Human cytomegalovirus latency-associated proteins elicit immune-suppressive IL-10 producing CD4⁺ T cells.

Human cytomegalovirus (HCMV) is a widely prevalent human herpesvirus, which, after primary infection, persists in the host for life. In healthy individuals, the virus is well controlled by the HCMV-specific T cell response. A key feature of this persistence, in the face of a normally robust host immune response, is the establishment of viral latency. In contrast to lytic infection, which is characterised by extensive viral gene expression and virus production, long-term latency in cells of the myeloid lineage is characterised by highly restricted expression of viral genes, including UL138 and LUNA. Here we report that both UL138 and LUNA-specific T cells were detectable directly ex vivo in healthy HCMV seropositive subjects and that this response is principally CD4⁺ T cell mediated. These UL138-specific CD4⁺ T cells are able to mediate MHC class II restricted cytotoxicity and, importantly, show IFNγ effector function in the context of both lytic and latent infection. Furthermore, in contrast to CDCD4⁺ T cells specific to antigens expressed solely during lytic infection, both the UL138 and LUNA-specific CD4⁺ T cell responses included CD4⁺ T cells that secreted the immunosuppressive cytokine cIL-10. We also show that cIL-10 expressing CD4⁺ T-cells are directed against latently expressed US28 and UL111A. Taken together, our data show that latency-associated gene products of HCMV generate CD4⁺ T cell responses in vivo, which are able to elicit effector function in response to both lytic and latently infected cells. Importantly and in contrast to CD4⁺ T cell populations, which recognise antigens solely expressed during lytic infection, include a subset of cells that secrete the immunosuppressive cytokine cIL-10. This suggests that HCMV skews the T cell responses to latency-associated antigens to one that is overall suppressive in order to sustain latent carriage in vivo

Simultaneous optical polarimetry and X-ray data of the near synchronous polar RX J2115-5840

We present simultaneous optical polarimetry and X-ray data of the near synchronous polar RX J2115-5840. We model the polarisation data using the Stokes imaging technique of Potter et al. We find that the data are best modelled using a relatively high binary inclination and a small angle between the magnetic and spin axes. We find that for all spin-orbit beat phases, a significant proportion of the accretion flow is directed onto the lower hemisphere of the white dwarf, producing negative circular polarisation. Only for a small fraction of the beat cycle is a proportion of the flow directed onto the upper hemisphere. However, the accretion flow never occurs near the upper magnetic pole, whatever the orientation of the magnetic poles. This indicates the presence of a non-dipole field with the field strength at the upper pole significantly higher. We find that the brightest parts of the hard X-ray emitting region and the cyclotron region are closely coincident.Comment: 9 pages, accepted for publication in MNRAS 2 March 200

Strategies for living well with hormone-responsive advanced prostate cancer—a qualitative exploration

Purpose: Due to recent treatment advances, men are increasingly living longer with advanced prostate cancer (PCa). This study sought to understand men’s experiences of living with and adjusting to advanced hormone-responsive PCa and how this influenced their quality of life (QoL), in order to highlight how support could be optimized. / Methods: Participants were recruited through a UK wide survey—the ‘Life After Prostate Cancer Diagnosis’ study. In-depth telephone interviews were conducted with 24 men (aged 46–77 years) with advanced (stage IV) hormone-responsive PCa diagnosed 18–42 months previously. Thematic analysis was undertaken using a framework approach. / Results: Most participants perceived their QoL to be relatively good, which was influenced by the following factors (enablers to ‘living well’ with PCa): a sense of connectedness to others, engagement in meaningful activities, resources (social, cognitive, financial), ability to manage uncertainty, utilization of adjustment strategies and support, communication and information from health professionals. Barriers to ‘living well’ with PCa were often the converse of these factors. These also included more troublesome PCa-related symptoms and stronger perceptions of loss and restriction. / Conclusions: In our study, men living with advanced hormone-responsive PCa often reported a good QoL. Exploring the influences on QoL in men with advanced PCa indicates how future interventions might improve the QoL of men who are struggling. Further research is required to develop and test interventions that enhance QoL for these men

XMM-Newton observations of the eclipsing polar EP Dra

We present XMM-Newton observations of the eclipsing polar EP Dra which cover nearly 3 binary orbital cycles. The X-ray and UV data show evidence for a prominent dip before the eclipse which is due to the accretion stream obscuring the accretion region. The dip ingress is rapid in hard X-rays suggesting there is a highly collimated core of absorption. We find that a different level of absorption column density is required to match the observed count rates in different energy bands. We propose that this is due to the fact that different absorption components should be used to model the reprocessed X-rays, the shocked X-ray component and the UV emission and explore the affect that this has on the resulting fits to the spectrum. Further, there is evidence that absorption starts to obscure the softer X-rays shortly after the onset of the bright phase. This suggests that material is threaded by an unusually wide range of magnetic field lines, consistent with the suggestion of Bridge et al. We find that the period is slightly greater than that determined by Schwope & Mengel.Comment: Accepted for publication MNRAS, 6 page

The influence of oblique-angle forced exercise in surgically destabilized stifle joints is synergistic with bone, but antagonistic with cartilage in an ovine model of osteoarthritis

Large animal models of osteoarthritis are a necessary testing ground for FDA approval of human medicine applications. Sheep models have advantages over other available large animals, but development and progression of osteoarthritis in sheep is exceedingly slow, which handicaps progress in development of potential treatments. We combined oblique angle forced exercise to increase stress on the stifle, with surgical destabilization to hasten the development of osteoarthritis in ewes. Methods for early detection of clinical signs included radiography, urine, and serum biomarker assays and gait analysis and ex vivo we used microcomputed tomography and macroscopic joint analysis. Our model was able to produce clinically detectable signs of osteoarthritis in a relatively short period (14 weeks). Changes in bone were highly correlated between microcomputed tomography and radiographic analysis and changes in cartilage correlated well between urinary glycosaminoglycan levels and serum aggrecanase analyses. Exercise improved the negative effects of destabilization in bone but exacerbated the negative effects of destabilization in cartilage. These observations suggest that we may need to consider treatments for bone and cartilage separately. These results represent an improved large animal model of osteoarthritis with rapid onset of disease and superior detection of bone and soft tissue changes

Student Recital (April 25, 2012)

Verdi prati from Alcina, HWV 34 / George Frideric Handel Diane M. Card, alto Etude 13, Op. 60 / Matteo Carcassi Mark Gavin, guitar Concerto in A minor, Op. 3, No. 6 / Antonio Vivaldi (1678-1741) Allegro Gail Colombo, violin Se vuol ballare from Le Nozze di Figaro, K. 492 / Wolfgang Amadeus Mozart Black is the color of my true love’s hair / John Jacob Niles Greg Fernandes, bass Concertino in D Major, Op. 5 / Oscar Rieding Carla Mason, violin Fruhlingsglaube, D. 686, Op. 20, No. 2 / Franz Schubert Samuel Lathrop, tenor Been A Long Day / Frank Loesser from How to Succeed in Business Without Really Trying Stephanie Blood, soprano Margeret Leahy, soprano Samuel Lathrop, tenor Sonata for Eb Alto Saxophone, Op. 19 / Paul Creston III. With Gaiety Sean Every, alto saxophonehttps://vc.bridgew.edu/student_concerts/1019/thumbnail.jp

Revisiting Date and Party Hubs: Novel Approaches to Role Assignment in Protein Interaction Networks

The idea of 'date' and 'party' hubs has been influential in the study of protein-protein interaction networks. Date hubs display low co-expression with their partners, whilst party hubs have high co-expression. It was proposed that party hubs are local coordinators whereas date hubs are global connectors. Here we show that the reported importance of date hubs to network connectivity can in fact be attributed to a tiny subset of them. Crucially, these few, extremely central, hubs do not display particularly low expression correlation, undermining the idea of a link between this quantity and hub function. The date/party distinction was originally motivated by an approximately bimodal distribution of hub co-expression; we show that this feature is not always robust to methodological changes. Additionally, topological properties of hubs do not in general correlate with co-expression. Thus, we suggest that a date/party dichotomy is not meaningful and it might be more useful to conceive of roles for protein-protein interactions rather than individual proteins. We find significant correlations between interaction centrality and the functional similarity of the interacting proteins.Comment: 27 pages, 5 main figures, 4 supplementary figure

LATERAL BRANCHING OXIDOREDUCTASE acts in the final stages of strigolactone biosynthesis inArabidopsis

Strigolactones are a group of plant compounds of diverse but related chemical structures. They have similar bioactivity across a broad range of plant species, act to optimize plant growth and development, and promote soil microbe interactions. Carlactone, a common precursor to strigolactones, is produced by conserved enzymes found in a number of diverse species. Versions of the MORE AXILLARY GROWTH1 (MAX1) cytochrome P450 from rice and Arabidopsis thaliana make specific subsets of strigolactones from carlactone. However, the diversity of natural strigolactones suggests that additional enzymes are involved and remain to be discovered. Here, we use an innovative method that has revealed a missing enzyme involved in strigolactone metabolism. By using a transcriptomics approach involving a range of treatments that modify strigolactone biosynthesis gene expression coupled with reverse genetics, we identified LATERAL BRANCHING OXIDOREDUCTASE (LBO), a gene encoding an oxidoreductase-like enzyme of the 2-oxoglutarate and Fe(II)-dependent dioxygenase superfamily. Arabidopsis lbo mutants exhibited increased shoot branching, but the lbo mutation did not enhance the max mutant phenotype. Grafting indicated that LBO is required for a graft-transmissible signal that, in turn, requires a product of MAX1. Mutant lbo backgrounds showed reduced responses to carlactone, the substrate of MAX1, and methyl carlactonoate (MeCLA), a product downstream of MAX1. Furthermore, lbo mutants contained increased amounts of these compounds, and the LBO protein specifically converts MeCLA to an unidentified strigolactone-like compound. Thus, LBO function may be important in the later steps of strigolactone biosynthesis to inhibit shoot branching in Arabidopsis and other seed plants

Survival, neurocognitive function, and health-related quality of life outcomes after rituximab-methotrexate, BCNU, teniposide, and prednisolone for primary CNS lymphoma:Final results of the HOVON 105/ALLG NHL 24 study

Background. Studies on the efficacy of rituximab in primary CNS lymphoma (PCNSL) reported conflicting results. Our international randomized phase 3 study showed that the addition of rituximab to high-dose methotrexate, BCNU, teniposide, and prednisolone (MBVP) in PCNSL was not efficacious in the short term. Here we present long-term results after a median follow-up of 82.3 months. Methods. One hundred and ninety-nine eligible newly diagnosed, nonimmunocompromised patients with PCNSL aged 18–70 years with WHO performance status 0–3 was randomized between treatment with MBVP chemotherapy with or without rituximab, followed by high-dose cytarabine consolidation in responding patients, and reduced-dose WBRT in patients aged ≤ 60 years. Event-free survival was the primary endpoint. Overall survival rate, neurocognitive functioning (NCF), and health-related quality of life (HRQoL) were additionally assessed, with the IPCG test battery, EORTC QLQ-C30 and QLQ-BN20 questionnaires, respectively. Results. For event-free survival, the hazard ratio was 0.85, 95% CI 0.61–1.18, P = .33. Overall survival rate at 5 years for MBVP and R-MBVP was 49% (39–59) and 53% (43–63) respectively. In total, 64 patients died in the MBVP arm and 55 in the R-MBVP arm, of which 69% were due to PCNSL. At the group level, all domains of NCF and HRQoL improved to a clinically relevant extent after treatment initiation, and remained stable thereafter up to 60 months of follow-up, except for motor speed which deteriorated between 24 and 60 months. Although fatigue improved initially, high levels persisted in the long term. Conclusions. Long-term follow-up confirms the lack of added value of rituximab in addition to MBVP and HD-cytarabine for PCNSL.</p