Naturally processed measles virus peptide eluted from class II HLA-DRB1*03 recognized by T lymphocytes from human blood

AbstractThis is the first report of the direct identification of a HLA-DRB1*03 measles-derived peptide from measles virus infected EBV-transformed B cells. We purified HLA-DR3-peptide complexes from EBV-B cells infected with measles virus (Edmonston strain) and sequenced the HLA-DR3-peptides by mass spectrometry. A class II peptide, derived from a measles phosphoprotein, ASDVETAEGGEIHELLRLQ (P1, residues 179–197), exhibited the capacity to stimulate peripheral blood mononuclear cells to proliferate. Our data provides direct evidence that the antigenic peptide of measles virus was processed by antigen-presenting cells, presented in the context of HLA class II molecules, and was recognized by peripheral blood T cells from healthy individuals previously immunized with measles vaccine. The approach described herein provides a useful methodology for the future identification of HLA-presented pathogen-derived epitopes using mass spectrometry. The study of cell-mediated immune responses to the measles-derived peptide in immune persons should provide significant insight into the design and development of new vaccines

Caspase-resistant ROCK1 expression prolongs survival of Eµ-Myc B cell lymphoma mice

Apoptosis is characterized by membrane blebbing and apoptotic body formation. Caspase cleavage of ROCK1 generates an active fragment that promotes actin-myosin mediated contraction and membrane blebbing during apoptosis. Expression of caspase-resistant non-cleavable ROCK1 (Rock1 NC) prolonged survival of mice that rapidly develop B cell lymphomas due to Eµ-Myc transgene expression. Eµ-Myc; Rock1 NC mice had significantly fewer bone marrow cells relative to Eµ-Myc mice expressing wild-type ROCK1 (Rock1 WT), which was associated with altered cell cycle profiles. Circulating macrophage numbers were lower in Eµ-Myc; Rock1 NC mice, but there were higher levels of bone marrow macrophages, consistent with spontaneous cell death in Eµ-Myc; Rock1 NC mice bone marrows being more inflammatory. Rock1 WT recipient mice transplanted with pre-neoplastic Eµ-Myc; Rock1 NC bone marrow cells survived longer than mice transplanted with Eµ-Myc; Rock1 WT cells, indicating that the survival benefit was intrinsic to the Eµ-Myc; Rock1 NC bone marrow cells. The results suggest that the apoptotic death of Eµ-Myc; Rock1 NC cells generates a proliferation-suppressive microenvironment in bone marrows that reduces cell numbers and prolongs B cell lymphoma mouse survival

Immunogenic death of hepatocellular carcinoma cells in mice expressing caspase-resistant ROCK1 is not replicated by ROCK inhibitors

The morphological changes during apoptosis help facilitate “immunologically silent” cell death. Caspase cleavage of the ROCK1 kinase results in its activation, which drives the forceful contraction of apoptotic cells. We previously showed that when ROCK1 was mutated to render it caspase-resistant, there was greater liver damage and neutrophil recruitment after treatment with the hepatotoxin diethylnitrosamine (DEN). We now show that acute DEN-induced liver damage induced higher levels of pro-inflammatory cytokines/chemokines, indicative of immunogenic cell death (ICD), in mice expressing non-cleavable ROCK1 (ROCK1nc). Hepatocellular carcinoma (HCC) tumours in ROCK1nc mice had more neutrophils and CD8+ T cells relative to mice expressing wild-type ROCK1, indicating that spontaneous tumour cell death also was more immunogenic. Since ICD induction has been proposed to be tumour-suppressive, the effects of two distinct ROCK inhibitors on HCC tumours was examined. Both fasudil and AT13148 significantly decreased tumour numbers, areas and volumes, but neither resulted in greater numbers of neutrophils or CD8+ T cells to be recruited. In the context of acute DEN-induced liver damage, AT13148 inhibited the recruitment of dendritic, natural killer and CD8+ T cells to livers. These observations indicate that there is an important role for ROCK1 cleavage to limit immunogenic cell death, which was not replicated by systemic ROCK inhibitor administration. As a result, concomitant administration of ROCK inhibitors with cancer therapeutics would be unlikely to result in therapeutic benefit by inducing ICD to increase anti-tumour immune responses

Quantum self-consistency of AdS×ΣAdS \times \Sigma brane models

Continuing on our previous work, we consider a class of higher dimensional brane models with the topology of $AdS_{D_1+1} \times \Sigma$, where $\Sigma$ is a one-parameter compact manifold and two branes of codimension 1 are located at the orbifold fixed points. We consider a set-up where such a solution arises from Einstein-Yang-Mills theory and evaluate the one-loop effective potential induced by gauge fields and by a generic bulk scalar field. We show that this type of brane models resolves the gauge hierarchy between the Planck and electroweak scales through redshift effects due to the warp factor $a=e^{-\pi kr}$. The value of $a$ is then fixed by minimizing the effective potential. We find that, as in the Randall Sundrum case, the gauge field contribution to the effective potential stabilises the hierarchy without fine-tuning as long as the laplacian $\Delta_\Sigma$ on $\Sigma$ has a zero eigenvalue. Scalar fields can stabilise the hierarchy depending on the mass and the non-minimal coupling. We also address the quantum self-consistency of the solution, showing that the classical brane solution is not spoiled by quantum effects.Comment: 10 page

Transcriptomics reveal the genetic coordination of early defense to Armillaria root rot (ARR) in Prunus spp

Armillaria root rot (ARR) poses a significant threat to the long-term productivity of stone-fruit and nut crops in the predominant production area of the United States. To mitigate this issue, the development of ARR-resistant and horticulturally-acceptable rootstocks is a crucial step towards the maintenance of production sustainability. To date, genetic resistance to ARR has been found in exotic plum germplasm and a peach/plum hybrid rootstock, ’MP-29‘. However, the widely-used peach rootstock Guardian® is susceptible to the pathogen. To understand the molecular defense mechanisms involved in ARR resistance in Prunus rootstocks, transcriptomic analyses of one susceptible and two resistant Prunus spp. were performed using two causal agents of ARR, including Armillaria mellea and Desarmillaria tabescens. The results of in vitro co-culture experiments revealed that the two resistant genotypes showed different temporal response dynamics and fungus-specific responses, as seen in the genetic response. Gene expression analysis over time indicated an enrichment of defense-related ontologies, including glucosyltransferase activity, monooxygenase activity, glutathione transferase activity, and peroxidase activity. Differential gene expression and co-expression network analysis highlighted key hub genes involved in the sensing and enzymatic degradation of chitin, GSTs, oxidoreductases, transcription factors, and biochemical pathways likely involved in Armillaria resistance. These data provide valuable resources for the improvement of ARR resistance in Prunus rootstocks through breeding

The geography of health knowledge/s

publication-status: Publishedtypes: Editorial CommentCopyright © 2004 Elsevier. NOTICE: This is the author’s version of a work accepted for publication by Elsevier. Changes resulting from the publishing process, including peer review, editing, corrections, structural formatting and other quality control mechanisms, may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Health and Place, 2004, Vol. 10, Issue 4, pp. pp. 293 - 297 DOI: 10.1016/j.healthplace.2004.07.003Editoria

Comparisons of the Orbiting Carbon Observatory-2 (OCO-2) X_(CO_2) measurements with TCCON

NASA's Orbiting Carbon Observatory-2 (OCO-2) has been measuring carbon dioxide column-averaged dry-air mole fraction, X_(CO_2), in the Earth's atmosphere for over 2 years. In this paper, we describe the comparisons between the first major release of the OCO-2 retrieval algorithm (B7r) and X_(CO2) from OCO-2's primary ground-based validation network: the Total Carbon Column Observing Network (TCCON). The OCO-2 X_(CO_2) retrievals, after filtering and bias correction, agree well when aggregated around and coincident with TCCON data in nadir, glint, and target observation modes, with absolute median differences less than 0.4 ppm and RMS differences less than 1.5 ppm. After bias correction, residual biases remain. These biases appear to depend on latitude, surface properties, and scattering by aerosols. It is thus crucial to continue measurement comparisons with TCCON to monitor and evaluate the OCO-2 X_(CO_2) data quality throughout its mission

Discovery of potent and selective MRCK inhibitors with therapeutic effect on skin cancer

The myotonic dystrophy-related Cdc42-binding kinases MRCKα and MRCKβ contribute to the regulation of actin-myosin cytoskeleton organization and dynamics, acting in concert with the Rho-associated coiled-coil kinases ROCK1 and ROCK2. The absence of highly potent and selective MRCK inhibitors has resulted in relatively little knowledge of the potential roles of these kinases in cancer. Here we report the discovery of the azaindole compounds BDP8900 and BDP9066 as potent and selective MRCK inhibitors that reduce substrate phosphorylation, leading to morphological changes in cancer cells along with inhibition of their motility and invasive character. In over 750 human cancer cell lines tested, BDP8900 and BDP9066 displayed consistent anti-proliferative effects with greatest activity in hematological cancer cells. Mass spectrometry identified MRCKα S1003 as an autophosphorylation site, enabling development of a phosphorylation-sensitive antibody tool to report on MRCKα status in tumor specimens. In a two-stage chemical carcinogenesis model of murine squamous cell carcinoma, topical treatments reduced MRCKα S1003 autophosphorylation and skin papilloma outgrowth. In parallel work, we validated a phospho-selective antibody with the capability to monitor drug pharmacodynamics. Taken together, our findings establish an important oncogenic role for MRCK in cancer, and they offer an initial preclinical proof of concept for MRCK inhibition as a valid therapeutic strategy

Timebanking and the co‐production of preventive social care with adults; what can we learn from the challenges of implementing person‐to‐person timebanks in England?

This paper explores the potential contribution of timebanking, an innovative volunteering scheme, to the co-production of preventive social care with adults in England. Interest in volunteering in social care has increased as one proposed solution to the international crisis of a rising demand for services in juxtaposition with decreased resources. Volunteering has been particularly promoted in preventive services that prevent or delay care needs arising. Despite sustained interest in volunteering and co-production in social care, little is known about how theory translates into practice. Reporting implementation data from a Realistic Evaluation of six case studies in England, this paper explores one volunteering scheme, timebanking. The research explores how timebanks were working, what contribution they can make to adult social care, and whether they are an example of co-production. Data collected included interviews, focus groups or open question responses on surveys from 84 timebank members, and semi-structured interviews with 13 timebank staff. Each timebank was visited at least twice, and all timebank activity was analysed for a period of 12 months. Data were triangulated to improve reliability. The research found that in practice, timebanks were not working as described in theory, there were small numbers of person-to-person exchanges and some timebanks had abandoned this exchange model. Timebanks faced significant implementation challenges including managing risk and safeguarding and the associated bureaucracy, a paternalistic professional culture and the complexity of the timebank mechanism which required adequate resources. Lessons for timebanks are identified, as well as transferable lessons about co-production and volunteering in social care if such schemes are to be successful in the future