bluuebunny/crossref_metadata_2025 huggingface dataset:
Ignoring Versus Exploring Differences Between Groups: Effects of Salient Color‐Blindness and Multiculturalism on Intergroup Attitudes and Behavior
Authors: Sasaki Stacey J. , Vorauer Jacquie D.
Published: March 2013

Multiculturalism and color‐blindness represent distinct, and in many ways conflicting, approaches to intergroup relations. We provide a review of the research and theory guiding use of these ideologies as prejudice reduction strategies: Is it best for individuals to ignore category memberships and focus on fundamental human qualities that everyone shares, as color‐blindness would suggest? Or should people adhere to multicultural ideals, recognizing and indeed celebrating differences between groups? After describing these ideologies and their respective theoretical underpinnings, we examine their effects on attitudes, perceptions, and intergroup interaction behavior. We emphasize in particular the link from color‐blindness to self‐focus and prevention orientation and from multiculturalism to an other‐focused learning orientation. Although color‐blindness can have positive effects in the short term, the efforts that it prompts to inhibit and suppress negative responses can be taxing and difficult to sustain. Multiculturalism triggers more positive intergroup attitudes and behavior in nonconflictual circumstances, but has the opposite effect in threatening situations. Nonetheless, because it leads to a focus on learning about others in intergroup situations multiculturalism has the virtue of generally fostering greater attention and responsiveness to outgroup members.
Lack of recognition of HLA class I mismatches outside α1/α2 domains by CD8+ alloreactive T lymphocytes: the HLA‐B44 paradigm
Authors: Bettens F. , Schanz U. , Tiercy J.‐M.
Published: March 2013

Transplantation with hematopoietic stem cells (HSC) from a donor with a single human leukocyte antigen (HLA) mismatch can be proposed to those patients lacking an HLA identical sibling donor or an unrelated donor matched for the HLA‐A, ‐B, ‐C, DRB1, DQB1 loci. Incompatibilities at HLA classes I and II loci are associated with an increased risk of graft‐versus‐host disease (GVHD) and mortality, although no consensus exists yet on the relative importance of specific allele disparities on clinical outcome. Donor search algorithms are now complicated by the growing number of new HLA alleles, in particular those that differ outside the peptide‐binding site of the HLA molecules. We report here an in vitro cellular assay to quantify CD8+CD137+ alloreactive cytotoxic T lymphocytes (CTLs) in a one‐way mixed lymphocyte reaction. Two unique combinations with a single HLA mismatch in the HLA‐B44 serotype differing by one amino acid in the α3 domain were investigated. We show that the B*44:27 versus B*44:02 mismatch was not recognized by CTLs in both directions. At days 10 and 20, the frequency of CD8+CD137+T cells was comparable to that measured in the autologous stimulation (0.3–3.9%). A B*44:02 versus B*44:03 mismatch was, however, well recognized at day 10 (7.2%) and day 20 (17.8%). This is the first demonstration that a single HLA‐B mismatch involving a residue outside the peptide‐binding site is not recognized in an in vitro functional assay and may probably be considered as a permissive incompatibility in vivo.
Real-Time Observation of Surface Bond Breaking with an X-ray Laser
Authors: Dell'Angela M. , Anniyev T. , Beye M. , Coffee R. , Föhlisch A. , Gladh J. , Katayama T. , Kaya S. , Krupin O. , LaRue J. , Møgelhøj A. , Nordlund D. , Nørskov J. K. , Öberg H. , Ogasawara H. , Öström H. , Pettersson L. G. M. , Schlotter W. F. , Sellberg J. A. , Sorgenfrei F. , Turner J. J. , Wolf M. , Wurth W. , Nilsson A.
Published: March 2013

Surface Molecules Not Quite Desorbing

The dynamics of molecules desorbing from or adsorbing on surfaces requires that molecules rapidly gain or lose a large amount or translational and rotational energy to enter or leave the gas phase. An intermediate precursor state has long been invoked in which molecules interact weakly with the surface but translate along it and exchange energy without forming localized surface bonds.

Dell'Angela
et al.

(p.
1302
) found evidence for such a state in changes in x-ray absorption and emission spectra of CO molecules adsorbed on a ruthenium surface after optical excitation rapidly heated the surface. The use of a free electron laser provided high time resolution for x-ray spectroscopy studies. Density function theory and modeling of high temperature states revealed a state that forms from molecules that have not overcome the desorption barrier during heating and that are bonded less strongly than the chemisorbed state.
A Flawed Challenge Worth Pondering
Mind and Cosmos
Why the Materialist Neo-Darwinian Conception of Nature Is Almost Certainly False

by Thomas Nagel

Oxford University Press, Oxford, 2012. 140 pp. $24.95, £15.99. ISBN 9780199919758.
Authors: Musholt Kristina
Published: March 2013

Nagel argues that the natural sciences leave "us necessarily in the dark about consciousness" and that thus they "cannot provide the basic form of intelligibility for this world."
Creating Flexible Calcite Fibers with Proteins
Authors: Sethmann Ingo
Published: March 2013

Fracture-resistant calcium carbonate fibers were made by using a protein that normally directs silica spicule formation in sponges.

[Also see Report by

Natalio
et al.

]
Cracking the Mercury Methylation Code
Authors: Poulain Alexandre J. , Barkay Tamar
Published: March 2013

Identification of two genes involved in mercury methylation may help to develop biomarkers to track and manage mercury contamination in the environment.

[Also see Report by

Parks
et al.

]
Approaching the Limits
Harvesting the Biosphere
What We Have Taken from Nature

by Vaclav Smil

MIT Press, Cambridge, MA, 2012. 315 pp. $29, £19.95. ISBN 9780262018562.
Authors: Running Steven W.
Published: March 2013

Ranging from prehistory to the present, Smil offers a quantitative global survey of human exploitation of the living world.
How HIF-1α Handles Stress
Authors: Huang L. Eric
Published: March 2013

A transcription factor responds to low oxygen by controlling gene expression, DNA replication, and cell division to promote survival.
The Frequency of Very Large Earthquakes
Authors: Chinnery Michael A. , North Robert G.
Published: March 2013

Observational data relating surface wave magnitude
M
s
to seismic moment
M
0
are used to convert a well-known frequency-
M
s
plot into a frequency-
M
0
relationship, which turns out to be remarkably linear. There is no evidence of an upper bound to
M
0
, on the basis of presently available evidence. The possibility exists that extremely large earthquakes (
M
0
= 10
31
dyne-centimeters or greater) may occur from time to time.
Dramatic Fossils Suggest Early Birds Were Biplanes
Authors: Balter Michael
Published: March 2013

Eleven beautifully preserved skeletons of early birds provide evidence that having four wings—not two—was the ancestral condition for early birds.
War Stories
Authors: Enserink Martin
Published: March 2013

In 2003, the world successfully fought off a new disease that could have become a global catastrophe. A decade after the SARS outbreak, how much safer are we?
SARS: Chronology of the Epidemic
Authors: Enserink Martin
Published: March 2013

In 2003, the world successfully fought off a new disease that could have become a global catastrophe. Here's what happened from the first case to the end of the epidemic.
Understanding the Enemy
Authors: Normile Dennis
Published: March 2013

Research sparked by the SARS outbreak increased the understanding of emerging diseases, though much remains to be learned.
A Conserved Region of Leptospiral Immunoglobulin-Like A and B Proteins as a DNA Vaccine Elicits a Prophylactic Immune Response against Leptospirosis
Authors: Forster Karine M. , Hartwig Daiane D. , Seixas Fabiana K. , Bacelo Kátia L. , Amaral Marta , Hartleben Cláudia P. , Dellagostin Odir A.
Published: March 2013

The leptospiral immunoglobulin-like (Lig) proteins LigA and LigB possess immunoglobulin-like domains with 90-amino-acid repeats and are adhesion molecules involved in pathogenicity. They are conserved in pathogenicLeptospiraspp. and thus are of interest for use as serodiagnostic antigens and in recombinant vaccine formulations. The N-terminal amino acid sequences of the LigA and LigB proteins are identical, but the C-terminal sequences vary. In this study, we evaluated the protective potential of five truncated forms of LigA and LigB proteins fromLeptospira interrogansserovar Canicola as DNA vaccines using the pTARGET mammalian expression vector. Hamsters immunized with the DNA vaccines were subjected to a heterologous challenge withL. interrogansserovar Copenhageni strain Spool via the intraperitoneal route. Immunization with a DNA vaccine encoding LigBrep resulted in the survival of 5/8 (62.5%) hamsters against lethal infection (P< 0.05). None of the control hamsters or animals immunized with the other vaccine preparations survived. The vaccine induced an IgG antibody response and, additionally, conferred sterilizing immunity in 80% of the surviving animals. Our results indicate that the LigBrep DNA vaccine is a promising candidate for inclusion in a protective leptospiral vaccine.
The p53 Protein Does Not Facilitate Adenovirus Type 5 Replication in Normal Human Cells
Authors: Chahal Jasdave S. , Flint S. J.
Published: March 2013

Although several adenovirus type 5 (Ad5) proteins prevent deleterious consequences of activation of p53, it has been reported that viral replication proceeds more efficiently when human tumor cells produce wild-type compared to mutant p53. We have now exploited RNA interference and lentiviral vectors to achieve essentially complete knockdown of p53 in normal human cells: no effects on the kinetics or efficiency of viral gene expression or production of infectious particles were observed.
Dendritic Cell Immunoreceptor Regulates Chikungunya Virus Pathogenesis in Mice
Authors: Long Kristin M. , Whitmore Alan C. , Ferris Martin T. , Sempowski Gregory D. , McGee Charles , Trollinger Bianca , Gunn Bronwyn , Heise Mark T.
Published: March 2013

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus responsible for recent epidemic outbreaks of debilitating disease in humans. Alphaviruses are known to interact with members of the C-type lectin receptor family of pattern recognition proteins, and given that the dendritic cell immunoreceptor (DCIR) is known to act as a negative regulator of the host inflammatory response and has previously been associated with rheumatoid arthritis, we evaluated DCIR's role in response to CHIKV infection. Although we observed an increase in the proportion of dendritic cells at the site of CHIKV infection at 24 to 36 h postinfection, these cells showed decreased cell surface DCIR, suggestive of DCIR triggering and internalization.In vitro, bone marrow-derived dendritic cells from DCIR-deficient (DCIR−/−) mice exhibited altered cytokine expression following exposure to CHIKV. DCIR−/−mice exhibited more severe disease signs than wild-type C57BL6/J mice following CHIKV infection, including a more rapid and more severe onset of virus-induced edema and enhanced weight loss. Histological examination revealed that DCIR-deficient animals exhibited increased inflammation and damage in both the fascia of the inoculated foot and the ankle joint, and DCIR deficiency skewed the CHIKV-induced cytokine response at the site of infection at multiple times postinfection. Early differences in virus-induced disease between C57BL6/J and DCIR−/−mice were independent of viral replication, while extended viral replication correlated with enhanced foot swelling and tissue inflammation and damage in DCIR−/−compared to C57BL6/J mice at 6 to 7 days postinfection. These results suggest that DCIR plays a protective role in limiting the CHIKV-induced inflammatory response and subsequent tissue and joint damage.
A Proautophagic Antiviral Role for the Cellular Prion Protein Identified by Infection with a Herpes Simplex Virus 1 ICP34.5 Mutant
Authors: Korom Maria , Wylie Kristine M. , Wang Hong , Davis Katie L. , Sangabathula Meher S. , DeLassus Gregory S. , Morrison Lynda A.
Published: March 2013

The cellular prion protein (PrP) often plays a cytoprotective role by regulating autophagy in response to cell stress. The stress of infection with intracellular pathogens can stimulate autophagy, and autophagic degradation of pathogens can reduce their replication and thus help protect the infected cells. PrP also restricts replication of several viruses, but whether this activity is related to an effect on autophagy is not known. Herpes simplex virus 1 (HSV-1) effectively counteracts autophagy through binding of its ICP34.5 protein to the cellular proautophagy protein beclin-1. Autophagy can reduce replication of an HSV-1 mutant, Δ68H, which is incapable of binding beclin-1. We found that deletion of PrP in mice complements the attenuation of Δ68H, restoring its capacity to replicate in the central nervous system (CNS) to wild-type virus levels after intracranial or corneal infection. Cultured primary astrocytes but not neurons derived from PrP
−/−
mice also complemented the attenuation of Δ68H, enabling Δ68H to replicate at levels equivalent to wild-type virus. Ultrastructural analysis showed that normal astrocytes exhibited an increase in the number of autophagosomes after infection with Δ68H compared with wild-type virus, but PrP
−/−
astrocytes failed to induce autophagy in response to Δ68H infection. Redistribution of EGFP-LC3 into punctae occurred more frequently in normal astrocytes infected with Δ68H than with wild-type virus, but not in PrP
−/−
astrocytes, corroborating the ultrastructural analysis results. Our results demonstrate that PrP is critical for inducing autophagy in astrocytes in response to HSV-1 infection and suggest that PrP positively regulates autophagy in the mouse CNS.
Crystal Structure of Enterovirus 71 RNA-Dependent RNA Polymerase Complexed with Its Protein Primer VPg: Implication for a
trans
Mechanism of VPg Uridylylation
Authors: Chen Cheng , Wang Yaxin , Shan Chao , Sun Yuna , Xu Peng , Zhou Honggang , Yang Cheng , Shi Pei-Yong , Rao Zihe , Zhang Bo , Lou Zhiyong
Published: March 2013

Picornavirus RNA replication is initiated by VPg uridylylation, during which the hydroxyl group of the third tyrosine residue of the virally encoded protein VPg is covalently linked to two UMP molecules by RNA-dependent RNA polymerase (RdRp; also known as 3D
pol
). We previously identified site 311, located at the base of the palm domain of the enterovirus 71 (EV71) RdRp, to be the site for EV71 VPg binding and uridylylation. Here we report the crystal structure of EV71 3D
pol
complexed with VPg. VPg was anchored at the bottom of the palm domain of the 3D
pol
molecule and exhibited an extended V-shape conformation. The corresponding interface on 3D
pol
was mainly formed by residues within site 311 and other residues in the palm and finger domains. Mutations of the amino acids of 3D
pol
involved in the VPg interaction (
3D
L319A,
3D
D320A, and
3D
Y335A) significantly disrupted VPg binding to 3D
pol
, resulting in defective VPg uridylylation. In contrast, these mutations did not affect the RNA elongation activity of 3D
pol
. In the context of viral genomic RNA, mutations that abolished VPg uridylylation activity were lethal for EV71 replication. Further
in vitro
analysis showed that the uridylylation activity was restored by mixing VPg-binding-defective and catalysis-defective mutants, indicating a
trans
mechanism for EV71 VPg uridylylation. Our results, together with previous results of other studies, demonstrate that different picornaviruses use distinct binding sites for VPg uridylylation.
tatExon 1 Exhibits Functional Diversity during HIV-1 Subtype C Primary Infection
Authors: Rossenkhan Raabya , MacLeod Iain J. , Sebunya Theresa K. , Castro-Nallar Eduardo , McLane Mary Fran , Musonda Rosemary , Gashe Berhanu A. , Novitsky Vlad , Essex M.
Published: March 2013

Human immunodeficiency virus type 1 (HIV-1) Tat is a mediator of viral transcription and is involved in the control of virus replication. However, associations between HIV-1 Tat diversity and functional effects during primary HIV-1 infection are still unclear. We estimated selection pressures intatexon 1 using the mixed-effects model of evolution with 672 viral sequences generated from 20 patients infected with HIV-1 subtype C (HIV-1C) over 500 days postseroconversion.tatexon 1 residues 3, 4, 21, 24, 29, 39, and 68 were under positive selection, and we established that specific amino acid signature patterns were apparent in primary HIV-1C infection compared with chronic infection. We assessed the impact of these mutations on long terminal repeat (LTR) activity and found that Tat activity was negatively affected by the Ala21substitution identified in 13/20 (65%) of patients, which reduced LTR activity by 88% (±1%) (P< 0.001). The greatest increase in Tat activity was seen with the Gln35/Lys39double mutant that resulted in an additional 49% (±14%) production of LTR-driven luciferase (P= 0.012). There was a moderate positive correlation between Tat-mediated LTR activity and HIV-1 RNA in plasma (P= 0.026;r= 0.400) after 180 days postseroconversion that was reduced by 500 days postseroconversion (P= 0.043;r= 0.266). Although Tat activation of the LTR is not a strong predictor of these clinical variables, there are significant linear relationships between Tat transactivation and patients' plasma viral loads and CD4 counts, highlighting the complex interplay between Tat mutations in early HIV-1C infection.
Modulation of Mitogen-Activated Protein Kinase-Activated Protein Kinase 3 by Hepatitis C Virus Core Protein
Authors: Ngo Huong T. T. , Pham Long V. , Kim Jong-Wook , Lim Yun-Sook , Hwang Soon B.
Published: March 2013

Hepatitis C virus (HCV) is highly dependent on cellular proteins for its own propagation. In order to identify the cellular factors involved in HCV propagation, we performed protein microarray assays using the HCV core protein as a probe. Of ∼9,000 host proteins immobilized in a microarray, approximately 100 cellular proteins were identified as HCV core-interacting partners. Of these candidates, mitogen-activated protein kinase-activated protein kinase 3 (MAPKAPK3) was selected for further characterization. MAPKAPK3 is a serine/threonine protein kinase that is activated by stress and growth inducers. Binding of HCV core to MAPKAPK3 was confirmed by
in vitro
pulldown assay and further verified by coimmunoprecipitation assay. HCV core protein interacted with MAPKAPK3 through amino acid residues 41 to 75 of core and the N-terminal half of kinase domain of MAPKAPK3. In addition, both RNA and protein levels of MAPKAPK3 were elevated in both HCV subgenomic replicon cells and cell culture-derived HCV (HCVcc)-infected cells. Silencing of MAPKAPK3 expression resulted in decreases in both protein and HCV infectivity levels but not in the intracellular HCV RNA level. We showed that MAPKAPK3 increased HCV IRES-mediated translation and MAPKAPK3-dependent HCV IRES activity was further increased by core protein. These data suggest that HCV core may modulate MAPKAPK3 to facilitate its own propagation.
Dissociation between Transmissible Spongiform Encephalopathy (TSE) Infectivity and Proteinase K-Resistant PrP
Sc
Levels in Peripheral Tissue from a Murine Transgenic Model of TSE Disease
Authors: Dobie Karen , Barron Rona
Published: March 2013

Most current diagnostic tests for transmissible spongiform encephalopathies (TSE) rely on the presence of proteinase K (PK)-resistant PrP
Sc
(PrP-res) in postmortem tissues as an indication of TSE disease. However, a number of studies have highlighted a discrepancy between TSE infectivity and PrP-res levels in both natural and experimental cases of TSE disease. Previously, we have shown high TSE infectivity levels in the brain tissue of mice that have a clinical TSE disease with associated vacuolar pathology but little or no detectable PrP-res. Here, the levels of TSE infectivity and PrP-res within a peripheral tissue of this mouse model were investigated. Biochemical analysis showed that low levels of PrP-res were present in the spleen tissue in comparison to the levels observed in the spleen of mice infected with ME7 or 79A. However, upon subpassage of brain and spleen tissue from clinically ill mice with little or no PrP-res detectable, similar short incubation periods to disease were observed, indicating that infectivity levels were similarly high in both tissues. Thus, the discrepancy between PrP-res and TSE infectivity was also present in the peripheral tissues of this disease model. This result indicates that peripheral tissues can contain higher levels of infectivity given the correct combination of host species, PrP genotype, and TSE agent. Therefore, the assumption that the levels of peripheral infectivity are lower than those in the central nervous system is not always correct, and this could have implications for current food safety regulations.
The Herpes Simplex Virus 2 UL21 Protein Is Essential for Virus Propagation
Authors: Le Sage Valerie , Jung Masany , Alter Jake D. , Wills Elizabeth G. , Johnston Susan M. , Kawaguchi Yasushi , Baines Joel D. , Banfield Bruce W.
Published: March 2013

Herpes simplex virus 2 (HSV-2) is an important human pathogen that is the major cause of genital herpes infections and a significant contributor to the epidemic spread of human immunodeficiency virus infections. The
UL21
gene is conserved throughout the
Alphaherpesvirinae
subfamily and encodes a tegument protein that is dispensable for HSV-1 and pseudorabies virus replication in cultured cells; however, its precise functions have not been determined. To investigate the role of UL21 in the HSV-2 replicative cycle, we constructed a
UL21
deletion virus (HSV-2 ΔUL21) using an HSV-2 bacterial artificial chromosome, pYEbac373. HSV-2 ΔUL21 was unable to direct the production of infectious virus in noncomplementing cells, whereas the repaired HSV-2 ΔUL21 strain grew to wild-type (WT) titers, indicating that UL21 is essential for virus propagation. Cells infected with HSV-2 ΔUL21 demonstrated a 2-h delay in the kinetics of immediate early viral gene expression. However, this delay in gene expression was not responsible for the inability of cells infected with HSV-2 ΔUL21 to produce virus insofar as late viral gene products accumulated to WT levels by 24 h postinfection (hpi). Electron and fluorescence microscopy studies indicated that DNA-containing capsids formed in the nuclei of ΔUL21-infected cells, while significantly reduced numbers of capsids were located in the cytoplasm late in infection. Taken together, these data indicate that HSV-2 UL21 has an early function that facilitates viral gene expression as well as a late essential function that promotes the egress of capsids from the nucleus.
A rare and forgotten diagnosis of gastrointestinal bleeding: primary aortoduodenal fistula
Authors: Guner Ali , Mentese Umit , Kece Can , Kucuktulu Uzer
Published: March 2013

Upper gastrointestinal (UGI) bleeding is a common medical condition among adults. Bleeding is mainly caused by the gastric or proximal duodenum, but rarely by the distal duodenum. Aortoduodenal fistula is one of the causes of UGI bleeding that results in a life-threatening condition if not treated properly. It is commonly observed in patients who have undergone previous aortic surgery and rarely occurs in patients without a history of aortic surgery. Diagnosis of aortoenteric fistula is difficult unless there is a high level of clinical suspicion. In this article, we aim to present a patient with aortoduodenal fistula and discuss the clinical presentation, as well as the diagnostic and therapeutic options of this disease.
Seeing you through London 2012: eye care at the Olympics
Authors: D'Ath Penny J , Thomson W David , Wilson Clare M
Published: March 2013

Background

Provision of eye care services for competitors and their support teams has become an integral part of the modern Olympic Games.

Aim

To describe the organisation of the eye clinic at London 2012 over a 4-week period and provide outline audit data.

Methods

The clinic employed multidisciplinary eye care professionals and utilised state-of-the-art instrumentation to provide the highest level of eye care.

Results

A total of 1406 patients from 154 countries attended the clinic over the Olympic Games, of which, 276 were competitors. All individuals received a comprehensive refractive and ocular health examination. Minor ocular injuries, glaucoma, diabetic retinopathy and macular degeneration were among the conditions detected and managed. Most patients attended the clinic to have their refractive status checked: 973 spectacles and 50 pairs of contact lenses were dispensed.

Conclusions

It is hoped that this account of the provision of eye care at London 2012 will assist with the planning of this service at future events.
Recent advances in management of alkaptonuria (invited review; best practice article)
Authors: Ranganath Lakshminarayan R , Jarvis Jonathan C , Gallagher James A
Published: March 2013

Alkaptonuria (AKU) is an autosomal recessive condition arising as a result of a genetic deficiency of the enzyme homogentisate 1,2 dioxygenase and characterised by accumulation of homogentisic acid (HGA). Oxidative conversion of HGA leads to production of a melanin-like polymer in a process termed ochronosis. The binding of ochronotic pigment to the connective tissues of the body leads to multisystem disorder dominated by premature severe spondylo-arthropathy. Other systemic features include stones (renal, prostatic, salivary, gall bladder), renal damage/failure, osteopenia/fractures, ruptures of tendons/muscle/ligaments, respiratory compromise, hearing loss and aortic valve disease. Detection of these features requires systematic investigation. Treatment in AKU patients is palliative and unsatisfactory. Ascorbic acid, low protein diet and physiotherapy have been tried but do not alter the underlying metabolic defect. Regular surveillance to detect and treat complications early is important. Palliative pain management is a crucial issue in AKU. Timely spinal surgery and arthroplasty are the major treatment approaches at present. A potential disease modifying drug, nitisinone, inhibits 4-hydroxy-phenyl-pyruvate-dioxygenase and decreases formation of HGA and could prevent or slow the progression of disease in AKU. If nitisinone therapy is able to complement the biochemical ‘cure’ with improved outcomes, it will completely alter the way we approach the management of this disease. Greater efforts to improve recognition and registration of the disease will be worthwhile. Improved laboratory diagnostics to monitor the tyrosine metabolic pathway that includes plasma metabolites including tyrosine to monitor efficacy, toxicity and safety postnitisinone will also be required.
Characterisation of the pharmacokinetics of ethinylestradiol and drospirenone in extended-cycle regimens: population pharmacokinetic analysis from a randomised Phase III study
Authors: Reif Stefanie , Snelder Nelleke , Blode Hartmut
Published: March 2013

Objectives

The primary objective of this analysis was to characterise the steady-state pharmacokinetics (PK) of ethinylestradiol (EE) and drospirenone (DRSP) in a randomised Phase III study that investigated the contraceptive efficacy and safety of three different regimens of EE 20 µg/DRSP 3 mg.

Methods

Non-linear mixed-effects modelling was used to develop population PK models for EE and DRSP. EE and DRSP serum concentrations were determined in blood samples obtained from approximately 1100 healthy young women on two occasions during the first cycle (Week 3) and after 6 months (Week 27) of EE 20 µg/DRSP 3 mg use. EE 20 µg/DRSP 3 mg was administered as a flexible extended regimen [24–120 days’ active hormonal intake followed by 4 days with no tablet intake (tablet-free interval)], a conventional 28-day cyclic regimen (24 days’ active hormonal intake followed by 4 days of placebo tablets) or a fixed extended regimen (120 days’ uninterrupted active hormonal intake followed by a 4-day tablet-free interval) over 1 year.

Results

The population PK of EE and DRSP in this population were successfully described using the developed population models. All three regimens led to similar steady-state drug exposure during long-term treatment. Only minor changes (≤8%) in the steady-state PK of EE and DRSP were observed between Week 3 and Week 27 of an extended regimen. Body weight (BW) and age had a small, statistically significant impact on the PK of EE and DRSP (BW only) in a covariate analysis, however, these changes were not considered to be clinically relevant.

Conclusions

Extending the established 24/4-day regimen of EE 20 µg/DRSP 3 mg does not change the known steady-state PK of EE and DRSP, suggesting that the clinical efficacy is also similar. This is in line with the published clinical results from this study.
Combined hormonal contraceptives and the risk of venous and arterial thromboembolism and cardiovascular death: misuse of automated databases
Authors: Shapiro Samuel
Published: March 2013

Background

In December 2011, the US Food and Drug Administration (FDA) convened a public Advisory Committee meeting to review evidence from a study commissioned by the agency. An analysis of findings derived from four databases was published on the FDA website, and presented at the meeting. Among users of combined hormonal contraceptives containing ethinylestradiol (EE) plus drospirenone (DRSP) the risks of venous (VTE) and arterial thromboembolism (ATE) were higher than among users of older reference contraceptives containing other progestogens. The findings have now been published in a peer-reviewed journal.

Objective

To evaluate the published evidence.

Methods

Generally accepted epidemiological principles of causality are applied.

Results

The findings did not satisfy the criteria of time order, bias, confounding, statistical stability and strength of association, duration-response, internal consistency, external consistency, or biological plausibility.

Conclusions

The best evidence continues to suggest that the increased risk of VTE in combined hormonal contraceptive users is dependent on the dose of estrogen, and independent of the progestogen used. The best evidence also suggests that DRSP does not increase the risk of ATE, and may reduce it.
High prevalence and incidence of human papillomavirus in a cohort of healthy young African female subjects
Authors: Watson-Jones Deborah , Baisley Kathy , Brown Joelle , Kavishe Bazil , Andreasen Aura , Changalucha John , Mayaud Philippe , Kapiga Saidi , Gumodoka Balthazar , Hayes Richard J , de Sanjosé Silvia
Published: March 2013

Objectives

We measured the prevalence and incidence of human papillomavirus (HPV) infection in young female subjects recruited for a safety and immunogenicity trial of the bivalent HPV-16/18 vaccine in Tanzania.

Methods

Healthy HIV negative female subjects aged 10–25 years were enrolled and randomised (2:1) to receive HPV-16/18 vaccine or placebo (Al(OH)3control). At enrolment, if sexually active, genital specimens were collected for HPV DNA, other reproductive tract infections and cervical cytology. Subjects were followed to 12 months when HPV testing was repeated.

Results

In total 334 participants were enrolled; 221 and 113 in vaccine and control arms, respectively. At enrolment, 74% of 142 sexually active subjects had HPV infection of whom 69% had >1 genotype. Prevalent infections were HPV-45 (16%), HPV-53 (14%), HPV-16 (13%) and HPV-58 (13%). Only age was associated with prevalent HPV infection at enrolment. Among 23 girls who reported age at first sex as 1 year younger than their current age, 15 (65.2%) had HPV infection. Of 187 genotype-specific infections at enrolment, 51 (27%) were present at 12 months. Overall, 67% of 97 sexually active participants with results at enrolment and 12 months had a new HPV genotype at follow-up. Among HPV uninfected female subjects at enrolment, the incidence of any HPV infection was 76 per 100 person-years.

Conclusions

Among young women in Tanzania, HPV is highly prevalent and acquired soon after sexual debut. Early HPV vaccination is highly recommended in this population.
Development and validation of an equine nerve block simulator to supplement practical skills training in undergraduate veterinary students
Authors: Gunning P. , Smith A. , Fox V. , Bolt D. M. , Lowe J. , Sinclair C. , Witte T. H. , Weller R.
Published: March 2013

Lameness is the most common presenting complaint in equine practice. Performing diagnostic nerve blocks is an integral part of any lameness work‐up, and is therefore an essential skill for equine practitioners. However, the opportunities for veterinary students to practice this skill are limited. The aim of this study was to design and validate an equine nerve block simulator. It was hypothesised that the simulator would improve students' ability and enhance their confidence in performing nerve blocks. A simulator was built using an equine forelimb skeleton and building foam. Wire wool targets were placed under the foam in the positions corresponding to the anatomical location of the most palmar digital, abaxial and low four‐point nerve blocks and attached to an electrical circuit. The circuit became complete when the operator placed a needle in the correct position and immediate audible feedback with a buzzer was provided. To validate the simulator, it was compared with two established teaching methods: cadaver training and theoretical training with a hand‐out. Cadaver‐trained students achieved the best results (73 per cent correct blocks), compared with simulator‐trained students (71 per cent correct blocks), and a hand‐out trained group (58 per cent correct blocks). Feedback obtained with a questionnaire showed that students enjoyed simulator training more, and that they felt more confident in performing diagnostic nerve blocks than the other two groups. The equine nerve block simulator provides a safe, cost‐effective method to supplement the teaching of diagnostic analgesia to undergraduate veterinary students.
Fatty acid ethanolamides modulate CD36-mRNA through dietary fatty acid manipulation in Syrian Golden hamsters
Authors: Lin Lin , Rideout Todd , Yurkova Natalia , Yang Haifeng , Eck Peter , Jones Peter J.H.
Published: March 2013

Fatty acids convert to fatty acid ethanolamides which associate with lipid signalling, fat oxidation, and energy balance; however, the extent to which dietary fatty acids manipulation can impact such control processes through fatty acid ethanolamides-related mechanisms remains understudied. The objective was to examine the impact of diets containing 6% corn oil, high oleic canola oil, docosahexaenoic acid + high oleic canola oil, and fish oil on plasma and organ levels of fatty acid ethanolamides, peroxisome proliferator-activated receptor-α regulatory targets, and lipid metabolism in Syrian Golden hamsters. After 29 days, in plasma, animals that were fed fish oil showed greater (p < 0.05) oleoylethanolamide and lower (p < 0.05) arachidonoylethanolamide and palmitoylethanolamide levels compared with other groups, while animals fed canola oil showed higher (p < 0.05) oleoylethanolamide levels in proximal intestine and liver than groups that were fed coin oil and fish oil. The canola oil group showed elevated (p < 0.01) fat oxidation (%) and over 3.0-fold higher (p < 0.05) hepatic-CD36 expression compared with the corn oil group. Hepatic-lipogenesis was lower (p < 0.05) in hamsters that were fed DHA-canola oil compared with the corn oil group. To conclude, dietary fatty acids produced shifts in plasma and organ levels of arachidonoylethanolamide, oleoylethanolamide, and palmitoylethanolamid, which were accompanied by changes in gene expression, lipogenesis, and energy expenditure, suggesting mechanisms through which dietary fatty acids influence disease risk.
Projected US timber and primary forest product market impacts of climate change mitigation through timber set-asides
Authors: Nepal Prakash , Ince Peter J. , Skog Kenneth E. , Chang Sun J.
Published: March 2013

Whereas climate change mitigation involving payments to forest landowners for accumulating carbon on their land may increase carbon stored in forests, it will also affect timber supply and prices. This study estimated the effect on US timber and primary forest product markets of hypothetical timber set-aside scenarios where US forest landowners would be paid to forego timber harvests for 100 years to increase carbon storage on US timberland. The scenarios featured payments to landowners of $0 (business-as-usual (BAU)), $10, and $15 per each additional metric ton (t) of carbon dioxide equivalent (CO2e) sequestered on the set-aside timberlands, with maximum annual expenditures of $3 billion. For the set-aside scenarios, reduction in timberland available for harvest resulted in increased timber prices and changes in US domestic production, consumption, net export, and timber market welfare. Economic analyses indicated that the scenario with more area set aside and the largest carbon mitigation benefit (lower carbon price, $10/t CO2e) would result in the largest decrease in market welfare, suggesting that climate change mitigation policies and programs would need to consider such impacts when evaluating the costs and benefits of climate change mitigation strategies in the forest sector.
EFFECTIVE ACTION FOR FERMIONS WITH ANOMALOUS MAGNETIC MOMENT FROM FOLDY–WOUTHUYSEN TRANSFORMATION
Authors: BARDUCCI A. , GIACHETTI R.
Published: March 2013

In this paper, we calculate the effective action for neutral particles with anomalous magnetic moment in an external magnetic and electric field. We show that we can take advantage from the Foldy–Wouthuysen transformation (FWT) for such systems, determined in our previous works: indeed, by this transformation we have explicitly evaluated the diagonalized Hamiltonian, allowing to present a closed form for the corresponding effective action and for the partition function at finite temperature from which the thermodynamical potentials can be calculated.
THE WORLDSHEET PERSPECTIVE OF T-DUALITY SYMMETRY IN STRING THEORY
Authors: MAHARANA JNANADEVA
Published: March 2013

The purpose of this paper is to present a pedagogical review of T-duality in string theory. The evolution of the closed string is envisaged on the worldsheet in the presence of its massless excitations. The duality symmetry is studied when some of the spacial coordinates are compactified on d-dimensional torus, Td. The known results are reviewed to elucidate that equations of motion for the compact coordinates are O(d, d) covariant, d being the number of compact directions. Next, the vertex operators of excited massive levels are considered in a simple compactification scheme. It is shown that the vertex operators for each massive level can be cast in a T-duality invariant form in such a case. Subsequently, the duality properties of superstring is investigated in the NSR formulation for the massless backgrounds such as graviton and antisymmetric tensor. The worldsheet superfield formulation is found to be very suitable for our purpose. The Hassan–Sen compactification is adopted and it is shown that the worldsheet equations of motion for compact superfields are O(d, d) covariant when the backgrounds are independent of superfields along compact directions. The vertex operators for excited levels are presented in the NS–NS sector and it is shown that they can be cast in T-duality invariant form for the case of Hassan–Sen compactification scheme. An illustrative example is presented to realize our proposal.
THE α, β AND γ PARAMETRIZATIONS OF CP-VIOLATING CKM PHASE
Authors: LI GUAN-NAN , LIN HSIU-HSIEN , XU DONG , HE XIAO-GANG
Published: March 2013

The CKM matrix describing quark mixing with three generations can be parametrized by three mixing angles and one CP-violating phase. In most of the parametrizations, the CP-violating phase chosen is not a directly measurable quantity and is parametrization dependent. In this work, we propose to use experimentally measurable CP-violating quantities, α, β or γ in the unitarity triangle as the phase in the CKM matrix, and construct explicit α, β and γ parametrizations. Approximate Wolfenstein-like expressions are also suggested. Since β is most accurately measured among these three phase angles, we consider β parametrization as the best one to use.
ONE SIZE DOES NOT FIT ALL — UNDERSTANDING THE FRONT-END AND BACK-END OF BUSINESS MODEL INNOVATION
Authors: GÜNZEL FRANZISKA , HOLM ANNA B.
Published: March 2013

Business model innovation is becoming a central research topic in management. However, a lack of a common understanding of the nature of the business model leads to disregarding its multifaceted structure when analyzing the business model innovation process. This article proposes a more detailed understanding of the business model innovation process by drawing on existing knowledge from new product development literature and examining the front-end and the back-end of business model innovation of three leading Danish newspapers. We studied how changes introduced during the development of digital news production and delivery have affected key components of these business models, namely value creation, proposition, delivery and capture in the period 2002–2011. Our findings suggest the need to distinguish between front-end and back-end business model innovation processes, and to recognize the importance of organizational learning when incumbents are faced with disruptive technologies.
FUZZY BRIDGED REFINEMENT DOMAIN ADAPTATION: LONG-TERM BANK FAILURE PREDICTION
Authors: BEHBOOD VAHID , LU JIE , ZHANG GUANGQUAN
Published: March 2013

Machine learning methods, such as neural network (NN) and support vector machine, assume that the training data and the test data are drawn from the same distribution. This assumption may not be satisfied in many real world applications, like long-term financial failure prediction, because the training and test data may each come from different time periods or domains. This paper proposes a novel algorithm known as fuzzy bridged refinement-based domain adaptation to solve the problem of long-term prediction. The algorithm utilizes the fuzzy system and similarity concepts to modify the target instances' labels which were initially predicted by a shift-unaware prediction model. The experiments are performed using three shift-unaware prediction models based on nine different settings including two main situations: (1) there is no labeled instance in the target domain; (2) there are a few labeled instances in the target domain. In these experiments bank failure financial data is used to validate the algorithm. The results demonstrate a significant improvement in the predictive accuracy, particularly in the second situation identified above.
COMPARISON OF PARALLEL PARTICLE SWARM OPTIMIZERS FOR GRAPHICAL PROCESSING UNITS AND MULTICORE PROCESSORS
Authors: ROBERGE VINCENT , TARBOUCHI MOHAMMED
Published: March 2013

In this paper, we present a parallel implementation of the particle swarm optimization (PSO) on graphical processing units (GPU) using CUDA. By fully utilizing the processing power of graphic processors, our implementation (CUDA-PSO) provides a speedup of 167× compared to a sequential implementation on CPU. This speedup is significantly superior to what has been reported in recent papers and is achieved by four optimizations we made to better adapt the parallel algorithm to the specific architecture of the NVIDIA GPU. However, because today's personal computers are usually equipped with a multicore CPU, it may be unfair to compare our CUDA implementation to a sequential one. For this reason, we implemented a parallel PSO for multicore CPUs using MPI (MPI-PSO) and compared its performance against our CUDA-PSO. The execution time of our CUDA-PSO remains 15.8× faster than our MPI-PSO which ran on a high-end 12-core workstation. Moreover, we show with statistical significance that the results obtained using our CUDA-PSO are of equal quality as the results obtained by the sequential PSO or the MPI-PSO. Finally, we use our parallel PSO for real-time harmonic minimization of multilevel power inverters with 20 DC sources while considering the first 100 harmonics and show that our CUDA-PSO is 294× faster than the sequential PSO and 32.5× faster than our parallel MPI-PSO.
Localization and function of Xinα in mouse skeletal muscle
Authors: Feng Han-Zhong , Wang Qinchuan , Reiter Rebecca S. , Lin Jenny L.-C. , Lin Jim J.-C. , Jin J.-P.
Published: March 2013

The Xin repeat-containing proteins were originally found in the intercalated discs of cardiac muscle with implicated roles in cardiac development and function. A pair of paralogous genes, Xinα ( Xirp1) and Xinβ ( Xirp2), is present in mammals. Ablation of the mouse Xinα ( mXinα) did not affect heart development but caused late-onset adulthood cardiac hypertrophy and cardiomyopathy with conductive defects. Both mXinα and mXinβ are also found in the myotendinous junction (MTJ) of skeletal muscle. Here we investigated the structural and functional significance of mXinα in skeletal muscle. In addition to MTJ and the contact sites between muscle and perimysium, mXinα but not mXinβ was found in the blood vessel walls, whereas both proteins were absent in neuromuscular junctions and nerve fascicles. Coimmunoprecipitation suggested association of mXinα with talin, vinculin, and filamin, but not β-catenin, in adult skeletal muscle, consistent with our previous report of colocalization of mXinα with vinculin. Loss of mXinα in mXinα-null mice had subtle effects on the MTJ structure and the levels of several MTJ components. Diaphragm muscle of mXinα-null mice showed hypertrophy. Compared with wild-type controls, mouse extensor digitorum longus (EDL) muscle lacking mXinα exhibited no overt change in contractile and relaxation velocities or maximum force development but better tolerance to fatigue. Loaded fatigue contractions generated stretch injury in wild-type EDL muscle as indicated by a fragmentation of troponin T. This effect was blunted in mXinα-null EDL muscle. The results suggest that mXinα play a role in MTJ conductance of contractile and stretching forces.
Relative CO2/NH3 selectivities of mammalian aquaporins 0–9
Authors: Geyer R. Ryan , Musa-Aziz Raif , Qin Xue , Boron Walter F.
Published: March 2013

Previous work showed that aquaporin 1 (AQP1), AQP4-M23, and AQP5 each has a characteristic CO2/NH3 and CO2/H2O permeability ratio. The goal of the present study is to characterize AQPs 0–9, which traffic to the plasma membrane when heterologously expressed in Xenopus oocytes. We use video microscopy to compute osmotic water permeability ( Pf) and microelectrodes to record transient changes in surface pH (ΔpHS) caused by CO2 or NH3 influx. Subtracting respective values for day-matched, H2O-injected control oocytes yields the channel-specific values Pf* and ΔpHS*. We find that Pf* is significantly >0 for all AQPs tested except AQP6. (ΔpHS*)CO2 is significantly >0 for AQP0, AQP1, AQP4-M23, AQP5, AQP6, and AQP9. (ΔpHS*)NH3 is >0 for AQP1, AQP3, AQP6, AQP7, AQP8, and AQP9. The ratio (ΔpHS*)CO2/ Pf* falls in the sequence AQP6 (∞) > AQP5 > AQP4-M23 > AQP0 ≅ AQP1 ≅ AQP9 > others (0). The ratio (ΔpHS*)NH3/ Pf* falls in the sequence AQP6 (∞) > AQP3 ≅ AQP7 ≅ AQP8 ≅ AQP9 > AQP1 > others (0). Finally, the ratio (ΔpHS*)CO2/(−ΔpHS*)NH3 falls in the sequence AQP0 (∞) ≅ AQP4-M23 ≅ AQP5 > AQP6 > AQP1 > AQP9 > AQP3 (0) ≅ AQP7 ≅ AQP8. The ratio (ΔpHS*)CO2/(−ΔpHS*)NH3 is indeterminate for both AQP2 and AQP4-M1. In summary, we find that mammalian AQPs exhibit a diverse range of selectivities for CO2 vs. NH3 vs. H2O. As a consequence, by expressing specific combinations of AQPs, cells could exert considerable control over the movements of each of these three substances.