Cis and trans regulatory mechanisms control AP2-mediated B cell receptor endocytosis via select tyrosine-based motifs.

Following antigen recognition, B cell receptor (BCR)-mediated endocytosis is the first step of antigen processing and presentation to CD4+ T cells, a crucial component of the initiation and control of the humoral immune response. Despite this, the molecular mechanism of BCR internalization is poorly understood. Recently, studies of activated B cell-like diffuse large B cell lymphoma (ABC DLBCL) have shown that mutations within the BCR subunit CD79b leads to increased BCR surface expression, suggesting that CD79b may control BCR internalization. Adaptor protein 2 (AP2) is the major mediator of receptor endocytosis via clathrin-coated pits. The BCR contains five putative AP2-binding YxxØ motifs, including four that are present within two immunoreceptor tyrosine-based activation motifs (ITAMs). Using a combination of in vitro and in situ approaches, we establish that the sole mediator of AP2-dependent BCR internalization is the membrane proximal ITAM YxxØ motif in CD79b, which is a major target of mutation in ABC DLBCL. In addition, we establish that BCR internalization can be regulated at a minimum of two different levels: regulation of YxxØ AP2 binding in cis by downstream ITAM-embedded DCSM and QTAT regulatory elements and regulation in trans by the partner cytoplasmic domain of the CD79 heterodimer. Beyond establishing the basic rules governing BCR internalization, these results illustrate an underappreciated role for ITAM residues in controlling clathrin-dependent endocytosis and highlight the complex mechanisms that control the activity of AP2 binding motifs in this receptor system

Exploring the effects of telehealth on medical human resources supply: a qualitative case study in remote regions

BACKGROUND: The availability of medical human resource supply is a growing concern for rural and remote communities in many countries. In the last decade, various telehealth experiences in Canada have highlighted the potential impact of this technology on professional practice. The purpose of this study was to explore physicians' and managers' perceptions regarding the potential of telehealth to support recruitment and retention of physicians in remote and rural regions. METHODS: A case study in Eastern Quebec was performed to explore this complex phenomenon. The analytical framework was based on two literature reviews and a Delphi study. Data were collected from semi-structured interviews with 41 physicians and 22 managers. Transcripts were produced and interview content was coded independently by two judges and validated by an expert panel. RESULTS: Interviews have highlighted the potential impact of telehealth on several factors influencing the recruitment and retention of physicians in rural and remote regions. The potential effects of telehealth on physicians' choice of practice location could be seen at the professional, organizational, educational and individual levels. For instance, telehealth could improve work satisfaction by allowing a regional on-call duty system and a better follow-up of patients. However, there are also certain limits related to telehealth, such as the fear that it would eventually replace all continuing medical education activities and onsite specialists in remoteregions. CONCLUSION: Telehealth is likely to have an impact on several factors related to medical workforce supply in remote and rural regions. However, the expected benefits will materialize if and only if this technology is properly integrated into organizations as a support to professional practice

Collaboration and knowledge exchange between scholars in Britain and the empire, 1830–1914

In recent years there has been a growing interest among historians in the British Empire as a space of knowledge production and circulation. Much of this work assumes that scholarly cooperation and collaboration between individuals and institutions within the Empire had the effect (and often also the aim) of strengthening both imperial ties and the idea of empire. This chapter argues, however, that many examples of scholarly travel, exchange, and collaboration were undertaken with very different goals in mind. In particular, it highlights the continuing importance of an ideal of scientific internationalism, which stressed the benefits of scholarship for the whole of humanity and prioritized the needs and goals of individual academic and scientific disciplines. As the chapter shows, some scholars even went on to develop nuanced critiques of the imperial project while using the very structures of empire to further their own individual, disciplinary and institutional goals

Establishment of a Bluetongue Virus Infection Model in Mice that Are Deficient in the Alpha/Beta Interferon Receptor

Bluetongue (BT) is a noncontagious, insect-transmitted disease of ruminants caused by the bluetongue virus (BTV). A laboratory animal model would greatly facilitate the studies of pathogenesis, immune response and vaccination against BTV. Herein, we show that adult mice deficient in type I IFN receptor (IFNAR(−/−)) are highly susceptible to BTV-4 and BTV-8 infection when the virus is administered intravenously. Disease was characterized by ocular discharges and apathy, starting at 48 hours post-infection and quickly leading to animal death within 60 hours of inoculation. Infectious virus was recovered from the spleen, lung, thymus, and lymph nodes indicating a systemic infection. In addition, a lymphoid depletion in spleen, and severe pneumonia were observed in the infected mice. Furthermore, IFNAR(−/−) adult mice immunized with a BTV-4 inactivated vaccine showed the induction of neutralizing antibodies against BTV-4 and complete protection against challenge with a lethal dose of this virus. The data indicate that this mouse model may facilitate the study of BTV pathogenesis, and the development of new effective vaccines for BTV

Regional Decline of Coral Cover in the Indo-Pacific: Timing, Extent, and Subregional Comparisons

A number of factors have recently caused mass coral mortality events in all of the world's tropical oceans. However, little is known about the timing, rate or spatial variability of the loss of reef-building corals, especially in the Indo-Pacific, which contains 75% of the world's coral reefs.We compiled and analyzed a coral cover database of 6001 quantitative surveys of 2667 Indo-Pacific coral reefs performed between 1968 and 2004. Surveys conducted during 2003 indicated that coral cover averaged only 22.1% (95% CI: 20.7, 23.4) and just 7 of 390 reefs surveyed that year had coral cover >60%. Estimated yearly coral cover loss based on annually pooled survey data was approximately 1% over the last twenty years and 2% between 1997 and 2003 (or 3,168 km(2) per year). The annual loss based on repeated measures regression analysis of a subset of reefs that were monitored for multiple years from 1997 to 2004 was 0.72 % (n = 476 reefs, 95% CI: 0.36, 1.08).The rate and extent of coral loss in the Indo-Pacific are greater than expected. Coral cover was also surprisingly uniform among subregions and declined decades earlier than previously assumed, even on some of the Pacific's most intensely managed reefs. These results have significant implications for policy makers and resource managers as they search for successful models to reverse coral loss

Renal HIV Expression Is Unaffected by Serum LPS Levels in an HIV Transgenic Mouse Model of LPS Induced Kidney Injury

Acute kidney injury (AKI) is associated with increased rates of mortality. For unknown reasons, HIV infected individuals have a higher risk of AKI than uninfected persons. We tested our hypothesis that increased circulating LPS increases renal expression of HIV and that HIV transgenic (Tg26) mice have increased susceptibility to AKI. Tg26 mice harbor an HIV transgene encoding all HIV genes except gag and pol, and develop a phenotype analogous to HIVAN. Mice were used at 4–6 weeks of age before the onset of gross renal disease. Mice were injected i.p. with LPS or sterile saline. Renal function, tubular injury, cytokine expression, and HIV transcription were evaluated in Tg26 and wild type (WT) mice. LPS injection induced a median 60.1-fold increase in HIV expression in spleen but no change in kidney. There was no significant difference in renal function, cytokine expression, or tubular injury scores at baseline or 24 hours after LPS injection. HIV transcription was also analyzed in vitro using a human renal tubular epithelial cell (RTEC) line. HIV transcription increased minimally in human RTEC, by 1.47 fold, 48 hours after LPS exposure. We conclude that Tg26 mice do not increase HIV expression or have increased susceptibility to LPS induced AKI. The increased risk of AKI in HIV infected patients is not mediated via increased renal expression of HIV in the setting of sepsis. Moreover, renal regulation of HIV transcription is different to that in the spleen

Psychology of Fragrance Use: Perception of Individual Odor and Perfume Blends Reveals a Mechanism for Idiosyncratic Effects on Fragrance Choice

Cross-culturally, fragrances are used to modulate body odor, but the psychology of fragrance choice has been largely overlooked. The prevalent view is that fragrances mask an individual's body odor and improve its pleasantness. In two experiments, we found positive effects of perfume on body odor perception. Importantly, however, this was modulated by significant interactions with individual odor donors. Fragrances thus appear to interact with body odor, creating an individually-specific odor mixture. In a third experiment, the odor mixture of an individual's body odor and their preferred perfume was perceived as more pleasant than a blend of the same body odor with a randomly-allocated perfume, even when there was no difference in pleasantness between the perfumes. This indicates that fragrance use extends beyond simple masking effects and that people choose perfumes that interact well with their own odor. Our results provide an explanation for the highly individual nature of perfume choice

The Glycan Shield of HIV Is Predominantly Oligomannose Independently of Production System or Viral Clade

The N-linked oligomannose glycans of HIV gp120 are a target for both microbicide and vaccine design. The extent of cross-clade conservation of HIV oligomannose glycans is therefore a critical consideration for the development of HIV prophylaxes. We measured the oligomannose content of virion-associated gp120 from primary virus from PBMCs for a range of viral isolates and showed cross-clade elevation (62–79%) of these glycans relative to recombinant, monomeric gp120 (∼30%). We also confirmed that pseudoviral production systems can give rise to notably elevated gp120 oligomannose levels (∼98%), compared to gp120 derived from a single-plasmid viral system using the HIVLAI backbone (56%). This study highlights differences in glycosylation between virion-associated and recombinant gp120

Biophysical Property and Broad Anti-HIV Activity of Albuvirtide, a 3-Maleimimidopropionic Acid-Modified Peptide Fusion Inhibitor

Albuvirtide (ABT) is a 3-maleimimidopropionic acid (MPA)-modified peptide HIV fusion inhibitor that can irreversibly conjugate to serum albumin. Previous studies demonstrated its in vivo long half-life and potent anti-HIV activity. Here, we focused to characterize its biophysical properties and evaluate its antiviral spectrum. In contrast to T20 (Enfuvirtide, Fuzeon), ABT was able to form a stable α-helical conformation with the target sequence and block the fusion-active six-helix bundle (6-HB) formation in a dominant-negative manner. It efficiently inhibited HIV-1 Env-mediated cell membrane fusion and virus entry. A large panel of 42 HIV-1 pseudoviruses with different genotypes were constructed and used for the antiviral evaluation. The results showed that ABT had potent inhibitory activity against the subtypes A, B and C that predominate the worldwide AIDS epidemics, and subtype B′, CRF07_BC and CRF01_AE recombinants that are currently circulating in China. Furthermore, ABT was also highly effective against HIV-1 variants resistant to T20. Taken together, our data indicate that the chemically modified peptide ABT can serve as an ideal HIV-1 fusion inhibitor