bluuebunny/crossref_metadata_2025 huggingface dataset:
Adaptive Mutations Resulting in Enhanced Polymerase Activity Contribute to High Virulence of Influenza A Virus in Mice
Authors: Rolling Thierry , Koerner Iris , Zimmermann Petra , Holz Kristian , Haller Otto , Staeheli Peter , Kochs Georg
Published: April 2009

High virulence of influenza virus A/Puerto Rico/8/34 in mice carrying the Mx1 resistance gene was recently shown to be determined by the viral surface proteins and the viral polymerase. Here, we demonstrated high-level polymerase activity in mammalian host cells but not avian host cells and investigated which mutations in the polymerase subunits PB1, PB2, and PA are critical for increased polymerase activity and high virus virulence. Mutational analyses demonstrated that an isoleucine-to-valine change at position 504 in PB2 was the most critical and strongly enhanced the activity of the reconstituted polymerase complex. An isoleucine-to-leucine change at position 550 in PA further contributed to increased polymerase activity and high virulence, whereas all other mutations in PB1, PB2, and PA were irrelevant. To determine whether this pattern of acquired mutations represents a preferred viral strategy to gain virulence, two independent new virus adaptation experiments were performed. Surprisingly, the conservative I504V change in PB2 evolved again and was the only mutation present in an aggressive virus variant selected during the first adaptation experiment. In contrast, the virulent virus selected in the second adaptation experiment had a lysine-to-arginine change at position 208 in PB1 and a glutamate-to-glycine change at position 349 in PA. These results demonstrate that a variety of minor amino acid changes in the viral polymerase can contribute to enhanced virulence of influenza A virus. Interestingly, all virulence-enhancing mutations that we identified in this study resulted in substantially increased viral polymerase activity.
Fibrils of Prostatic Acid Phosphatase Fragments Boost Infections with XMRV (Xenotropic Murine Leukemia Virus-Related Virus), a Human Retrovirus Associated with Prostate Cancer
Authors: Hong Seunghee , Klein Eric A. , Das Gupta Jaydip , Hanke Kirsten , Weight Christopher J. , Nguyen Carvell , Gaughan Christina , Kim Kyeong-Ae , Bannert Norbert , Kirchhoff Frank , Munch Jan , Silverman Robert H.
Published: April 2009

The xenotropic murine leukemia virus-related virus (XMRV) has recently been detected in prostate cancer tissues and may play a role in tumorigenesis. It is currently unclear how this virus is transmitted and which factors promote its spread in the prostate. We show that amyloidogenic fragments known as semen-derived enhancer of virus infection (SEVI) originating from prostatic acid phosphatase greatly increase XMRV infections of primary prostatic epithelial and stromal cells. Hybrid simian/human immunodeficiency chimeric virus particles pseudotyped with XMRV envelope protein were used to demonstrate that the enhancing effect of SEVI, or of human semen itself, was at the level of viral attachment and entry. SEVI enhanced XMRV infectivity but did not bypass the requirement for the xenotropic and polytropic retrovirus receptor 1. Furthermore, XMRV RNA was detected in prostatic secretions of some men with prostate cancer. The fact that the precursor of SEVI is produced in abundance by the prostate indicates that XMRV replication occurs in an environment that provides a natural enhancer of viral infection, and this may play a role in the spread of this virus in the human population.
Vaccine-Induced Cellular Responses Control Simian Immunodeficiency Virus Replication after Heterologous Challenge
Authors: Wilson Nancy A. , Keele Brandon F. , Reed Jason S. , Piaskowski Shari M. , MacNair Caitlin E. , Bett Andrew J. , Liang Xiaoping , Wang Fubao , Thoryk Elizabeth , Heidecker Gwendolyn J. , Citron Michael P. , Huang Lingyi , Lin Jing , Vitelli Salvatore , Ahn Chanook D. , Kaizu Masahiko , Maness Nicholas J. , Reynolds Matthew R. , Friedrich Thomas C. , Loffredo John T. , Rakasz Eva G. , Erickson Stephen , Allison David B. , Piatak Michael , Lifson Jeffrey D. , Shiver John W. , Casimiro Danilo R. , Shaw George M. , Hahn Beatrice H. , Watkins David I.
Published: April 2009

All human immunodeficiency virus (HIV) vaccine efficacy trials to date have ended in failure. Structural features of the Env glycoprotein and its enormous variability have frustrated efforts to induce broadly reactive neutralizing antibodies. To explore the extent to which vaccine-induced cellular immune responses, in the absence of neutralizing antibodies, can control replication of a heterologous, mucosal viral challenge, we vaccinated eight macaques with a DNA/Ad5 regimen expressing all of the proteins of SIVmac239 except Env. Vaccinees mounted high-frequency T-cell responses against 11 to 34 epitopes. We challenged the vaccinees and eight naïve animals with the heterologous biological isolate SIVsmE660, using a regimen intended to mimic typical HIV exposures resulting in infection. Viral loads in the vaccinees were significantly less at both the peak (1.9-log reduction;
P
< 0.03) and at the set point (2.6-log reduction;
P
< 0.006) than those in control naïve animals. Five of eight vaccinated macaques controlled acute peak viral replication to less than 80,000 viral RNA (vRNA) copy eq/ml and to less than 100 vRNA copy eq/ml in the chronic phase. Our results demonstrate that broad vaccine-induced cellular immune responses can effectively control replication of a pathogenic, heterologous AIDS virus, suggesting that T-cell-based vaccines may have greater potential than previously appreciated.
Primary High-Dose Murine Norovirus 1 Infection Fails To Protect from Secondary Challenge with Homologous Virus
Authors: Liu Guangliang , Kahan Shannon M. , Jia Yali , Karst Stephanie M.
Published: April 2009

Human noroviruses in theCaliciviridaefamily are the major cause of nonbacterial epidemic gastroenteritis worldwide. Primary human norovirus infection does not elicit lasting protective immunity, a fact that could greatly affect the efficacy of vaccination strategies. Little is known regarding the pathogenesis of human noroviruses or the immune responses that control them because there has previously been no small-animal model or cell culture system of infection. Using the only available small-animal model of norovirus infection, we found that primary high-dose murine norovirus 1 (MNV-1) infection fails to afford protection against a rechallenge with a homologous virus. Thus, MNV-1 represents a valuable model with which to dissect the pathophysiological basis for the lack of lasting protection against human norovirus infection. Interestingly, the magnitude of protection afforded by a primary MNV-1 infection inversely correlates with the inoculum dose. Future studies will elucidate the mechanisms by which noroviruses avoid the induction of protective immunity and the role played by the inoculum dose in this process, ultimately translating this knowledge into successful vaccination approaches.
Human Immunodeficiency Virus Type 1 Gag p24 Alters the Composition of Immunoproteasomes and Affects Antigen Presentation
Authors: Steers Nicholas J. , Peachman Kristina K. , McClain Sasha R. , Alving Carl R. , Rao Mangala
Published: April 2009

Proteasomes are the major source of proteases responsible for the generation of peptides bound to major histocompatibility complex class I molecules. Antigens, adjuvants, and cytokines can modulate the composition and enzymatic activity of proteasomes and thus alter the epitopes generated. In the present study, we examined the effect of human immunodeficiency virus type 1 (HIV-1) p24 on proteasomes from a dendritic cell line (JAWS II), from a macrophage cell line (C2.3), and from murine primary bone marrow-derived macrophages and dendritic cells. HIV-1 p24 downregulated PA28β and the β2i subunit of the immunoproteasome complex in JAWS II cells but did not decrease the immunoproteasome subunits in macrophages, whereas in primary dendritic cells, PA28α, β2i, and β5i were downregulated. Exposure of JAWS II cells and primary dendritic cells to HIV-1 p24 for 90 min significantly decreased the presentation of ovalbumin to a SIINFEKL-specific CD8+T-cell hybridoma. The decrease in antigen presentation and the downmodulation of the immunoproteasome subunits in JAWS II cells and primary dendritic cells could be overcome by pretreating the cells with gamma interferon for 6 h or by exposing the cells to HIV-1 p24 encapsulated in liposomes containing lipid A. These results suggest that early antigen processing kinetics could influence the immunogenicity of CD8+T-cell epitopes generated.
Theiler's Murine Encephalomyelitis Virus Leader Protein Is the Only Nonstructural Protein Tested That Induces Apoptosis When Transfected into Mammalian Cells
Authors: Fan Jilao , Son Kyung-No , Arslan Sevim Yildiz , Liang Zhiguo , Lipton Howard L.
Published: April 2009

Theiler's murine encephalomyelitis virus (TMEV) induces two distinct cell death programs, necrosis and apoptosis. The apoptotic pathway is of particular interest because TMEV persists in the central nervous system of mice, largely in infiltrating macrophages, which undergo apoptosis. Infection of murine macrophages in culture induces apoptosis that is Bax dependent through the intrinsic or mitochondrial pathway, restricting infectious-virus yields and raising the possibility that apoptosis represents a mechanism to attenuate TMEV yet promote macrophage-to-macrophage spread during persistent infection. To help define the cellular stressors and upstream signaling events leading to apoptosis during TMEV infection, we screened baby hamster kidney (BHK-21) cells transfected to express individual nonstructural genes (except 3B) of the low-neurovirulence BeAn virus strain for cell death. Only expression of the leader protein led to apoptosis, as assessed by fluorescence-activated cell sorting analysis of propidium iodide- and annexin V-stained transfected cells, immunoblot analysis of poly(ADP-ribose) polymerase and caspase cleavages, electron microscopy, and inhibition of apoptosis by the pancaspase inhibitor qVD-OPh. After transfection, Bak and not Bax expression increased, suggesting that the apical pathway leading to activation of these Bcl-2 multi-BH-domain proapoptotic proteins differs in BeAn virus infection versus L transfection. Mutation to remove the CHCC Zn finger motif from L, a motif required by L to mediate inhibition of nucleocytoplasmic trafficking, significantly reduced L-protein-induced apoptosis in both BHK-21 and M1-D macrophages.
Adenovirus Vectors Expressing Hantavirus Proteins Protect Hamsters against Lethal Challenge with Andes Virus
Authors: Safronetz David , Hegde Nagendra R. , Ebihara Hideki , Denton Michael , Kobinger Gary P. , St. Jeor Stephen , Feldmann Heinz , Johnson David C.
Published: April 2009

Hantaviruses infect humans following aerosolization from rodent feces and urine, producing hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. Due to the high rates of mortality and lack of therapies, vaccines are urgently needed. Nonreplicating adenovirus (Ad) vectors that express Andes hantavirus (ANDV) nucleocapsid protein (AdN) or glycoproteins (AdG
N
and AdG
C
) were constructed. Ad vectors were tested for their ability to protect Syrian hamsters from a lethal ANDV infection that mimics the pulmonary disease seen in humans. When administered once, all three Ad vectors, individually or in combination, elicited a robust immune response that protected hamsters. No vaccinated animal died, and there were no obvious clinical signs of disease. Further, hantavirus RNA was not detected by sensitive reverse transcription-PCR in tissues and blood of hamsters immunized with both AdG
N
and AdG
C
. Cellular immunity appeared to be important for protection because the AdN vector completely protected animals. All three Ad vectors produced strong cytotoxic T-lymphocyte responses directed to hantavirus proteins in mice. Moreover, hamsters vaccinated with AdN, AdG
N
, or AdG
C
produced no detectable neutralizing antibodies yet were protected. These Ad vectors represent the first vaccines that prevent lethal hantavirus disease and, in some instances (AdG
N
and AdG
C
), provide sterile immunity. These observations set the stage for a more detailed characterization of the types of immunity required to protect humans from hantavirus infections.
Onset of Human Cytomegalovirus Replication in Fibroblasts Requires the Presence of an Intact Vimentin Cytoskeleton
Authors: Miller Matthew S. , Hertel Laura
Published: April 2009

Like all viruses, herpesviruses extensively interact with the host cytoskeleton during entry. While microtubules and microfilaments appear to facilitate viral capsid transport toward the nucleus, evidence for a role of intermediate filaments in herpesvirus entry is lacking. Here, we examined the function of vimentin intermediate filaments in fibroblasts during the initial phase of infection of two genotypically distinct strains of human cytomegalovirus (CMV), one with narrow (AD169) and one with broad (TB40/E) cell tropism. Chemical disruption of the vimentin network with acrylamide, intermediate filament bundling in cells from a patient with giant axonal neuropathy, and absence of vimentin in fibroblasts from vimentin
−/−
mice severely reduced entry of either strain. In vimentin null cells, viral particles remained in the cytoplasm longer than in vimentin
+/+
cells. TB40/E infection was consistently slower than that of AD169 and was more negatively affected by the disruption or absence of vimentin. These findings demonstrate that an intact vimentin network is required for CMV infection onset, that intermediate filaments may function during viral entry to facilitate capsid trafficking and/or docking to the nuclear envelope, and that maintenance of a broader cell tropism is associated with a higher degree of dependence on the vimentin cytoskeleton.
Biological Effect of Muller's Ratchet: Distant Capsid Site Can Affect Picornavirus Protein Processing
Authors: Escarmís Cristina , Perales Celia , Domingo Esteban
Published: April 2009

Repeated bottleneck passages of RNA viruses result in accumulation of mutations and fitness decrease. Here, we show that clones of foot-and-mouth disease virus (FMDV) subjected to bottleneck passages, in the form of plaque-to-plaque transfers in BHK-21 cells, increased the thermosensitivity of the viral clones. By constructing infectious FMDV clones, we have identified the amino acid substitution M54I in capsid protein VP1 as one of the lesions associated with thermosensitivity. M54I affects processing of precursor P1, as evidenced by decreased production of VP1 and accumulation of VP1 precursor proteins. The defect is enhanced at high temperatures. Residue M54 of VP1 is exposed on the virion surface, and it is close to the B-C loop where an antigenic site of FMDV is located. M54 is not in direct contact with the VP1-VP3 cleavage site, according to the three-dimensional structure of FMDV particles. Models to account for the effect of M54 in processing of the FMDV polyprotein are proposed. In addition to revealing a distance effect in polyprotein processing, these results underline the importance of pursuing at the biochemical level the biological defects that arise when viruses are subjected to multiple bottleneck events.
Multiple Integrated Copies and High-Level Production of the Human Retrovirus XMRV (Xenotropic Murine Leukemia Virus-Related Virus) from 22Rv1 Prostate Carcinoma Cells
Authors: Knouf Emily C. , Metzger Michael J. , Mitchell Patrick S. , Arroyo Jason D. , Chevillet John R. , Tewari Muneesh , Miller A. Dusty
Published: April 2009

The human retrovirus XMRV (xenotropic murine leukemia virus-related virus) is associated with prostate cancer, most frequently in humans with a defect in the antiviral defense protein RNase L, suggesting a role for XMRV in prostate carcinogenesis. However, XMRV has not been found in prostate carcinoma cells. Here we show that 22Rv1 prostate carcinoma cells produce high-titer virus that is nearly identical in properties and sequence to XMRV isolated by others and consist primarily of a single clone of cells with at least 10 integrated copies of XMRV, warranting further study of a possible role for XMRV integration in carcinogenesis.
Murine Norovirus Infection Has No Significant Effect on Adaptive Immunity to Vaccinia Virus or Influenza A Virus
Authors: Hensley Scott E. , Pinto Amelia K. , Hickman Heather D. , Kastenmayer Robin J. , Bennink Jack R. , Virgin Herbert W. , Yewdell Jonathan W.
Published: April 2009

Murine norovirus (MNV) is endemic in many research mouse colonies. Although MNV infections are typically asymptomatic in immunocompetent mice, the effects of MNV infection on subsequent experimental viral infections are poorly documented. Here, we infected C57BL/6 mice with MNV and then with either vaccinia virus or influenza A virus. MNV infection had no effect on CD8
+
T-cell or antibody responses to secondary viruses or to secondary virus-induced morbidity or mortality. While our findings suggest that MNV has little influence on host immunity in immunocompetent mice, we would urge caution regarding the potential effects of MNV on immune responses to viruses and other pathogens, which must be determined on a system-by-system basis.
The NS1 Protein of a Human Influenza Virus Inhibits Type I Interferon Production and the Induction of Antiviral Responses in Primary Human Dendritic and Respiratory Epithelial Cells
Authors: Haye Kester , Burmakina Svetlana , Moran Thomas , García-Sastre Adolfo , Fernandez-Sesma Ana
Published: April 2009

The NS1 protein of the influenza A virus is a potent virulence factor that inhibits type I interferon (IFN) synthesis, allowing the virus to overcome host defenses and replicate efficiently. However, limited studies have been conducted on NS1 function using human virus strains and primary human cells. We used NS1 truncated mutant influenza viruses derived from the human isolate influenza A/TX/91 (TX WT, where WT is wild type) to study the functions of NS1 in infected primary cells. Infection of primary differentiated human tracheo-bronchial epithelial cells with an NS1 truncated mutant demonstrated limited viral replication and enhanced type I IFN induction. Additionally, human dendritic cells (DCs) infected with human NS1 mutant viruses showed higher levels of activation and stimulated naïve T-cells better than TX WT virus-infected DCs. We also compared infections of DCs with TX WT and our previously characterized laboratory strain A/PR/8/34 (PR8) and its NS1 knockout strain, deltaNS1. TX WT-infected DCs displayed higher viral replication than PR8 but had decreased antiviral gene expression at late time points and reduced naïve T-cell stimulation compared to PR8 infections, suggesting an augmented inhibition of IFN production and human DC activation. Our findings show that human-derived influenza A viruses have a high capacity to inhibit the antiviral state in a human system, and here we have evaluated the possible mechanism of this inhibition. Lastly, C-terminal truncations in the NS1 protein of human influenza virus are sufficient to make the virus attenuated and more immunogenic, supporting its use as a live attenuated influenza vaccine in humans.
Quantitative Fluorescence Resonance Energy Transfer Microscopy Analysis of the Human Immunodeficiency Virus Type 1 Gag-Gag Interaction: Relative Contributions of the CA and NC Domains and Membrane Binding
Authors: Hogue Ian B. , Hoppe Adam , Ono Akira
Published: April 2009

The human immunodeficiency virus type 1 structural polyprotein Pr55
Gag
is necessary and sufficient for the assembly of virus-like particles on cellular membranes. Previous studies demonstrated the importance of the capsid C-terminal domain (CA-CTD), nucleocapsid (NC), and membrane association in Gag-Gag interactions, but the relationships between these factors remain unclear. In this study, we systematically altered the CA-CTD, NC, and the ability to bind membrane to determine the relative contributions of, and interplay between, these factors. To directly measure Gag-Gag interactions, we utilized chimeric Gag-fluorescent protein fusion constructs and a fluorescence resonance energy transfer (FRET) stoichiometry method. We found that the CA-CTD is essential for Gag-Gag interactions at the plasma membrane, as the disruption of the CA-CTD has severe impacts on FRET. Data from experiments in which wild-type (WT) and CA-CTD mutant Gag molecules are coexpressed support the idea that the CA-CTD dimerization interface consists of two reciprocal interactions. Mutations in NC have less-severe impacts on FRET between normally myristoylated Gag proteins than do CA-CTD mutations. Notably, when nonmyristoylated Gag interacts with WT Gag, NC is essential for FRET despite the presence of the CA-CTD. In contrast, constitutively enhanced membrane binding eliminates the need for NC to produce a WT level of FRET. These results from cell-based experiments suggest a model in which both membrane binding and NC-RNA interactions serve similar scaffolding functions so that one can functionally compensate for a defect in the other.
Uncoupling Human Immunodeficiency Virus Type 1
gag
and
pol
Reading Frames: Role of the Transframe Protein p6* in Viral Replication
Authors: Leiherer Andreas , Ludwig Christine , Wagner Ralf
Published: April 2009

Apart from its regulatory role in protease (PR) activation, little is known about the function of the human immunodeficiency virus type 1 transframe protein p6* in the virus life cycle. p6* is located between the nucleocapsid and PR domains in the Gag-Pol polyprotein precursor and is cleaved by PR during viral maturation. We have recently reported that the central region of p6* can be extensively mutated without abolishing viral infectivity and replication in vitro. However, mutagenesis of the entire p6*-coding sequence in the proviral context is not feasible without affecting the superimposed frameshift signal or the overlapping p1-p6
gag
sequences. To overcome these limitations, we created a novel NL4-3-derived provirus by displacing the original frameshift signal to the 3′ end of the
gag
gene, thereby uncoupling the p6* gene sequence from the p1-p6
gag
reading frame. The resulting virus (AL) proved to be replication competent in different cell cultures and thus represents an elegant tool for detailed analysis of p6* function. Hence, extensive deletions or substitutions were introduced into the p6* gene sequence of the AL provirus, and effects on particle release, protein processing, and viral infectivity were evaluated. Interestingly, neither the deletion of 63% of all p6* residues nor the partial substitution by a heterologous sequence affected virus growth and infectivity, suggesting that p6* is widely dispensable for viral in vitro replication. However, the insertion of a larger reporter sequence interfered with virus production and maturation, implying that the length or conformation of this spacer region might be critical for p6* function.
Proteomic characterisation of pancreatic islet β-cells stimulated with pancreatic carcinoma cell conditioned medium
Authors: Song G , Cui Y , Zhong N , Han J
Published: April 2009

Aim:

To characterise the protein expression profiles of pancreatic islet β-cells affected by cancer cells, and to identify the potential islet molecules related to pancreatic cancer-associated diabetes.

Methods:

The cellular proteins of islet β-cell line INS-1 in response to conditioned medium (CM) prepared from pancreatic cancer cells were analysed using fluorescence-labelled 2D gel-based proteomics (2D-DIGE).

Results:

10 proteins were over-expressed and five were under-expressed in cancer CM-stimulated β-cells. Five differently expressed proteins were selected for further validation by Western blot analysis. HSP60 and peripherin, which have previously been reported to be associated with type 1 diabetes, and Prp19, a DNA repair protein, were up-regulated in INS-1 cells after cancer cell CM stimulation; HMOX1 and GRP78 were down-regulated. The islets adjacent to human pancreatic carcinomas showed increased peripherin expression than normal pancreatic islets.

Conclusion:

These results provide new information regarding the regulation of protein expression in pancreatic cancer-associated diabetes.
Erring on the side of life: the case of Terri Schiavo: Table 1
Authors: Merrell D A
Published: April 2009

In debates over life and death it is often said that one should err on the side of caution—that is, on the side of life. In the light of the recent case of Terri Schiavo, it is explained how the “err-on-the-side-of-life” argument proceeds, and an objection to it is offered.
Under what conditions do patients want to be informed about their risk of a complication? A vignette study
Authors: Janssen N B A T , Oort F J , Fockens P , Willems D L , de Haes H C J M , Smets E M A
Published: April 2009

Background:

Discussing treatment risks has become increasingly important in medical communication. Still, despite regulations, physicians must decide how much and what kind of information to present.

Objective:

To investigate patients’ preference for information about a small risk of a complication of colonoscopy, and whether medical and personal factors contribute to such preference. To propose a disclosure policy related to our results.

Design:

Vignettes study.

Setting:

Department of Gastroenterology, Academic Medical Centre, the Netherlands.

Patients:

810 consecutive colonoscopy patients.

Intervention:

A home-sent questionnaire containing three vignettes. Vignettes varied in the indication for colonoscopy, complication severity and level of risk. Patients were invited to indicate their wish to be informed and the importance of such information. In addition, sociodemograhic, illness-related and psychological characteristics were assessed.

Main outcome measurements:

Wish to be informed and importance of information.

Results:

Of 810 questionnaires, 68% were returned. Patients generally wished to be informed about low-risk complications, regardless of the indication for colonoscopy or the severity of the complication. The level of risk did matter, though (OR = 2.48, SE = 0.28, p = 0.001). The information was considered less important if done for population screening purposes or diagnosis of colon cancer, if the complication was less severe (bleeding) and if the risk was smaller (0.01% and 0.1%). Patients’ information preference was also related to age, mood and coping style.

Limitations:

Difficulty of vignettes.

Conclusions:

Patients generally wish to be informed about all possible risks. However, this might become uninformative. A stepwise approach is suggested.
Resourceexpenditurenot resourceallocation: response to McDougall on cloning and dignity
Authors: Williams M J
Published: April 2009

This paper offers some comments on bioethical debates about resource allocation in healthcare. It is stimulated by Rosalind McDougall’s argument that it is an affront to the human dignity of people with below “liberties-level” health to fund human reproductive cloning. McDougall is right to underline the relevance of resource prioritisation to the ethics of research and provision of new biomedical technologies. This paper argues that bioethicists should be careful when offering comments about such issues. In particular, it emphasises the need to represent accurately the reality of the situation—especially when we are passing judgement on technologies that are in their infancy and whose practical application is yet to be confirmed. The paper also emphasises the importance of the actual context to bioethical debate, and note that it would be better to talk about resourceexpenditurerather than resourceallocationwhen it comes to discussing the rights and wrongs of how money is spent. It also reiterates the claims made by other writers that social and political philosophy need to have a transparent and considered role in debates about resources.
Paying a high price for low costs: why there should be no legal constraints on the profits that can be made on drugs for tropical diseases
Authors: Sonderholm J
Published: April 2009

This paper deals with the question of how to price drugs for tropical diseases. The thesis defended in the paper is: (i) there should be no legal constraints on the profits pharmaceutical companies can make on their products for tropical diseases. In essence, (i) expresses the idea that drugs for tropical diseases should be treated as any other product on the free market and that the producers of these drugs should be allowed to sell their products at whatever price the market can bear. The main argument in favour of (i) is first outlined. Five common arguments against (i) are thereafter discussed, and it is argued that all of these fail in their intended purpose.
Attorney General forces Infectious Diseases Society of America to redo Lyme guidelines due to flawed development process: Table 1
Authors: Johnson L , Stricker R B
Published: April 2009

Lyme disease is one of the most controversial illnesses in the history of medicine. In 2006 the Connecticut Attorney General launched an antitrust investigation into the Lyme guidelines development process of the Infectious Diseases Society of America (IDSA). In a recent settlement with IDSA, the Attorney General noted important commercial conflicts of interest and suppression of scientific evidence that had tainted the guidelines process. This paper explores two broad ethical themes that influenced the IDSA investigation. The first is the growing problem of conflicts of interest among guidelines developers, and the second is the increasing centralisation of medical decisions by insurance companies, which use treatment guidelines as a means of controlling the practices of individual doctors and denying treatment for patients. The implications of the first-ever antitrust investigation of medical guidelines and the proposed model to remediate the tainted IDSA guidelines process are also discussed.
Is there a duty to share genetic information?
Authors: Liao S M
Published: April 2009

A number of prominent bioethicists, such as Parker, Lucassen and Knoppers, have called for the adoption of a system in which by default genetic information is shared among family members. This paper suggests that a main reason given in support of this call to share genetic information among family members is the idea that genetic information is essentially familial in nature. On examining this “familial nature of genetics” argument, the paper shows that most genetic information is only shared in a weaker way among family members and does not necessarily lead to the actual manifestation of particular diseases. The upshot is that the idea that genetic information is familial in nature does not provide sufficient ground for moving towards a system in which by default genetic information is shared among family members.
Positing a difference between acts and omissions: the principle of justice, Rachels’ cases and moral weakness
Authors: Mohindra R
Published: April 2009

The difficulty in discovering a difference between killing and letting die has led many philosophers to deny the distinction. This paper seeks to develop an argument defending the distinction between killing and letting die. In relation to Rachels’ cases, the argument is that (a) even accepting that Smith and Jones may select equally heinous options from the choices they have available to them, (b) the fact that the choices available to them are different is morally relevant, and (c) this difference in available choices can be used to distinguish between the agents in certain circumstances. It is the principle of justice, as espoused by Aristotle, which requires that equal things are treated equally and that unequal things are treated unequally that creates a presumption that Smith and Jones should be treated differently. The magnitude of this difference can be amplified by other premises, making the distinction morally relevant in practical reality.
“You can’thandlethe truth”; medical paternalism and prenatal alcohol use
Authors: Gavaghan C
Published: April 2009

The publication of the latest contribution to the alcohol-in-pregnancy debate, and the now customary flurry of media attention it generated, have precipitated the renewal of a series of ongoing debates about safe levels of consumption and responsible prenatal conduct. The University College London (UCL) study’s finding that low levels of alcohol did not contribute to adverse behavioural outcomes—and may indeed have made a positive contribution in some cases—is unlikely to be the last word on the subject. Proving a negative correlation is notoriously difficult (technically, impossible), and other studies have offered alternative claims. The author is not an epidemiologist, and the purpose of this article is not to evaluate the competing empirical claims. However, the question of what information and advice healthcare practitioners ought to present to pregnant women, or prospectively or potentially pregnant women, in a situation of uncertainty is one to which healthcare ethicists may have a contribution to make. In this article, it is argued that the total abstinence policy advocated by the UK’s Department of Health, and even more stridently by the British Medical Association, sits uneasily with recent data and is far from ethically unproblematic. In particular, the “precautionary” approach advocated by these bodies displays both scant regard for the autonomy of pregnant and prospectively pregnant women and a confused grasp of the principles of beneficence and non-maleficence.
Reply to Di Nucci: why the counterexamples succeed
Authors: Strong C
Published: April 2009

In my essay, a critique of “the best secular argument against abortion” I reconstructed and criticised two versions of Don Marquis’s well-known argument against abortion. In critiquing the version I call the “essence argument”, I presented counterexamples to one of the premises in that argument. In this issue of the journal, Ezio Di Nucci takes note of the fact that I used the term “valuable future” in the premise but used the term “future like ours” in the counterexamples. Because the terms are different, Di Nucci claimed that my counterexamples had no bearing on the premise and are therefore unsuccessful. The main error in Di Nucci’s objection is a failure to acknowledge that Marquis uses the terms “valuable future” and “future like ours” interchangeably. For the purpose of reconstructing Marquis’s argument, the term “valuable future” is to be taken in a sense that means the same as “future like ours”. Once this point is recognised, Di Nucci’s objection falls apart.
Runoff and inorganic nitrogen export from Boreal Plain watersheds six years after wildfire and one year after harvest
Authors: Pelster David E. , Burke Janice M. , Prepas Ellie E.
Published: April 2009

This investigation in the Swan Hills, Alberta, located on the Canadian Boreal Plain, examined May through October runoff before, during and six years after wildfire in a 4th order watershed, compared to a 3rd order reference watershed. It also examined runoff and inorganic nitrogen flow-weighted mean concentration and areal export for 1 year after winter harvest in four 1st order watersheds compared to five reference 1st and 2nd order watersheds. Runoff and areal exports were normalized to precipitation at each site. Runoff impact ratios (year 1 post-disturbance value divided by the pre-disturbance value) for burned and harvested watersheds were 60 and 70% higher, respectively, than reference watersheds (P = 0.06). Runoff from the burned watershed remained elevated 6 years after fire. A trend for higher nitrate and ammonium concentrations, combined with higher runoff yielded impact ratios for areal ammonium and nitrate exports that were 130 and 170% higher, respectively, in harvested than reference watersheds (P = 0.08 for both). The proportion of the watershed harvested was positively related to runoff (r2 = 0.94, P = 0.03) and ammonium impact ratios (r2 = 0.96, P = 0.02), but not nitrate impact ratios (P = 0.30). Areal nitrate export in snowmelt was low in harvested watersheds compared to their pre-harvest condition and to reference watersheds.
Water and nutrient inputs, outputs, and storage in Canadian boreal forest wetlands: a review
Authors: Pelster D. , Burke J.M. , Couling K. , Luke S.H. , Smith D.W. , Prepas E.E.
Published: April 2009

Boreal wetlands, primarily peatlands, are important global carbon (C) reservoirs and integral components of regional hydrological networks. This paper summarizes our current state of knowledge regarding components of water and nutrient budgets in northern wetlands, with a focus on Canada. Boreal wetland water budgets are strongly influenced by the following: seasonal weather patterns as they relate to the timing of precipitation and meltwater inputs and evapotranspiration (ET) losses;; vegetation cover in the wetland and surrounding uplands as it relates to rain and snow interception and evapotranspiration;; and connectivity of the wetland to the regional hydrological network. Key factors that influence boreal wetland phosphorus (P) budgets are: spatial and temporal variability in the water table as they relate to reduction–oxidation conditions and rewetting of highly decomposed peat;; concentrations of metals and ions involved in P complexation and release;; vegetation age and type (herbaceous versus woody);; and seasonal weather patterns as they relate to water retention time. As with other components of the boreal forest, wetlands are often limited in bioavailable nitrogen (N), therefore bulk deposition and symbiotic fixation are key N sources. Within many wetlands, N is rapidly cycled through vegetation and microbial communities, and converted to gaseous N or exported as organic N in outflows. In terms of C budgets, boreal wetlands are important reservoirs, converting inorganic and organic C inputs to peat. Climate change and anthropogenic N loading threaten the water and C balance in boreal wetlands.
Science and the industrial planning process in the western Canadian boreal forest: a case study
Authors: Russell Jonathan S. , Smith Daniel W. , Putz Gordon , Prepas Ellie E.
Published: April 2009

This investigation presents new and aggressive approaches to link the results of scientific endeavor to management of a portion of the Canadian boreal forest, within the framework of the detailed forest management plan (DFMP) process of a forestry company in the province of Alberta. The first component in the DFMP was landscape projection, whereby cumulative impacts of key natural and anthropogenic disturbance agents were modelled under current and altered climate conditions. The second component addressed two types of impact assessment. The Biodiversity Assessment Project (BAP) modelled ecosystem diversity at landscape and habitat levels, as well as developed habitat supply models, relative to changing vegetation composition, management practices, and stand age. Models were used during the development of a preferred forest management strategy to address undesirable ecological predictions. In the Forest Watershed and Riparian Disturbance (FORWARD) project, a variant of the soil and water assessment tool was developed to model the impacts of watershed disturbance on streamflow. In the third component of the DFMP, timber supply scenarios were devised based on maximizing annual allowable harvest in a sustained yield fashion, while incorporating elements of the BAP and FORWARD project as constraints in harvest sequence optimization. This initiative is an example of an industry-led effort to manage forests using a system that is regionally centered, science based, peer reviewed, and considers multiple activities and their cumulative environmental effects.
Modelling nitrogen composition in streams on the Boreal Plain using genetic adaptive general regression neural networks
Authors: Li Xiangfei , Nour Mohamed H. , Smith Daniel W. , Prepas Ellie E.
Published: April 2009

Increased release of nitrogen to hydrological networks due to watershed disturbance may cause aquatic problems and affect water uses. Therefore, effective nitrogen modelling is an important element of total watershed management. The objective of this study was to develop an artificial neural network modelling tool to predict nitrogen concentrations in streams using easily accessible data as model inputs. Genetic adaptive general regression neural network (GA-GRNN) models were applied to predict nitrate, ammonium, and total dissolved nitrogen concentrations in three forested watersheds in Alberta, Canada. The performance and generality of the developed models for dry and wet weather conditions in the studied watersheds were verified by the coefficient of multiple determination, the root mean squared error, swapping the testing and validation data sets, and plotting measured and predicted values over time. The successful application of GA-GRNN models to predict nitrogen compositions in the watersheds by using five major input variables and relevant time-lagged inputs, fully demonstrated the models’ generality. It implies the high potential of applying GA-GRNN models for predicting other surface water quality parameters on other watersheds with similar or different characteristics.
Effect of watershed subdivision on water-phase phosphorus modelling: An artificial neural network modelling application
Authors: Nour Mohamed H. , Smith Daniel W. , El-Din Mohamed Gamal , Prepas Ellie E.
Published: April 2009

This study is an effort to incorporate low-cost time-variant remote sensing (RS) information in watershed-scale total phosphorus (TP) modelling. Four watershed subdivisions were delineated to assess the impact of watershed subdivision on the prediction accuracy of TP concentration in stream water. Four TP artificial neural network (ANN) models were designed to incorporate RS data into a semi-distributed approach. The remotely derived enhanced vegetation index and the normalized difference water index were successful in representing vegetation dynamics in the devised models. The models were applied to a 15.6 km2 watershed in the Canadian Boreal Plain. Eight measures of goodness-of-fit statistics were used for model evaluation. Although statistical model evaluation did favour the finest resolution in this case study, the differences in performance indicators among the four models were insignificant for any practical application. The encouraging results from this exercise demonstrate the applicability of the ANN semi-distributed modelling approach and the usefulness of RS data in simulating TP dynamics. Such models can potentially serve as valuable tools for watershed-scale forest management.
Towards a generic neural network model for the prediction of daily streamflow in ungauged boreal plain watersheds
Authors: Nour Mohamed H. , Smith Daniel W. , Gamal El-Din Mohamed , Prepas Ellie E.
Published: April 2009

Most of the currently available streamflow neural network models are either recurrent neural networks or feed-forward multi-layer perceptron (FF-MLP) requiring past flow values for lead time prediction. These models cannot be used for modelling ungauged watersheds because past flow values are not available in such cases. This study proposes a FF-MLP algorithm that relies only on low-cost, readily available meteorological data and careful time series manipulation prior to model building, and thus, is suitable for modelling streamflow in ungauged watersheds. The proposed approach was tested on four watersheds (5 to 130 km2) in the Canadian Boreal forest and was found to provide an efficient modelling alternative for daily streamflow predictions. To assess the possibility of successful model transferability from a gauged watershed to a hydrologically similar ungauged watershed, a new remotely sensed hydrologic similarity measure — SWMIR_SI — was proposed and was found to provide a successful indicator of basin similarity. The square of Pearson’s correlation coefficient, r2, was evaluated to exceed 0.71 when SWMIR_SI was regressed to models’ “goodness-of-fit” statistics reflecting the usefulness of the approach.
Cumulative effects management and the role of predictive models in the new policy for regulating land disturbance in Alberta
Authors: McEachern Preston
Published: April 2009

This contribution describes the recent evolution from sector-based environmental management to cumulative effects management (CEM) in Alberta under a new policy direction titled the Alberta Land-use Framework. This paper focuses on the role of models and hypothesis testing in a CEM and performance assurance framework rather than a critique of CEM itself. Two opposing approaches are currently pursued in Alberta to establish the metrics of CEM. Both are outlined and a case is made for reliance on ecologically defined criteria over the potentially dangerous approach of setting socially desired outcomes first. The challenges Alberta regulators face that must be overcome for an ecosystem approach are described under four categories: (1) model suitability, (2) data availability, (3) science representation, and (4) suitability for a regulatory framework. Two case studies are presented that exemplify the success of following an ecosystem modelling approach to CEM and the pitfalls that can occur if the wrong indicators (i.e., ecological end-points that are insensitive to the disturbance) are selected in the CEM approach.
Modification of SWAT for modelling streamflow from forested watersheds on the Canadian Boreal Plain
Authors: Watson Brett M. , McKeown Ruth A. , Putz Gordon , MacDonald J. Douglas
Published: April 2009

Several modifications were made to the Soil and Water Assessment Tool (SWAT) to better represent processes occurring within forested watersheds on the Boreal Plain in Canada. The modified model, called SWATBF, was applied to the Willow Creek watershed (15.1 km2) in north central Alberta. The performance of the model for the calibration period (2001–2003) was good with coefficients of efficiency of 0.89 and 0.81 being achieved for the prediction of monthly and daily runoff, respectively. However, it was found that SWATBF did not perform as well for the validation period (2004–2006) with the monthly and daily coefficients of efficiency being 0.44 and 0.27, respectively. Potential sources of error to explain the decline in model performance for the validation period are discussed. SWATBF has the potential to be used as a tool by forest managers for predicting the effects of land use change on the Boreal Plain provided that it can be satisfactorily validated.
MAGNETIC PROPERTIES OF (GdxZr1-x)2CoAl3 SYSTEM
Authors: LUPŞA ILEANA , PETRIŞOR T.
Published: May 2009

The magnetic properties of the ( Gd x Zr 1-x)2 CoAl 3 system were investigated in the 4–700 K temperature range and fields up to 70 kOe. The systems seem to be ferrimagnetically ordered. In the ordered state, the Co moments opposite to the gadolinium ones have very low values. The paramagnetic properties evidence over a characteristic temperature T*, a Curie–Weiss type behavior and the presence of the effective magnetic moments on Co atoms. The paramagnetic behavior of cobalt is analyzed in the spin fluctuations model.
ON THE NUMERICAL MODELING OF OPTICAL-SWITCHING IN NON-LINEAR PHASE-SHIFTED GRATING
Authors: SURYANTO A.
Published: April 2009

We discuss the transmission properties of non-linear phase-shifted grating. Using a direct integration method, we show that phase-shift in linear sinusoidal grating introduces a very narrow resonance in the band gap with very high amplification factor. Using frequency in the vicinity of this resonance, we show that the threshold of switching can be reduced significantly. Based on the direct integration method, it is shown that Coupled-Mode Theory may produce inaccurate results for the case of both linear and non-linear grating structure with and without phase-shift.