bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of the LWYIK Motif Located in the Human Immunodeficiency Virus Type 1 Transmembrane gp41 Protein as a Distinct Determinant for Viral Infection
Authors: Chen Steve S.-L. , Yang Polung , Ke Po-Yuan , Li Hsiao-Fen , Chan Woan-Eng , Chang Ding-Kwo , Chuang Chin-Kai , Tsai Yu , Huang Shu-Chen 
Published: November 2008

ABSTRACT

The highly conserved LWYIK motif located immediately proximal to the membrane-spanning domain of the gp41 transmembrane protein of human immunodeficiency virus type 1 has been proposed as being important for the surface envelope (Env) glycoprotein's association with lipid rafts and gp41-mediated membrane fusion. Here we employed substitution and deletion mutagenesis to understand the role of this motif in the virus life cycle. None of the mutants examined affected the synthesis, precursor processing, CD4 binding, oligomerization, or cell surface expression of the Env, nor did they alter Env incorporation into the virus. All of the mutants, particularly the ΔYI, ΔIK, and ΔLWYIK mutants, in which the indicated residues were deleted, exhibited greatly reduced one-cycle viral replication and the Env
trans
-complementation ability. All of these deletion mutant proteins were still localized in the lipid rafts. With the exception of the Trp-to-Ala (WA) mutant, which exhibited reduced viral infectivity albeit with normal membrane fusion, all mutants displayed loss of some or almost all of the membrane fusion ability. Although these deletion mutants partially inhibited in
trans
wild-type (WT) Env-mediated fusion, they were more effective in dominantly interfering with WT Env-mediated viral entry when coexpressed with the WT Env, implying a role of this motif in postfusion events as well. Both T20 and L43L peptides derived from the two gp41 extracellular C- and N-terminal α-helical heptad repeats, respectively, inhibited WT and ΔLWYIK Env-mediated viral entry with comparable efficacies. Biotin-tagged T20 effectively captured both the fusion-active, prehairpin intermediates of WT and mutant gp41 upon CD4 activation. Env without the deletion of the LWYIK motif still effectively mediated lipid mixing but inhibited content mixing. Our study demonstrates that the immediate membrane-proximal LWYIK motif acts as a unique and distinct determinant located in the gp41 C-terminal ectodomain by promoting enlargement of fusion pores and postfusion activities.
Studies of an Influenza A Virus Temperature-Sensitive Mutant Identify a Late Role for NP in the Formation of Infectious Virions
Authors: Noton Sarah L. , Simpson-Holley Martha , Medcalf Elizabeth , Wise Helen M. , Hutchinson Edward C. , McCauley John W. , Digard Paul 
Published: November 2008

ABSTRACT

The influenza A virus nucleoprotein (NP) is a single-stranded RNA-binding protein that encapsidates the virus genome and has essential functions in viral-RNA synthesis. Here, we report the characterization of a temperature-sensitive (
ts
) NP mutant (US3) originally generated in fowl plague virus (A/chicken/Rostock/34). Sequence analysis revealed a single mutation, M239L, in NP, consistent with earlier mapping studies assigning the
ts
lesion to segment 5. Introduction of this mutation into A/PR/8/34 virus by reverse genetics produced a
ts
phenotype, confirming the identity of the lesion. Despite an approximately 100-fold drop in the viral titer at the nonpermissive temperature, the mutant US3 polypeptide supported wild-type (WT) levels of genome transcription, replication, and protein synthesis, indicating a late-stage defect in function of the NP polypeptide. Nucleocytoplasmic trafficking of the US3 NP was also normal, and the virus actually assembled and released around sixfold more virus particles than the WT virus, with normal viral-RNA content. However, the particle/PFU ratio of these virions was 50-fold higher than that of WT virus, and many particles exhibited an abnormal morphology. Reverse-genetics studies in which A/PR/8/34 segment 7 was swapped with sequences from other strains of virus revealed a profound incompatibility between the M239L mutation and the A/Udorn/72 M1 gene, suggesting that the
ts
mutation affects M1-NP interactions. Thus, we have identified a late-acting defect in NP that, separate from its function in RNA synthesis, indicates a role for the polypeptide in virion assembly, most likely involving M1 as a partner.
Human Immunodeficiency Virus Type 1 Nef Incorporation into Virions Does Not Increase Infectivity
Authors: Laguette Nadine , Benichou Serge , Basmaciogullari Stéphane 
Published: November 2008

ABSTRACT
The viral protein Nef contributes to the optimal infectivity of human and simian immunodeficiency viruses. The requirement for Nef during viral biogenesis particles suggests that Nef might play a role in this process. Alternatively, because Nef is incorporated into viruses, it might play a role when progeny virions reach target cells. We challenged these hypotheses by manipulating the amounts of Nef incorporated in viruses while keeping its expression level constant in producer cells. This was achieved by forcing the incorporation of Nef into viral particles by fusing a Vpr sequence to the C-terminal end of Nef. A cleavage site for the viral protease was introduced between Nef and Vpr to allow the release of Nef fragments from the fusion protein during virus maturation. We show that the resulting Nef-CS-Vpr fusion partially retains the ability of Nef to downregulate cell surface CD4 and that high amounts of Nef-CS-Vpr are incorporated into viral particles compared with what is seen for wild-type Nef. The fusion protein is processed during virion maturation and releases Nef fragments similar to those found in viruses produced in the presence of wild-type Nef. Unlike viruses produced in the presence of wild-type Nef, viruses produced in the presence of Nef-CS-Vpr do not have an increase in infectivity and are as poorly infectious as viruses produced in the absence of Nef. These findings demonstrate that the presence of Nef in viral particles is not sufficient to increase human immunodeficiency virus type 1 infectivity and suggest that Nef plays a role during the biogenesis of viral particles.
Sensitivity and specificity of clinical signs for assessment of dehydration in endurance athletes
Authors: McGarvey J , Thompson J , Hanna C , Noakes T D , Stewart J , Speedy D 
Published: November 2008

ObjectiveTo investigate the diagnostic accuracy of commonly used signs of dehydration in marathon runners.DesignThe diagnostic accuracy of 5 clinical signs/symptoms thought to indicate dehydration (altered skin turgor, dry oral mucous membranes, sunken eyes, an inability to spit and the sensation of thirst) was assessed by comparing the presence of these markers with the criterion standard of body weight change over a marathon footrace.Setting2006 Auckland MarathonParticipants606 competitors in the full marathon Assessment: Body weight was measured before and immediately after the marathon. The 5 clinical signs/symptoms were assessed immediately after the marathon.Main outcome measuresDiagnostic accuracy of clinical signs/symptoms to detect dehydration greater than 3% of body weight.Results606 complete data sets were obtained. 3 clinical signs were associated with greater percentage weight loss: sunken eyes (mean percentage weight loss with symptom 2.6% (standard deviation 1.5), without 2.3% (1.5)); decreased skin turgor (with 3.0% (1.4), without 2.3% (1.5)) and the sensation of thirst (with 2.5% (1.5), without 2.3% (1.5)). The ability to spit and dry oral mucous membranes were unrelated to percentage weight loss. No signs/symptoms showed acceptably high validity for detecting a weight loss equal to or greater than 3% of body weight.ConclusionsThe 5 parameters (decreased skin turgor, sensation of thirst, sunken eyes, inability to spit and dry mucous membranes) tested in this study did not precisely identify runners with total weight loss.3% at the end of a marathon.
AID and the law
Authors: Cusine D J 
Published: November 2008

The present state of the law is unsatisfactory. The exact effect on the marriage of the parties has not been decided although in English law if artificial insemination by donor (AID) takes place without consent that would appear to be a ground for divorce since 1969. The law regards a child born as a result of AID as illegitimate and draws no distinction between the case where the husband consents and where he does not. Theoretically, an offence is committed if the birth entry is falsified, presumably in cases where the husband consents. The AID child, like any other illegitimate child, has rights against the natural parents, but he is in a worse position than most illegitimate children, in that he may not have any information about his father.It is now possible to freeze sperm and so preserve it over longer periods. All the problems associated with AID are present also when sperm is preserved in banks, but if the law is in an unsatisfactory state in relation to AID this is even more true in relation to sperm banks. The main criticism of the Feversham Report (1960) could be that it recommended, broadly speaking, the `status quo' but scientific progress has now overtaken and left the Feversham findings well behind. What, therefore, is required is a full consideration of the subject of AID and, on the basis of that, some statutory code regulating all its aspects.
Transplantation
Authors: Calne R Y 
Published: November 2008

In this paper Professor Calne pleads for a more informed approach to the problem of donor transplants, particularly in cases of kidney disease. He is concerned to inform both the medical profession and lay people. Establishing a computerized register of names and addresses of those who do not wish to have their organs used for transplantation after death would allow enquiries to be made immediately after death.The second point of emphasis is that death of the brain is the death of the individual. A code of practice is suggested which should be followed in all transplantation centres and would allay the fears of the public and encourage the cooperation of doctors.
Injuries to unborn children: Extracts from the report of the Law Commission
Authors: Cooke Samuel , Bicknell Claud , Diamond Aubrey L. , Hodgson Derek , Marsh Norman S. , Sharp J M Cartwright 
Published: November 2008

We are printing, by kind permission of the Law Commission, two sections of the report of the Law Commission on injuries to unborn children. This report was the result of a request to the Law Commission by the Lord Chancellor at the time (Lord Hailsham of Saint Marylebone) to advise on `what the nature and extent of civil liability for antenatal injury should be'. The Law Commission followed its usual practice in such circumstances of consulting various bodies and obtaining expert advice on the subject and then embodying the results in a working paper (Working Paper No. 47 - injuries to unborn children) published on 19 January 1973, which preceded their report (Cmnd 5709). Meanwhile a Royal Commission is considering much wider issues of civil liability for injury (including antenatal injury) but the terms of reference for the Law Commission were much narrower and confined to the position of children injured before birth. In the section relating to the present law the report makes it clear that it is probable that liability under the common law already exists.The Scottish Law Commission has also issued a report (Cmnd 5371). They were given different terms of reference and came to somewhat different conclusions.We are printing from this long report the paragraphs discussing the medical background and the summary of recommendations. As will be evident on reading the paragraphs on the medical background to injuries to the unborn child, events are moving very rapidly, particularly in the study of congenital defects and the effects of drugs but the problems of proof present great difficulty. Other causes of injury to the unborn child are better known to the general public: for example, those following the illness, infection and disease of the mother during pregnancy, injury caused in attempted termination of pregnancy and the risks resulting from the mother's condition. The summary of the recommendations sets out very clearly the legal position of the unborn child, as the Law Commission sees it, arising from injury before birth, the final conclusion being that `legislation is desirable'.These extracts from the report, apart from their intrinsic interest, lead on to the paper by Mr Kennedy and Dr Edwards in which they set out their criticisms of it, and provide quick references to the original document.
A plea for a touch of realism: reply to P Whitaker
Authors: Lamb David 
Published: November 2008

This reply to P Whitaker's `Resource allocation: a plea for a touch of realism' acknowledges that health-care ethics should be relevant to events in the real world, but questions the extent to which philosophical inquiry should be confined to parameters determined by existing sociopolitical forces.The reading of the daily paper is the morning prayer of the realist.
The ethics of medical involvement in torture: commentary
Authors: Hare R M 
Published: November 2008

Torture does need to be defined if we are to know exactly what we are seeking to ban; but no single definition will do, because there are many possible ones, and we may want to treat different practices that might be called torture differently. Compare the case of homicide; we do not want to punish manslaughter as severely as murder, and may not want to punish killing in self-defence at all. There are degrees of torture as of murder. Unclarities simply play into the hands of would-be torturers.Downie is unsuccessful in deriving the duty of doctors not to be involved in torture from an analysis of the word `doctor'. It may be contrary to the role-duty of doctors to participate in torture; but there might be other duties which overrode this role-duty. The right approach is to ask what principles for the conduct of doctors have the highest acceptance-utility, or, as Kant might have equivalently put it, what the impartial furtherance of everyone's ends demands. This approach yields the result that torture (suitably defined) should be banned absolutely. It also yields prescriptions for the conduct of doctors where, in spite of them, torture is taking place.
Quality care—commonplace or chimera
Authors: Donald B. L. , Southern R. M. 
Published: November 2008

Publicity for (and laterly increased economic stringency which makes more likely), failures of care in the NHS engender concern for care quality while its assurance remains the subject of a fragmented and unhelpful literature. A selective attempt is made to examine some underlying principles by posing and answering three questions. What is the quality of care? What basic principles must be followed in defining `standards'? How then may quality be assured?Any definition of care must be multi-faceted and in common use pervaded with the patients' pre-occupation with a search for cures. Nevertheless, it is argued that there are gains in restricting the technical use of the term `care' to those systematic processes of health services and their culture which impinge on the personal experience of patients and which fashion their response.In contemporary society care ought to be designed to restore and enhance the independence, dignity and choice of the patient. Although there is a contrary tendency to abandon problems of care to the professionals, standards for care should be judged ultimately not from the specialised professional but from the viewpoint of lay people whose behaviour in the outside world fashions those norms by which independence, dignity and choice are judged.A number of difficulties in identifying and securing improvements in care are discussed. In particular, it is argued that such is the interdependence of the style of management of an institution and the style of care it provides that enforcement of high quality care is likley to be a contradiction in terms. Only trained and sensitive staff can act intuitively and pre-emptively to prevent even incipient deterioration in care. They cannot carefully foster at all times the independence and dignity of their patients unless they are treated in a similar way as professional employees.As an initial step in improving the quality of care a simple start is urged upon implementing an inventory of checks. These are designed to establish the identification and operation of health care policies and practices which give appropriate recognition to the characteristics of care that patients and public expect, coming as they do from a lay rather than professional world. The article concludes with an appropriate inventory of questions to be put to professionals by those laymen who are increasingly imported into health care management through community representation (in CHCs) and staff participation (in joint consultation) and whose interest and concern should be harnessed appropriately.
The faces of death
Authors: Popa G , Hanganu Ecaterina 
Published: November 2008

The individual's reaction to imminent death depends on his concept of the existential meaning of death.There are two main, but opposing, concepts, one positive and the other tragic. The first sees death as a transition to another mode of being. Within that three main modalities are to be distinguished, in which is considered either as an element in the cosmic harmony, the reintegration of the individual into the universal (the `Tagorian' mode); or secondly the possibility of man's external existence through his transfer, together with his entire physical and psychological apparatus, to a realm of legend (the `Mioritic' mode); or thirdly the culmination of life, the moment of maximum existential concentration overflowing into the universe and encircling it (the `Rilkian' mode).The second concept, the tragic concept, sees death either as a desired solution, which puts an end to the nothingness of life (the `Tracklian' mode); or as a nonsense, as an absurd injustice of nature (the `common' mode); or as a necessity of which we do not know the meaning, a dialectical moment of eternal change (the `Stoic' mode).The psychological care of the dying involves identification with the patient's concept of death, in order to maintain his morale and possibly diminish his terror of death. The doctor must therefore be a good psychologist and a genuine philosopher, in the strictest sense of the word.
Ethical considerations of psychosurgery: the unhappy legacy of the pre-frontal lobotomy
Authors: Gostin Larry O 
Published: November 2008

There is no subject at the interface of law, psychiatry and medical ethics which is more controversial than psychosurgery. The divergent views of the treatment begin with its definition. The World Health Organisation1and others2define psychosurgery as the selective surgical removal or destruction of nerve pathways or normal brain tissue with a view to influencing behaviour. However, proponents of psychosurgery demur on the basis that the `modern' treatment is concerned predominantly with emotional illness, without any specific effect upon behaviour. The alternative definition offered is `the surgical treatment of certain psychiatric illnesses by means of localised lesions placed in specific cerebral sites.3It is difficult entirely to accept this definition because, as examined below, scientific psychiatry is not yet in a position to directly treat psychiatric illness solely through surgical intervention. There is no reliable theoretical relationship between particular cerebral sites (which are normal and healthy) and an identifiable psychiatric illness or symptomatology. Given this state of psychiatric understanding, it is misleading to suggest fine distinctions between generalised alteration of behaviour or mood and treatment of an illness. Highly divergent practices and theories (relating to the multiplicity of conditions treated, surgical methods adopted and areas of the brain operated upon) further undermine exaggerated claims that psychosurgery can scientifically `treat' specific illness through precise surgical intervention. Nonetheless, contemporary psychosurgery does not contain quite the same `broadbrush' approach of its ancestors and it can lay some legitimate claim as an effective empirical treatment in narrowly limited circumstances. Major ethical problems still, however, arise and these will be discussed in this article.
THE WEBT CAMPAIGN ON 3C279 IN 2006
Authors: BÖTTCHER M. 
Published: November 2008

The quasar 3C 279 was the target of an extensive multiwavelength monitoring campaign from January through April 2006, including an optical-IR-radio Whole Earth Blazar Telescope (WEBT) campaign and Target of Opportunity X-ray and soft γ-ray observations with Chandra and INTEGRAL in mid-January 2006, with additional X-ray coverage by RXTE and Swift XRT as well as independent very-high-energy (VHE) γ-ray observations by MAGIC, which led to the first-ever reported tentative detection of a quasar at VHE γ-rays. In this paper we summarize the results of the WEBT campaign. The source exhibited substantial variability of optical flux and spectral shape, with a characteristic time scale of a few days. The variability patterns throughout the optical BVRI bands were very closely correlated with each other, while there was no obvious correlation between the optical and radio variability. In intriguing contrast to other (in particular, BL Lac type) blazars, we find a lag of shorter-wavelength behind longer-wavelength variability throughout the RVB wavelength ranges, with a time delay increasing with increasing frequency. Spectral hardening during flares appears delayed with respect to a rising optical flux. This, in combination with the very steep IR-optical continuum spectral index of αo ~ 1.5 – 2.0, may indicate a highly oblique magnetic field configuration near the base of the jet, leading to inefficient particle acceleration and a very steep electron injection spectrum. An alternative explanation through a slow (time scale of several days) acceleration mechanism would require an unusually low magnetic field of B < 0.2 G , about an order of magnitude lower than inferred from previous analyses of simultaneous SEDs of 3C 279 and other FSRQs with similar properties.
A dynamic decision network framework for online media adaptation in stroke rehabilitation
Authors: Chen Yinpeng , Xu Weiwei , Sundaram Hari , Rikakis Thanassis , Liu Sheng-Min 
Published: November 2008

In this article, we present a media adaptation framework for an immersive biofeedback system for stroke patient rehabilitation. In our biofeedback system, media adaptation refers to changes in audio/visual feedback as well as changes in physical environment. Effective media adaptation frameworks help patients recover generative plans for arm movement with potential for significantly shortened therapeutic time. The media adaptation problem has significant challenges—(a) high dimensionality of adaptation parameter space; (b) variability in the patient performance across and within sessions; (c) the actual rehabilitation plan is typically a non-first-order Markov process, making the learning task hard.Our key insight is to understand media adaptation as a real-time feedback control problem. We use a mixture-of-experts based Dynamic Decision Network (DDN) for online media adaptation. We train DDN mixtures per patient, per session. The mixture models address two basic questions—(a) given a specific adaptation suggested by the domain experts, predict the patient performance, and (b) given the expected performance, determine the optimal adaptation decision. The questions are answered through an optimality criterion based search on DDN models trained in previous sessions. We have also developed new validation metrics and have very good results for both questions on actual stroke rehabilitation data.