Pacific for the Conservation and Sustainable Use of Biodiversity beyond National Jurisdiction
Authors: Quirk Genevieve C. , Harden-Davies Harriet R.
Published: November 2017

unga Resolution 69/292 requires that the development of an international legally binding instrument (ilbi) for the conservation and sustainable use of biodiversity in areas beyond national jurisdiction (abnj) under the United Nations Convention on the Law of the Sea should not undermine existing relevant legal instruments and frameworks and relevant global, regional and sectoral bodies. The South West Pacific regional oceans governance framework is reviewed, highlighting the importance of dedicated mechanisms for cooperation in the integration of regional institutions and in collective diplomacy for the development of an ilbi. It is argued a sufficiently inclusive description of existing arrangements under an ilbi is needed to not undermine the competence or integration of the regional architecture for oceans’ governance. Shared governance principles between an ilbi and existing regional governance architecture could play an important role in preserving coherence and contribute to ensuring regional standards for conservation of bbnj are not diminished.
The Relevance of the Southern Ocean to the Development of a Global Regime for Marine Areas beyond National Jurisdiction—An Uncommon Commons
Authors: Johnson Constance M.
Published: November 2017

The Southern Ocean’s areas beyond national jurisdiction (abnj) are uncommon in a number of ways. This article first discusses features of the Southern Ocean’s uncommonness that may be relevant to the relationship between the Antarctic Treaty System (ats) and the development of the international legally binding instrument on the conservation and sustainable use of marine biological diversity of abnj under United Nations General Assembly Resolution 69/292 (ilbi). Second, the article considers the potential relationship between the ilbi and the ats. Third, the article discusses the current approach of the ats to governance of the Southern Ocean’s abnj by focusing on two particular topics which are to be included in the development of the ilbi. The topics discussed are measures (such as area-based management, including marine protected areas) and marine genetic resources.
What is Art?
Authors: Andina Tiziana
Published: November 2017

‘What is art?’ is one of the classic questions that philosophy has addressed over the ages, from the ancients to today. Taking as its starting point debates over the various definitions of art found in history, this article presents and discusses some of the major theories offered by both the analytic and continental traditions. It then looks at the theoretical reasons that led twentieth-century philosophy to reopen the question of definition, and in many cases inquire into the ontology of art itself. Finally, a series of considerations are addressed to help shift the problem of definition onto a new plane, one that is able to respond to the challenges of the performing and participatory arts, which more than any other form of art present particularly unconventional ontologies.
Clarifying the identity of Geastrum campestre var. famatinum (Geastrales, Basidiomycota)
Authors: ZAMORA JUAN CARLOS , DIOS MARIA MARTHA , MORENO GABRIEL
Published: November 2017

The identity of the holotype specimen of G. campestre var. famatinum is investigated through both morphological and molecular approaches. Morphological data and molecular data of ITS, 28S, rpb1 and atp6 DNA regions confirm that G. campestre var. famatinum is a different species to G. campestre var. campestre, and that it should belong to G. sect. Hariotia instead of G. sect. Campestria. However, the analyses performed also show that the type specimen of G. campestre var. famatinum is better included within the intraspecific variation of a previously described species, G. parvisporum, so both names are considered as heterotypic synonyms.
A new species of Rhizocybe (tricholomatoid clade, Agaricales) from Yunnan, China
Authors: DING YUXIANG , TIAN ENJING , ALVARADO PABLO
Published: November 2017

The new species name Rhizocybe alba is proposed here to accommodate some specimens recently collected from Kunming in the Yunnan province of China. The new species has a completely white basidiomata, a compressed and tortuous stipe, and conspicuous white rhizomorphs. A detailed description, drawings and images of the new species are provided, as well as two different phylogenetic analyses based on ITS data and a four-loci (28S and 18S rDNA, tef1, rpb2) DNA sequence alignment.