A mechanistic basis for potent, glycoprotein B-directed gammaherpesvirus neutralization

Glycoprotein B (gB) is a conserved, essential component of gammaherpes virions and so potentially vulnerable to neutralization. However, few good gB-specific neutralizing antibodies have been identified. Here, we show that murid herpesvirus 4 is strongly neutralized by mAbs that recognize an epitope close to one of the gB fusion loops. Antibody binding did not stop gB interacting with its cellular ligands or initiating its fusion-associated conformation change, but did stop gB resolving stably to its post-fusion form, and so blocked membrane fusion to leave virions stranded in late endosomes. The conservation of gB makes this mechanism a possible general route to gammaherpesvirus neutralization

New evidence on Allyn Young's style and influence as a teacher

This paper publishes the hitherto unpublished correspondence between Allyn Abbott Young's biographer Charles Blitch and 17 of Young's former students or associates. Together with related biographical and archival material, the paper shows the way in which this adds to our knowledge of Young's considerable influence as a teacher upon some of the twentieth century's greatest economists. The correspondents are as follows: James W Angell, Colin Clark, Arthur H Cole, Lauchlin Currie, Melvin G de Chazeau, Eleanor Lansing Dulles, Howard S Ellis, Frank W Fetter, Earl J Hamilton, Seymour S Harris, Richard S Howey, Nicholas Kaldor, Melvin M Knight, Bertil Ohlin, Geoffrey Shepherd, Overton H Taylor, and Gilbert Walker

Altered plasticity of the parasympathetic innervation in the recovering rat submandibular gland following extensive atrophy

Adult rat submandibular glands have a rich autonomic innervation, with parasympathetic and sympathetic nerves working in synergy rather than antagonistically. Ligation of the secretory duct rapidly causes atrophy and the loss of most acini, which are the main target cell for parasympathetic nerves. Following deligation, there is a recovery of gland structure and function, as assessed by autonomimetic stimulation. This study examines whether the parasympathetic nerves reattach to new target cells to form functional neuro-effector junctions. Under recovery anaesthesia, the submandibular duct of adult male rats was ligated via an intra-oral approach to avoid damaging the chorda-lingual nerve. Four weeks later, rats were either killed or anaesthetized and the ligation clip removed. Following a further 8 weeks, both submandibular ducts were cannulated under terminal anaesthesia. Salivary flows were then stimulated electrically (chorda-lingual nerve at 2, 5 and 10 Hz) and subsequently by methacholine (whole-body infusion at two doses). Glands were excised, weighed and divided for further in vitro studies or fixed for histological examination. Ligation of ducts caused 75% loss of gland weight, with the loss of most acinar cells. Of the remaining acini, only 50% were innervated despite unchanged choline acetyltransferase activity, suggesting few parasympathetic nerves had died. Following deligation, submandibular glands recovered half their weight and had normal morphology. Salivary flows from both glands (per unit of gland tissue) were similar when evoked by methacholine but greater from the deligated glands when evoked by nerve stimulation. This suggests that parasympathetic nerves had reattached to new target cells in the recovered glands at a greater ratio than normal, confirming reinnervation of the regenerating gland

Exploitation of Herpesviral Transactivation Allows Quantitative Reporter Gene-Based Assessment of Virus Entry and Neutralization

Herpesviral entry is a highly elaborated process requiring many proteins to act in precise conjunction. Neutralizing antibodies interfere with this process to abrogate viral infection. Based on promoter transactivation of a reporter gene we established a novel method to quantify herpesvirus entry and neutralization by antibodies. Following infection with mouse and human cytomegalovirus and Herpes simplex virus 1 we observed promoter transactivation resulting in substantial luciferase expression (>1000-fold). No induction was elicited by UV-inactivated viruses. The response was MOI-dependent and immunoblots confirmed a correlation between luciferase induction and pp72-IE1 expression. Monoclonal antibodies, immune sera and purified immunoglobulin preparations decreased virus-dependent luciferase induction dose-dependently, qualifying this approach as surrogate virus neutralization test. Besides the reduced hands-on time, this assay allows analysis of herpesvirus entry in semi-permissive and non-adherent cells, which were previously non-assessable but play significant roles in herpesvirus pathology

Trade in the Shadow of Power : Japanese Industrial Exports in the Interwar years

During the interwar years, Japanese industrialisation accelerated alongside the expansion of industrial exports to regional markets. Trade blocs in the interwar years were used as an instrument of imperial power to foster exports and as a substitute for productivity to encourage industrial production. The historiography on Japanese industrialisation in the interwar years describes heavy industries' interests in obtaining access to wider markets to increase economies of scale and reduce unit costs. However, this literature provides no quantitative evidence that proves the success of those mechanisms in expanding exports. In this paper we scrutinise how Japan—a relatively poor country—used colonial as well as informal power interventions to expand regional markets for its exports, especially for the most intensive human capital sector of the industrializing economy

Postpartum behaviour as predictor of weight change from before pregnancy to one year postpartum

<p>Abstract</p> <p>Background</p> <p>Postpartum weight retention affects many women and increases the risk of becoming overweight. The research objective was to study modifiable factors contributing to weight change at one year postpartum.</p> <p>Methods</p> <p>In this prospective cohort, postpartum behavior, such as physical activity, sedentary behavior, sleep, and intake of total energy, total fat and saturated fatty acids of 118 Dutch women were assessed in 2003/2004 by self-report at 6 weeks, 6 and 12 months postpartum. Mean postpartum scores were computed for the behavioral measures. In linear regression models it was determined which factors were associated with average weight change from before pregnancy to one year postpartum. Furthermore, factors associated with substantial postpartum weight retention (≥ 5 kg) were also studied in logistic regression models.</p> <p>Results</p> <p>At one year postpartum, the average weight of participants had increased by 0.9 kg (SD 4.4). Moreover, 20% of the women retained ≥ 5 kg. Women who perceived themselves more physically active than others were almost ten times less likely to retain ≥ 5 kg than women who perceived themselves equally active (OR = 0.11, 95%CI: 0.02 - 0.66). Exceeding the guideline for saturated fatty acid intake (OR = 3.40, 95%CI: 1.04 - 11.11), total gestational weight gain (OR = 1.14/kg, 95%CI: 1.01 - 1.27), and not having completed post high school education (OR = 5.13, 95%CI: 1.66 - 15.90) increased the odds of retaining ≥ 5 kg.</p> <p>Conclusions</p> <p>Since one in five women had substantial weight retention postpartum, effective interventions for the prevention of weight retention are much needed. Future studies should evaluate whether interventions focusing on the identified modifiable postpartum factors are successful in reducing weight retention after childbirth.</p

OGRDB: a reference database of inferred immune receptor genes

The immune rejection of allografts is mediated by T cells via two distinct pathways: the direct and the indirect pathways. Direct alloresponse to intact donor MHC molecules is ensured by T cells which are polyclonal and directed toward a variety of antigens. This response is highly sensitive to treatment by immunosuppressive drugs including Cyclosporin A. Indirect alloresponse is oligoclonal and involves a few dominant antigen peptides on donor MHC. In contrast to its direct counterpart, indirect allorecognition is thought to be poorly sensitive to blockade by cyclosporin A. It is likely that indirect and direct types of alloresponses play different roles in the physiology of the rejection process. T cell responses occurring via direct allorecognition play a critical role during the early phase of acute graft rejection by sensitizing the host to graft antigens. Alternatively, once such sensitization has taken place, indirect type of alloresponse may become predominant and presumably represent the driving force in the actual destruction of transplanted tissues. In addition, we and others have provided strong circumstantial evidence indicating that secondary T cell responses via indirect allorecognition spread to new determinants on donor MHC and tissue-specific antigens. This phenomenon is likely to play an important role in late and chronic rejection, a major obstacle to long-term graft acceptance in clinical transplantation. Finally, a series of studies have demonstrated that early, pre-transplant treatment with tolerogenic donor-derived MHC peptides can protect the graft from rejection in rodents. Although the mechanisms involved in MHC-peptide-induced tolerance are ill defined, this strategy represents a promising approach for ensuring long-lasting graft acceptance in the absence of widespread immunosuppression. It is now crucial to further explore the mechanims involved in immunogenicity and tolerogenicity of MHC peptides and to initiate clinical studies to evaluate the efficacy of blocking indirect alloresponses in transplanted patients

Vaccination with murid herpesvirus-4 glycoprotein B reduces viral lytic replication but does not induce detectable virion neutralization

Herpesviruses characteristically disseminate from immune hosts. Therefore in the context of natural infection, antibody neutralizes them poorly. Murid herpesvirus-4 (MuHV-4) provides a tractable model with which to understand gammaherpesvirus neutralization. MuHV-4 virions blocked for cell binding by immune sera remain infectious for IgG-Fc receptor+ myeloid cells, so broadly neutralizing antibodies must target the virion fusion complex – glycoprotein B (gB) or gH/gL. While gB-specific neutralizing antibodies are rare, its domains I+II (gB-N) contain at least one potent neutralization epitope. Here, we tested whether immunization with recombinant gB presenting this epitope could induce neutralizing antibodies in naive mice and protect them against MuHV-4 challenge. Immunizing with the full-length gB extracellular domain induced a strong gB-specific antibody response and reduced MuHV-4 lytic replication but did not induce detectable neutralization. gB-N alone, which more selectively displayed pre-fusion epitopes including neutralization epitopes, also failed to induce neutralizing responses, and while viral lytic replication was again reduced this depended completely on IgG Fc receptors. gB and gB-N also boosted neutralizing responses in only a minority of carrier mice. Therefore, it appears that neutralizing epitopes on gB are intrinsically difficult for the immune response to target

Measurement of vertebral rotation in adolescent idiopathic scoliosis with low-dose CT in prone position - method description and reliability analysis

<p>Abstract</p> <p>Background</p> <p>To our knowledge there is no report in the literature on measurements of vertebral rotation with low-dose computed tomography (CT) in prone position.</p> <p>Aims</p> <p>To describe and test the reliability of this new method, compare it with other methods in use and evaluate the influence of body position on the degree of vertebral rotation measured by different radiological methods.</p> <p>Study design</p> <p>Retrospective study.</p> <p>Methods</p> <p>25 consecutive patients with adolescent idiopathic scoliosis scheduled for surgery (17 girls, 8 boys) aged 15 ± 2 years (mean ± SD) were included in the analysis of this study. The degree of the vertebral rotation was in all patients measured according to the method of Perdriolle on standing plain radiographs and on supine CT scanogram, and according to the method of Aaro and Dahlborn on axial CT images in prone position and on magnetic resonance imaging (MRI) in supine position. The measurements were done by one neuroradiologist at two different occasions. Bland and Altman statistical approach was used in the reliability assessment.</p> <p>Results</p> <p>The reliability of measuring vertebral rotation by axial CT images in prone position was almost perfect with an intraclass correlation coefficient of 0.95, a random error of the intraobserver differences of 2.3°, a repeatability coefficient of 3.2° and a coefficient of variation of 18.4%. Corresponding values for measurements on CT scanogram were 0.83, 5.1°, 7.2°, and 32.8%, respectively, indicating lower reliability of the latter modality and method. The degree of vertebral rotation measured on standing plain radiographs, prone CT scanogram, axial images on CT in prone position and on MRI in supine position were 25.7 ± 9.8°, 21.9 ± 8.3°, 17.4 ± 7.1°, and 16.1 ± 6.5°, respectively. The vertebral rotation measured on axial CT images in prone position was in average 7.5% larger than that measured on axial MRI in supine position.</p> <p>Conclusions</p> <p>This study has shown that measurements of vertebral rotation in prone position were more reliable on axial CT images than on CT scanogram. The measurement of vertebral rotation on CT (corrected to the pelvic tilt) in prone position imposes lower impact of the recumbent position on the vertebral rotation than did MRI in supine position. However, the magnitude of differences is of doubtful clinical significance.</p

Glycoprotein B switches conformation during murid herpesvirus 4 entry

Herpesviruses are ancient pathogens that infect all vertebrates. The most conserved component of their entry machinery is glycoprotein B (gB), yet how gB functions is unclear. A striking feature of the murid herpesvirus 4 (MuHV-4) gB is its resistance to neutralization. Here, we show by direct visualization of infected cells that the MuHV-4 gB changes its conformation between extracellular virions and those in late endosomes, where capsids are released. Specifically, epitopes on its N-terminal cell-binding domain become inaccessible, whilst non-N-terminal epitopes are revealed, consistent with structural changes reported for the vesicular stomatitis virus glycoprotein G. Inhibitors of endosomal acidification blocked the gB conformation switch. They also blocked capsid release and the establishment of infection, implying that the gB switch is a key step in entry. Neutralizing antibodies could only partially inhibit the switch. Their need to engage a less vulnerable, upstream form of gB, because its fusion form is revealed only in endosomes, helps to explain why gB-directed MuHV-4 neutralization is so difficult