bluuebunny/crossref_metadata_2025_split huggingface dataset:
How can we improve our understanding of cardiovascular safety liabilities to develop safer medicines?
Authors: Laverty HG , Benson C , Cartwright EJ , Cross MJ , Garland C , Hammond T , Holloway C , McMahon N , Milligan J , Park BK , Pirmohamed M , Pollard C , Radford J , Roome N , Sager P , Singh S , Suter T , Suter W , Trafford A , Volders PGA , Wallis R , Weaver R , York M , Valentin JP 
Published: February 2011

Given that cardiovascular safety liabilities remain a major cause of drug attrition during preclinical and clinical development, adverse drug reactions, and post‐approval withdrawal of medicines, the Medical Research Council Centre for Drug Safety Science hosted a workshop to discuss current challenges in determining, understanding and addressing ‘Cardiovascular Toxicity of Medicines’. This article summarizes the key discussions from the workshop that aimed to address three major questions: (i) what are the key cardiovascular safety liabilities in drug discovery, drug development and clinical practice? (ii) how good are preclinical and clinical strategies for detecting cardiovascular liabilities? and (iii) do we have a mechanistic understanding of these liabilities? It was concluded that in order to understand, address and ultimately reduce cardiovascular safety liabilities of new therapeutic agents there is an urgent need to:
Fully characterize the incidence, prevalence and impact of drug‐induced cardiovascular issues at all stages of the drug development process.
Ascertain the predictive value of existing non‐clinical models and assays towards the clinical outcome.
Understand the mechanistic basis of cardiovascular liabilities; by addressing areas where it is currently not possible to predict clinical outcome based on preclinical safety data.
Provide scientists in all disciplines with additional skills to enable them to better integrate preclinical and clinical data and to better understand the biological and clinical significance of observed changes.
Develop more appropriate, highly relevant and predictive tools and assays to identify and wherever feasible to eliminate cardiovascular safety liabilities from molecules and wherever appropriate to develop clinically relevant and reliable safety biomarkers.
Pharmacological relevance and potential of sphingosine 1‐phosphate in the vascular system
Authors: Schuchardt Mirjam , Tölle Markus , Prüfer Jasmin , van der Giet Markus 
Published: February 2011

Sphingosine‐1‐phosphate (S1P) was identified as a crucial molecule for regulating immune responses, inflammatory processes as well as influencing the cardiovascular system. S1P mediates differentiation, proliferation and migration during vascular development and homoeostasis. S1P is a naturally occurring lipid metabolite and is present in human blood in nanomolar concentrations. S1P is not only involved in physiological but also in pathophysiological processes. Therefore, this complex signalling system is potentially interesting for pharmacological intervention. Modulation of the system might influence inflammatory, angiogenic or vasoregulatory processes. S1P activates G‐protein coupled receptors, namely S1P1–5, whereas only S1P1–3 is present in vascular cells. S1P can also act as an intracellular signalling molecule. This review highlights the pharmacological potential of S1P signalling in the vascular system by giving an overview of S1P‐mediated processes in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). After a short summary of S1P metabolism and signalling pathways, the role of S1P in EC and VSMC proliferation and migration, the cause of relaxation and constriction of arterial blood vessels, the protective functions on endothelial apoptosis, as well as the regulatory function in leukocyte adhesion and inflammatory responses are summarized. This is followed by a detailed description of currently known pharmacological agonists and antagonists as new tools for mediating S1P signalling in the vasculature. The variety of effects influenced by S1P provides plenty of therapeutic targets currently under investigation for potential pharmacological intervention.LINKED ARTICLES This article is one of a set of reviews submitted to BJP in connection with talks given at the September 2010 meeting of the International Society of Hypertension in Vancouver, Canada. To view the other articles in this collection visit http://dx.doi.org/10.1111/j.1476‐5381.2010.01167.x, http://dx.doi.org/10.1111/j.1476‐5381.2011.01235.x and http://dx.doi.org/10.1111/j.1476‐5381.2011.01366.x
Newman, the Church of England and the Catholic Church
Authors: Rowell Geoffrey 
Published: February 2011

AbstractNewman was formed in the Church of England and all his major theological concerns were developed in an Anglican context. The rebuttal of utilitarian scepticism in the University Sermons; the ecclesial context of Christian faith and life in The Lectures on the Prophetical Office of the Church; the strong sense of mystery in Newman's epistemology and apologetic; the sacramental character of Christian truth are all significantly part of the Anglican inheritance that he took to the Roman Catholic Church. Furthermore Newman's early formation was ‘pre-Victorian’– he was engaged when writing his Essay on Scriptural Miracles with earlier debates with the Deists, as well as sharing in the rediscovery of the imagination that characterised Coleridge and the Romantic Movement. This paper explores these and other issues to show an important part of Newman's enduring Anglican inheritance.
Generation of melanocytes from neural crest cells
Authors: Sommer Lukas 
Published: February 2011

SummaryThe neural crest is a transient structure in vertebrate embryos that generates multiple neural and mesenchymal cell types as well as melanocytes. Melanocytes in the skin either derive directly from neural crest cells populating the skin via a dorsolateral migratory pathway or arise by detaching from nerves innervating the skin. Several transcription factors, such as FoxD3, Sox10, Pax3, and Mitf, take part in a genetic network regulating melanocyte formation from the neural crest. The activity of these intrinsic factors is controlled and modulated by extracellular signals including canonical Wnt, Edn, Kitl, and other signals that remain to be identified. Here, we summarize the current view of how melanocytes are specified from the neural crest and put this process into the context of spatiotemporal lineage decisions in neural crest cells.
Sur le rang des courbes elliptiques sur les corps de classes de Hilbert
Authors: Templier Nicolas 
Published: February 2011

AbstractLetE/ℚ be an elliptic curve and letD<0 be a sufficiently large fundamental discriminant. If$E(\overline {\BmQ })$contains Heegner points of discriminantD, those points generate a subgroup of rank at least |D|δ, whereδ>0 is an absolute constant. This result is compatible with the Birch and Swinnerton-Dyer conjecture.
Neem Leaf Glycoprotein Partially Rectifies Suppressed Dendritic Cell Functions and Associated T Cell Efficacy in Patients with Stage IIIB Cervical Cancer
Authors: Roy Soumyabrata , Goswami Shyamal , Bose Anamika , Chakraborty Krishnendu , Pal Smarajit , Haldar Atanu , Basu Parthasarathi , Biswas Jaydip , Baral Rathindranath 
Published: February 2011

ABSTRACTMyeloid-derived dendritic cells (DCs) generated from monocytes obtained from stage IIIB cervical cancer (CaCx IIIB) patients show dysfunctional maturation; thus, antitumor T cell functions are dysregulated. In an objective to optimize these dysregulated immune functions, the present study is focused on the ability of neem leaf glycoprotein (NLGP), a nontoxic preparation of the neem leaf, to induce optimum maturation of dendritic cells from CaCx IIIB patients.In vitroNLGP treatment of immature DCs (iDCs) obtained from CaCx IIIB patients results in upregulated expression of various cell surface markers (CD40, CD83, CD80, CD86, and HLA-ABC), which indicates DC maturation. Consequently, NLGP-matured DCs displayed balanced cytokine secretions, with type 1 bias and noteworthy functional properties. These DCs displayed substantial T cell allostimulatory capacity and promoted the generation of cytotoxic T lymphocytes (CTLs). Although NLGP-matured DCs derived from CaCx monocytes are generally subdued compared to those with a healthy monocyte origin, considerable revival of the suppressed DC-based immune functions is notedin vitroat a fairly advanced stage of CaCx, and thus, further exploration ofex vivoandin vivoDC-based vaccines is proposed. Moreover, the DC maturating efficacy of NLGP might be much more effective in the earlier stages of CaCx, where the extent of immune dysregulation is less and, thus, the scope of further investigation may be explored.
Hydrolyzable Tannins (Chebulagic Acid and Punicalagin) Target Viral Glycoprotein-Glycosaminoglycan Interactions To Inhibit Herpes Simplex Virus 1 Entry and Cell-to-Cell Spread
Authors: Lin Liang-Tzung , Chen Ting-Ying , Chung Chueh-Yao , Noyce Ryan S. , Grindley T. Bruce , McCormick Craig , Lin Ta-Chen , Wang Guey-Horng , Lin Chun-Ching , Richardson Christopher D. 
Published: February 2011

ABSTRACT

Herpes simplex virus 1 (HSV-1) is a common human pathogen that causes lifelong latent infection of sensory neurons. Non-nucleoside inhibitors that can limit HSV-1 recurrence are particularly useful in treating immunocompromised individuals or cases of emerging acyclovir-resistant strains of herpesvirus. We report that chebulagic acid (CHLA) and punicalagin (PUG), two hydrolyzable tannins isolated from the dried fruits of
Terminalia chebula
Retz. (
Combretaceae
), inhibit HSV-1 entry at noncytotoxic doses in A549 human lung cells. Experiments revealed that both tannins targeted and inactivated HSV-1 viral particles and could prevent binding, penetration, and cell-to-cell spread, as well as secondary infection. The antiviral effect from either of the tannins was not associated with induction of type I interferon-mediated responses, nor was pretreatment of the host cell protective against HSV-1. Their inhibitory activities targeted HSV-1 glycoproteins since both natural compounds were able to block polykaryocyte formation mediated by expression of recombinant viral glycoproteins involved in attachment and membrane fusion. Our results indicated that CHLA and PUG blocked interactions between cell surface glycosaminoglycans and HSV-1 glycoproteins. Furthermore, the antiviral activities from the two tannins were significantly diminished in mutant cell lines unable to produce heparan sulfate and chondroitin sulfate and could be rescued upon reconstitution of heparan sulfate biosynthesis. We suggest that the hydrolyzable tannins CHLA and PUG may be useful as competitors for glycosaminoglycans in the management of HSV-1 infections and that they may help reduce the risk for development of viral drug resistance during therapy with nucleoside analogues.
Epstein-Barr Virus LMP1 Activates EGFR, STAT3, and ERK through Effects on PKCδ
Authors: Kung Che-Pei , Meckes David G. , Raab-Traub Nancy 
Published: February 2011

ABSTRACT
Epstein-Barr virus (EBV) is a ubiquitous herpesvirus that infects more than 90% of the world's adult population and is linked to multiple malignancies, including Burkitt lymphoma, Hodgkin disease, and nasopharyngeal carcinoma (NPC). The EBV oncoprotein LMP1 induces transcription of the epidermal growth factor receptor (EGFR), which is expressed at high levels in NPC. EGFR transcription is induced by LMP1 through a p50 NFκB1-Bcl-3 complex, and Bcl-3 is induced by LMP1-mediated activation of STAT3. This study reveals that LMP1, through its carboxyl-terminal activation domain 1 (LMP1-CTAR1), activates both STAT3 and EGFR in a serum-independent manner with constitutive serine phosphorylation of STAT3. Upon treatment with EGF, the LMP1-CTAR1-induced EGFR was additionally phosphorylated and STAT3 became phosphorylated on tyrosine, concomitant with upregulation of a subset of STAT3 target genes. The kinase responsible for LMP1-CTAR1-mediated serine phosphorylation of STAT3 was identified to be PKCδ using specific RNAi, a dominant negative PKCδ, and the PKCδ inhibitor rottlerin. Interestingly, inhibition of PKCδ also inhibited constitutive phosphorylation of EGFR and LMP1-CTAR1-induced phosphorylation of ERK. Inhibition of PKCδ blocked LMP1-CTAR1-mediated transformation of Rat-1 cells, likely through the inhibition of ERK activation. These findings indicate that LMP1 activates multiple distinct signaling pathways and suggest that PKCδ functions as a master regulator of EGFR, STAT3, and ERK activation by LMP1-CTAR1.
The Leader Proteinase of Foot-and-Mouth Disease Virus Negatively Regulates the Type I Interferon Pathway by Acting as a Viral Deubiquitinase
Authors: Wang Dang , Fang Liurong , Li Ping , Sun Li , Fan Jinxiu , Zhang Qingye , Luo Rui , Liu Xiangtao , Li Kui , Chen Huanchun , Chen Zhongbin , Xiao Shaobo 
Published: February 2011

ABSTRACT

The leader proteinase (L
pro
) of foot-and-mouth disease virus (FMDV) is a papain-like proteinase that plays an important role in FMDV pathogenesis. Previously, it has been shown that L
pro
is involved in the inhibition of the type I interferon (IFN) response by FMDV. However, the underlying mechanisms remain unclear. Here we demonstrate that FMDV Lb
pro
, a shorter form of L
pro
, has deubiquitinating activity. Sequence alignment and structural bioinformatics analyses revealed that the catalytic residues (Cys51 and His148) are highly conserved in FMDV Lb
pro
of all seven serotypes and that the topology of FMDV Lb
pro
is remarkably similar to that of ubiquitin-specific protease 14 (USP14), a cellular deubiquitylation enzyme (DUB), and to that of severe acute respiratory syndrome coronavirus (SARS-CoV) papain-like protease (PLpro), a coronaviral DUB. Both purified Lb
pro
protein and
in vivo
ectopically expressed Lb
pro
removed ubiquitin (Ub) moieties from cellular substrates, acting on both lysine-48- and lysine-63-linked polyubiquitin chains. Furthermore, Lb
pro
significantly inhibited ubiquitination of retinoic acid-inducible gene I (RIG-I), TANK-binding kinase 1 (TBK1), TNF receptor-associated factor 6 (TRAF6), and TRAF3, key signaling molecules in activation of type I IFN response. Mutations in Lb
pro
that ablate the catalytic activity (C51A or D163N/D164N) or disrupt the SAP (for
S
AF-A/B,
A
cinus, and
P
IAS) domain (I83A/L86A) abrogated the DUB activity of Lb
pro
as well as its ability to block signaling to the IFN-β promoter. Collectively, these results demonstrate that FMDV Lb
pro
possesses DUB activity in addition to serving as a viral proteinase and describe a novel mechanism evolved by FMDV to counteract host innate antiviral responses.
A Novel Human Polyomavirus Closely Related to the African Green Monkey-Derived Lymphotropic Polyomavirus
Authors: Scuda Nelly , Hofmann Jörg , Calvignac-Spencer Sébastien , Ruprecht Klemens , Liman Peter , Kühn Joachim , Hengel Hartmut , Ehlers Bernhard 
Published: February 2011

ABSTRACT
We identified a novel human polyomavirus from a kidney transplant patient under immunosuppressive treatment, by use of a generic PCR. The genome of the virus was completely amplified and sequenced. In phylogenetic analyses, it appeared as the closest relative to the African green monkey-derived lymphotropic polyomavirus (LPV). Further investigation of clinical samples from immunocompromised patients with specific nested PCR revealed additional positive samples, indicating that the virus naturally infects humans. The virus was tentatively named human polyomavirus 9 (HPyV9). The previously observed seroreactivity to LPV in human populations might find a partial explanation in the circulation of HPyV9.
The Early Interferon Response to Rotavirus Is Regulated by PKR and Depends on MAVS/IPS-1, RIG-I, MDA-5, and IRF3
Authors: Sen Adrish , Pruijssers Andrea J. , Dermody Terence S. , García-Sastre Adolfo , Greenberg Harry B. 
Published: February 2011

ABSTRACT

In mouse embryonic fibroblasts (MEFs), the bovine rotavirus (UK strain) but not the simian rhesus rotavirus (RRV) robustly triggers beta interferon (IFN-β) secretion, resulting in an IFN-dependent restriction of replication. We now find that both rotavirus strains trigger antiviral transcriptional responses early during infection and that both transcriptional responses and IFN-β secretion are completely abrogated in MAVS/IPS-1
−/−
MEFs. Replication of UK virus could be rescued in MAVS/IPS-1
−/−
MEFs, and synthesis of viral RNA significantly increased early during virus infection. UK virus induced IFN-β secretion and transcription of IFN-stimulated genes (ISGs) in both RIG-I
−/−
and MDA-5
−/−
MEFs, and neither receptor was essential by itself for the antiviral response to UK rotavirus. However, when receptors RIG-I and MDA-5 were depleted using RNA interference, we found that both contribute to the magnitude of the IFN response. IRF3 was found to be essential for MAVS/IPS-1-directed ISG transcription and IFN-β secretion during rotavirus infection. Interestingly, absence of the double-stranded RNA-dependent protein kinase PKR led to a profound defect in the capacity of host cells to secrete IFN-β in response to virus. Both PKR and IRF3 restricted the early replication of UK as indicated by significant increases in viral RNA in fibroblasts lacking either gene. Despite the loss in IFN-β secretion in PKR
−/−
MEFs, we did not observe decreased IRF3- or NF-κB-dependent early ISG transcription in these cells. Levels of transcripts encoding IFN-α4, IFN-α5, and IFN-β were high in infected PKR
−/−
MEFs, indicating that during rotavirus infection, PKR functions at a stage between IFN gene transcription and subsequent IFN-β secretion. These findings reveal that activation of the antiviral response by rotavirus is dependent on MAVS/IPS-1 and IRF3 and involves both RIG-I and MDA-5 and that IFN-β secretion during rotavirus infection is regulated by PKR.
Osteoprotegerin, RANKL and bone turnover in postmenopausal osteoporosis
Authors: Jabbar Suhair , Drury John , Fordham John N , Datta Harish K , Francis Roger M , Tuck Stephen P 
Published: February 2011

BackgroundOsteoprotegerin (OPG) and receptor activator of nuclear factor κ B ligand (RANKL) play a critical role in the regulation of bone turnover, but the relative importance of these two cytokines in the pathogenesis of postmenopausal osteoporosis is controversial.AimTo investigate the relationship between circulating levels of OPG, RANKL, bone turnover and bone mineral density (BMD) in postmenopausal women.MethodsA cross-sectional study of 185 women with osteoporosis and 185 age- and sex-matched control subjects was undertaken. Measurements were made of plasma OPG, RANKL, interleukin-6 (IL-6), sex steroids, calciotropic hormones, biochemical markers of bone turnover, BMD and anthropometry. Health questionnaires were administered.ResultsPlasma RANKL was significantly higher (p<0.0001) in women with osteoporosis (0.66±0.67 pmol/l) than in control subjects (0.37±0.38 pmol/l), as was plasma OPG (18.70±9.70 pmol/l in women with osteoporosis, 10.44±5.85 pmol/l in control subjects; p<0.0001). OPG/RANKL ratio was higher in women with osteoporosis (51.3) than in control subjects (36.6). The women with osteoporosis also had significantly higher biochemical markers of bone turnover, IL-6 and parathyroid hormone and lower 25-hydroxyvitamin D and oestradiol than the control subjects. Multiple regression analysis showed that lumbar spine and femoral neck BMD in postmenopausal women were best predicted by OPG and RANKL, giving an R2value of 15.5% and 14.9%, respectively.ConclusionsThis study indicates that the circulating levels of OPG and RANKL are inversely related to BMD and contribute to the development of osteoporosis in postmenopausal women.
The ideal application of surveillance technology in residential care for people with dementia
Authors: Niemeijer Alistair R , Frederiks Brenda J M , Depla Marja F I A , Legemaate Johan , Eefsting Jan A , Hertogh Cees M P M 
Published: February 2011

BackgroundAs our society is ageing, nursing homes are finding it increasingly difficult to deal with an expanding population of patients with dementia and a decreasing workforce. A potential answer to this problem might lie in the use of technology. However, the use and application of surveillance technology in dementia care has led to considerable ethical debate among healthcare professionals and ethicists, with no clear consensus to date.AimTo explore how surveillance technology is viewed by care professionals and ethicists working in the field, by investigating the ideal application of surveillance technology in the residential care of people with dementia.MethodsUse was made of the concept mapping method, a computer-assisted procedure consisting of five steps: brainstorming, prioritising, clustering, processing by the computer and analysis. Various participants (ranging from ethicists to physicians and nurses) were invited on the basis of their professional background.ResultsThe views generated are grouped into six categories ranging from the need for a right balance between freedom and security, to be beneficial and tailored to the resident, and clearly defined procedures to competent and caring personnel, active monitoring and clear normative guidance. The results are presented in the form of a graphic chart.ConclusionsThere appears to be an inherent duality in the views on using surveillance technology which is rooted in the moral conflict between safety and freedom. Elaboration of this ethical issue has proved to be very difficult.
Ultrasonographic evaluation of the adrenal glands in healthy dogs: repeatability, reproducibility, observer‐dependent variability, and the effect of bodyweight, age and sex
Authors: Mogicato G. , Layssol‐Lamour C. , Conchou F. , Diquelou A. , Raharison F. , Sautet J. , Concordet D. 
Published: February 2011

Adrenal length and width were determined from two‐dimensional ultrasound longitudinal images. In study 1, 540 measurements of adrenal glands were attempted from five healthy beagle dogs by three different observers with different levels of expertise in ultrasonography, to determine the variability of adrenal gland measurements. Of these, 484 measurements were included in the statistical analysis, since 16 measurements of the left adrenal gland and 40 for the right could not be visualised by the observer. In study 2, a single measurement of both adrenal glands was taken from each of 146 dogs by the most trained observer from study 1, and the effects of different health status (healthy dogs v dogs with non‐adrenal diseases), bodyweight, age and sex were assessed. A total of 267 measurements were included in the statistical analysis. The lowest intra‐ and inter‐day coefficient of variation values were observed for the left adrenal gland and by the most trained observer. The health status had no statistically significant effect on adrenal gland length or width, whereas age had a significant effect only for the left adrenal gland (the greater the age, the greater the width or length) and sex had a significant effect only for the right adrenal gland (the width was larger in males and the length larger in females). The bodyweight had a significant effect for the length of both adrenal glands (the greater the bodyweight, the greater the length), but not the width. The differences between sd and coefficient of variation values for the width of the left adrenal gland were not statistically significant between the three observers, whereas they were statistically significant for the right adrenal gland.