bluuebunny/crossref_metadata_2025_split huggingface dataset:
NS3 Helicase Domains Involved in Infectious Intracellular Hepatitis C Virus Particle Assembly
Authors: Ma Yinghong , Yates Jeremy , Liang Yuqiong , Lemon Stanley M. , Yi MinKyung 
Published: May 2008

ABSTRACT
A mutation within subdomain 1 of the hepatitis C virus (HCV) NS3 helicase (NS3-Q221L) (M. Yi, Y. Ma, J. Yates, and S. M. Lemon, J. Virol. 81:629-638, 2007) rescues a defect in production of infectious virus by an intergenotypic chimeric RNA (HJ3). Although NS3-Gln-221 is highly conserved across HCV genotypes, the Leu-221 substitution had no effect on RNA replication or NS3-associated enzymatic activities. However, while transfection of unmodified HJ3 RNA failed to produce either extracellular or intracellular infectious virus, transfection of HJ3 RNA containing the Q221L substitution (HJ3/QL) resulted in rapid accumulation of intracellular infectious particles with release into extracellular fluids. In the absence of the Q221L mutation, both NS5A and NS3 were recruited to core protein on the surface of lipid droplets, but there was no assembly of core into high-density, rapidly sedimenting particles. Further analysis demonstrated that a Q221N mutation minimally rescued virus production and led to a second-site I399V mutation in subdomain 2 of the helicase. Similarly, I399V alone allowed only low-level virus production and led to selection of an I286V mutation in subdomain 1 of the helicase which fully restored virus production, confirming the involvement of both major helicase subdomains in the assembly process. Thus, multiple mutations in the helicase rescue a defect in an early-intermediate step in virus assembly that follows the recruitment of NS5A to lipid droplets and precedes the formation of dense intracellular viral particles. These data reveal a previously unsuspected role for the NS3 helicase in early virion morphogenesis and provide a new perspective on HCV assembly.
Cryoelectron Microscopy Map of
Atadenovirus
Reveals Cross-Genus Structural Differences from Human Adenovirus
Authors: Pantelic Radosav S. , Lockett Linda J. , Rothnagel Rosalba , Hankamer Ben , Both Gerald W. 
Published: May 2008

ABSTRACT

A three-dimensional (3D) cryoelectron microscopy reconstruction of the prototype
Atadenovirus
(OAdV [an ovine adenovirus isolate]) showing information at a 10.6-Å resolution (0.5 Fourier shell correlation) was derived by single-particle analysis. This is the first 3D structure solved for any adenovirus that is not a
Mastadenovirus
, allowing cross-genus comparisons between structures and the assignment of genus-specific capsid proteins. Viable OAdV mutants that lacked the genus-specific LH3 and p32k proteins in purified virions were also generated. Negatively stained 3D reconstructions of these mutants were used to identify the location of protein LH3 and infer that of p32k within the capsid. The key finding was that LH3 is a critical protein that holds the outer capsid of the virus together. In its absence, the outer viral capsid is unstable. LH3 is located in the same position among the hexon subunits as its protein IX equivalent from mastadenoviruses but sits on top of the hexon trimers, forming prominent “knobs” on the virion surface that visually distinguish OAdV from other known AdVs. Electron density was also assigned to hexon and penton subunits and to proteins IIIa and VIII. There was good correspondence between OAdV density and human AdV hexon structures, which also validated the significant differences that were observed between the penton base protein structures.
Human Immunodeficiency Virus Type 1 Infection Increases the In Vivo Capacity of Peripheral Monocytes To Cross the Blood-Brain Barrier into the Brain and the In Vivo Sensitivity of the Blood-Brain Barrier to Disruption by Lipopolysaccharide
Authors: Wang Hongwei , Sun Jinglin , Goldstein Harris 
Published: May 2008

ABSTRACTHuman immunodeficiency virus type 1 (HIV-1), introduced into the brain by HIV-1-infected monocytes which migrate across the blood-brain barrier (BBB), infects resident macrophages and microglia and initiates a process that causes HIV-1-associated neurocognitive disorders. The mechanism by which HIV-1 infection circumvents the BBB-restricted passage of systemic leukocytes into the brain and disrupts the integrity of the BBB is not known. Circulating lipopolysaccharide (LPS), which can compromise the integrity of the BBB, is significantly increased in HIV-1-infected individuals. We hypothesized that HIV-1 infection increases monocyte capacity to migrate across the BBB, which is further facilitated by a compromise of BBB integrity mediated by the increased systemic LPS levels present in HIV-1-infected individuals. To investigate this possibility, we examined the in vivo BBB migration of monocytes derived from our novel mouse model, JR-CSF/EYFP mice, which are transgenic for both a long terminal repeat-regulated full-length infectious HIV-1 provirus and ROSA-26-regulated enhanced yellow fluorescent protein. We demonstrated that JR-CSF/EYFP mouse monocytes displayed an increased capacity to enter the brain by crossing either an intact BBB or a BBB whose integrity was partially compromised by systemic LPS. We also demonstrated that the JR-CSF mouse BBB was more susceptible to disruption by systemic LPS than the control wild-type mouse BBB. These results demonstrated that HIV-1 infection increased the ability of monocytes to enter the brain and increased the sensitivity of the BBB to disruption by systemic LPS, which is elevated in HIV-1-infected individuals. These mice represent a new in vivo system for studying the mechanism by which HIV-1-infected monocytes migrate into the brain.
Reduction in Severity of a Herpes Simplex Virus Type 1 Murine Infection by Treatment with a Ribozyme Targeting the U
L
20 Gene RNA
Authors: Liu Jia , Lewin Alfred S. , Tuli Sonal S. , Ghivizzani Steven C. , Schultz Gregory S. , Bloom David C. 
Published: May 2008

ABSTRACT

Hammerhead ribozymes were designed to target mRNA of several essential herpes simplex virus type 1 (HSV-1) genes. A ribozyme specific for the late gene U
L
20 was packaged in an adenovirus vector (Ad-U
L
20 Rz) and evaluated for its capacity to inhibit the viral replication of several HSV-1 strains, including that of the wild-type HSV-1 (17
syn
+ and KOS) and several acycloguanosine-resistant strains (PAAr5, tkLTRZ1, and ACGr4) in tissue culture. The Ad-U
L
20 Rz was also tested for its ability to block an HSV-1 infection, using the mouse footpad model. Mouse footpads were treated with either the Ad-U
L
20 Rz or an adenoviral vector expressing green fluorescent protein (Ad-GFP) and then infected immediately thereafter with 10
4
PFU of HSV-1 strain 17
syn
+. Ad-U
L
20 ribozyme treatment consistently led to a 90% rate of protection for mice from lethal HSV-1 infection, while the survival rate in the control groups was less than 45%. Consistent with this protective effect, treatment with the Ad-U
L
20 Rz reduced the viral DNA load in the feet, the dorsal root ganglia, and the spinal cord relative to that of the Ad-GFP-treated animals. This study suggests that ribozymes targeting essential genes of the late kinetic class may represent a new therapeutic strategy for inhibiting HSV infection.
Induction of Broad CD4+and CD8+T-Cell Responses and Cross- Neutralizing Antibodies against Hepatitis C Virus by Vaccination with Th1-Adjuvanted Polypeptides Followed by Defective Alphaviral Particles Expressing Envelope Glycoproteins gpE1 and gpE2 and Nonstructural Proteins 3, 4, and 5
Authors: Lin Yinling , Kwon Taewoo , Polo John , Zhu Yi-Fei , Coates Stephen , Crawford Kevin , Dong Christine , Wininger Mark , Hall John , Selby Mark , Coit Doris , Medina-Selby Angelica , McCoin Colin , Ng Philip , Drane Debbie , Chien David , Han Jang , Vajdy Michael , Houghton Michael 
Published: May 2008

ABSTRACTBroad, multispecific CD4+and CD8+T-cell responses to the hepatitis C virus (HCV), as well as virus-cross-neutralizing antibodies, are associated with recovery from acute infection and may also be associated in chronic HCV patients with a favorable response to antiviral treatment. In order to recapitulate all of these responses in an ideal vaccine regimen, we have explored the use of recombinant HCV polypeptides combined with various Th1-type adjuvants and replication-defective alphaviral particles encoding HCV proteins in various prime/boost modalities in BALB/c mice. Defective chimeric alphaviral particles derived from the Sindbis and Venezuelan equine encephalitis viruses encoding either the HCV envelope glycoprotein gpE1/gpE2 heterodimer (E1E2) or nonstructural proteins 3, 4, and 5 (NS345) elicited strong CD8+T-cell responses but low CD4+T helper responses to these HCV gene products. In contrast, recombinant E1E2 glycoproteins adjuvanted with MF59 containing a CpG oligonucleotide elicited strong CD4+T helper responses but no CD8+T-cell responses. A recombinant NS345 polyprotein also stimulated strong CD4+T helper responses but no CD8+T-cell responses when adjuvanted with Iscomatrix containing CpG. Optimal elicitation of broad CD4+and CD8+T-cell responses to E1E2 and NS345 was obtained by first priming with Th1-adjuvanted proteins and then boosting with chimeric, defective alphaviruses expressing these HCV genes. In addition, this prime/boost regimen resulted in the induction of anti-E1E2 antibodies capable of cross-neutralizing heterologous HCV isolates in vitro. This vaccine formulation and regimen may therefore be optimal in humans for protection against this highly heterogeneous global pathogen.
What to tell and how to tell: a qualitative study of information sharing in research for adults with intellectual disability
Authors: Andre-Barron D , Strydom A , Hassiotis A 
Published: May 2008

Objectives:To explore opinions and attitudes regarding the current information-giving practices in research involving adults with intellectual disabilities.Design:Qualitative focus group study with a purposive sample.Setting:An intellectual disabilities service within the NHSParticipants:A sample of 26 individuals including adults with mild intellectual disability, carers, clinicians, care managers and the charitable sector.Results:Three main themes were identified: process, format, and content. There was agreement that there is a need for improvement in the process and quality of information giving. With regard to the content of information, there was little discrepancy between the study findings and existing guidance.Conclusions:Information should be presented in different formats and prepared with input from appropriate professions. Additionally the roles of peers, carers and other professionals in the process of information giving should be considered.
Scientific responsibility for the dissemination and interpretation of genetic research: lessons from the “warrior gene” controversy
Authors: Wensley D , King M 
Published: May 2008

This paper discusses the announcement by a team of researchers that they identified a genetic influence for a range of “antisocial” behaviours in the New Zealand Māori population (dubbed the “warrior gene”). The behaviours included criminality, violence, gambling and alcoholism. The reported link between genetics and behaviour met with much controversy. The scientists were described as hiding behind a veneer of supposedly “objective” western science, using it to perpetuate “racist and oppressive discourses”.In this paper we examine what went wrong in the dissemination of the research. We chose as our framework the debate around the “internal/external” responsibilities of scientists. Using this discourse we argue that when the researchers ventured to explain their research in terms of social phenomena, they assumed a duty to ensure that their findings were placed “in context”. By “in context”, we argue that evidence of any genetic influence on behavioural characteristics should not be reported in isolation, but instead presented alongside other environmental, cultural and socio-economic influences that may also contribute to the studied behaviour. Rather than imposing a new obligation on scientists, we find this duty to contextualise results is in keeping with the spirit of codes of ethics already in place. Lessons from the “warrior gene” controversy may assist researchers elsewhere to identify potential areas of conflictbeforethey jeopardise research relationships, or disseminate findings in a manner that fuels misleading and/or potentially discriminatory attitudes in society.
National HIV treatment guidelines in Tanzania and Ethiopia: are they legitimate rationing tools?: Table 1
Authors: Johansson K A , Jerene D , Norheim O F 
Published: May 2008

Objective:To provide an ethical analysis of whether the Ethiopian and Tanzanian national HIV/AIDS treatment guidelines can be considered legitimate and fair rationing tools.Method:Qualitative study and ethical analysis involving guideline documents and interviews with nine key members involved in the development of the guidelines. The analysis followed an editing organising style. The theoretical framework was a guideline-specific framework based on theories of just resource allocation in healthcare and conditions that ensure fair processes in guideline development. According to this framework, legitimate rationing requires reasons for patient selection to be explicit, public and relevant, and decisions must be open to question and revision.Results:The only explicit rationing criteria that both guidelines recommended were clinical antiretroviral treatment indications. Explicit non-clinical rationing criteria were expressed in a separate Ethiopian implementation guideline. Neither of the guideline development processes fully satisfies minimal requirements of procedural fairness. There is a lack of transparency. The reasons for decisions are rarely given and are not publicly available. This reduces the opportunity for public questioning, debate and revisions. The guidelines were based on expert opinion and consensus. Recommendations from the WHO were copied without much discussion, disagreement or adjustment.Conclusions:The two national HIV treatment guidelines discussed are de facto mechanisms for rationing but were developed using methods that do not fully satisfy the requirements of fair processes.
Croatian physicians’ and nurses’ experience with ethical issues in clinical practice
Authors: Sorta-Bilajac I , Baždarić K , Brozović B , Agich G J 
Published: May 2008

Aim:To assess ethical issues in everyday clinical practice among physicians and nurses of the University Hospital Rijeka, Rijeka, Croatia.Subjects and methods:We surveyed the entire population of internal medicine, oncology and intensive care specialists and associated nurses employed at the University Hospital Rijeka, Rijeka, Croatia (n = 532). An anonymous questionnaire was used to explore the type and frequency of ethical dilemmas, rank of their difficulty, access to and use of ethics support services, training in ethics and confidence about knowledge in ethics. Physicians (n = 113, 55% of them female) ranged in age from 27 to 61 years, and nurses (n = 251, 95% female), from 20 to 52.Results:The most frequent ethical dilemmas concerned uncertain or impaired decision-making capacity (66% of physicians, 47% of nurses, p = 0.008), limitation of treatment at the end of life (60% of physicians, 31% of nurses, p<0.001) and disagreements among family members (47% of physicians, 31% of nurses, p = 0.025). The most difficult dilemmas concerned euthanasia and physician-assisted suicide (49% of physicians, 52% of nurses) and limitation of treatment at the end of life (14% of physicians, 18% of nurses). Only a minority reported ever using any kind of ethics support services (12% of physicians, 3% of nurses, p = 0.001) or being very confident about knowledge in ethics (5% of physicians, 6% of nurses).Conclusions:Similar ethical difficulties are present in the clinical practice of both physicians and nurses, with important differences in access and use of ethics support services. A need for systematic ethics educational activities was identified. Inclusion of individual ethics consultants in Croatian healthcare ethics support services is strongly advised.
Nurses’ attitudes towards artificial food or fluid administration in patients with dementia and in terminally ill patients: a review of the literature
Authors: Bryon E , de Casterlé B Dierckx , Gastmans C 
Published: May 2008

Objective:Although nurses have an important role in the care process surrounding artificial food or fluid administration in patients with dementia or in terminally ill patients, little is known about their attitudes towards this issue. The purpose of this study was to thoroughly examine nurses’ attitudes by means of a literature review.Method:An extensive systematic search of the electronic databases PubMed, Cinahl, PsycINFO, The Cochrane Library, FRANCIS, Philosopher’s Index and Social Sciences Citation Index was conducted to identify pertinent articles published from January 1990 to January 2007.Findings:Nurses’ arguments for or against could be categorised as ethical-legal, clinical or social-professional. The most important arguments explicitly for artificial food and fluid administration in patients with dementia or in terminally ill patients were sanctity of life, considering artificial food and fluid administration as basic nursing care, and giving reliable nutrition, hydration or medication. An explicit counter-argument was the high cost of treatment. Arguments used by opponents and proponents were quality of life and dignified death. The arguments were not strikingly different for the two patient populations. It turned out that the nurses’ ethical arguments remarkably reflected the current ethical debate. But some of their clinical presuppositions contradicted current clinical evidence.Conclusion:The interaction between clinical facts and ethical reflections makes the findings of this review extremely relevant for clinical ethics. A large need exists to clearly communicate to nurses the latest clinical evidence and the main results of ongoing ethical debates.
Systematic reviews of empirical bioethics
Authors: Strech D , Synofzik M , Marckmann G 
Published: May 2008

Background:Publications and discussions of survey research in empirical bioethics have steadily increased over the past two decades. However, findings often differ among studies with similar research questions. As a consequence, ethical reasoning that considers only parts of the existing literature and does not apply systematic reviews tends to be biased. To date, we lack a systematic review (SR) methodology that takes into account the specific conceptual and practical challenges of empirical bioethics.Methods:The steps of systematically reviewing empirical findings in bioethics are presented and critically discussed. In particular, (a) the limitations of traditional SR methodologies in the field of empirical bioethics are critically discussed, and (b) conceptual and practical recommendations for SRs in empirical bioethics that are (c) based on the authors’ review experiences in healthcare ethics are presented.Results:A 7-step approach for SRs of empirical bioethics is proposed: (1) careful definition of review question; (2) selection of relevant databases; (3) application of ancillary search strategies; (4) development of search algorithms; (5) relevance assessment of the retrieved references; (6) quality assessment of included studies; and (7) data analysis and presentation. Conceptual and practical challenges arise because of various peculiarities in reviewing empirical bioethics literature and can lead to biased results if they are not taken into account.Conclusions:If suitably adapted to the peculiarities of the field, SRs of empirical bioethics provide transparent information for ethical reasoning and decision-making that is less biased than single studies.
How do elderly spouse care givers of people with Alzheimer disease experience the disclosure of dementia diagnosis and subsequent care?
Authors: Laakkonen M-L , Raivio M M , Eloniemi-Sulkava U , Saarenheimo M , Pietilä M , Tilvis R S , Pitkälä K H 
Published: May 2008

Objectives:To examine the experiences of spousal care givers of Alzheimer patients to disclosure of dementia diagnosis and subsequent care.Methods:A random sample of 1943 spousal care givers of people receiving medication for Alzheimer disease (AD) was sent a cross-sectional postal survey about their opinions on the disclosure of dementia and follow-up care. A smaller qualitative study (n = 63) included open-ended questions concerning their experiences of the same topics.Results:The response rate for the survey was 77%. Of the respondents, 1214 of 1434 acknowledged themselves as their spouse’s care giver. The mean age of the care givers was 78.2 years, and that of demented spouses, 80.5 years. Of the care givers, 63% were women. The couples had long-lasting marriages (mean 52 years). Of the care givers, 93% reported that dementia had been disclosed openly to their spouse; 97% also preferred that physicians openly inform the patients of the dementia diagnosis, although 55% of their spouses with AD had developed depressive symptoms after the disclosure. Of the care givers, 71% felt they had received sufficient information about dementia. However, only 50% estimated that their spouses’ follow-up care had been well organised. The responses in the qualitative study indicated that many care givers felt grief and anxiety. They also expressed feelings of loneliness and uncertainty about how to deal with follow-up care for dementia.Conclusions:Elderly spousal care givers were quite satisfied with the information given them about dementia. However, the support with regard to the follow-up care of care-giving families failed to meet their needs adequately.
Ethical decision-making, passivity and pharmacy: Figure 1
Authors: Cooper R J , Bissell P , Wingfield J 
Published: May 2008

Background:Increasing interest in empirical ethics has enhanced understanding of healthcare professionals’ ethical problems and attendant decision-making. A four-stage decision-making model involving ethical attention, reasoning, intention and action offers further insights into how more than reasoning alone may contribute to decision-making.Aims:To explore how the four-stage model can increase understanding of decision-making in healthcare and describe the decision-making of an under-researched professional group.Methods:23 purposively sampled UK community pharmacists were asked, in semi-structured interviews, to describe ethical problems in their work and how they were resolved. Framework analysis of transcribed interviews utilised the four decision-making stages, together with constant comparative methods and deviant-case analysis.Results:Pharmacists were often inattentive and constructed problems in legal terms. Ethical reasoning was limited, but examples of appeals to consequences, the golden rule, religious faith and common-sense experience emerged. Ethical intention was compromised by frequent concern about legal prosecution. Ethical inaction was common, typified by pharmacists’ failure to report healthcare professionals’ bad practices, and ethical passivity emerged to describe these negative examples of the four decision-making stages. Pharmacists occasionally described more ethically active decision-making, but this often involved ethical uncertainty.Discussion:The four decision-making stages are a useful tool in considering how healthcare professionals try to resolve ethical problems in practice. They reveal processes often ignored in normative theories, and their recognition and the emergence of ethical passivity indicates the complexity of decision-making in practice. Ethical passivity may be deleterious to patients’ welfare, and concerns emerge about improving pharmacists’ ethical training and promoting ethical awareness and responsibility.