TLR-mediated activation of Waldenström macroglobulinemia B cells reveals an uncoupling from plasma cell differentiation

Waldenstr¨om macroglobulinemia (WM) is a rare malignancy in which clonal B cells infiltrate the bone marrow and give rise to a smaller compartment of neoplastic plasma cells that secrete monoclonal immunoglobulin M paraprotein. Recent studies into underlying mutations in WM have enabled a much greater insight into the pathogenesis of this lymphoma. However, there is considerably less characterization of the way in which WM B cells differentiate and how they respond to immune stimuli. In this study, we assess WM B-cell differentiation using an established in vitro model system. Using T-cell–dependent conditions, we obtained CD1381 plasma cells from WM samples with a frequency similar to experiments performed with B cells from normal donors. Unexpectedly, a proportion of the WM B cells failed to upregulate CD38, a surface marker that is normally associated with plasmablast transition and maintained as the cells proceed with differentiation. In normal B cells, concomitant Toll-like receptor 7 (TLR7) activation and B-cell receptor cross-linking drives proliferation, followed by differentiation at similar efficiency to CD40-mediated stimulation. In contrast, we found that, upon stimulation with TLR7 agonist R848, WM B cells failed to execute the appropriate changes in transcriptional regulators, identifying an uncoupling of TLR signaling from the plasma cell differentiation program. Provision of CD40L was sufficient to overcome this defect. Thus, the limited clonotypic WM plasma cell differentiation observed in vivo may result from a strict requirement for integrated activation

Cohort study of Western Australia computed tomography utilisation patterns and their policy implications

Background: Computed tomography (CT) scanning is a relatively high radiation dose diagnostic imaging modality with increasing concerns about radiation exposure burden at the population level in scientific literature. This study examined the epidemiology of adult CT utilisation in Western Australia (WA) in both the public hospital and private practice settings, and the policy implications. Methods: Retrospective cohort design using aggregate adult CT data from WA public hospitals and Medical Benefits Schedule (MBS) (mid-2006 to mid-2012). CT scanning trends by sex, age, provider setting and anatomical areas were explored using crude CT scanning rates, age-standardised CT scanning rates and Poisson regression modelling. Results: From mid-2006 to mid-2012 the WA adult CT scanning rate was 129 scans per 1,000 person-years (PY). Females were consistently scanned at a higher rate than males. Patients over 65 years presented the highest scanning rates (over 300 scans per 1,000 PY). Private practice accounted for 73% of adult CT scans, comprising the majority in every anatomical area. In the private setting females predominately held higher age-standardised CT scanning rates than males. This trend reversed in the public hospital setting. Patients over 85 years in the public hospital setting were the most likely age group CT scanned in nine of ten anatomical areas. Patients in the private practice setting aged 85+ years were relatively less prominent across every anatomical area, and the least likely age group scanned in facial bones and multiple areas CT scans.Conclusion: In comparison to the public hospital setting, the MBS subsidised private sector tended to service females and relatively younger patients with a more diverse range of anatomical areas, constituting the majority of CT scans performed in WA. Patient risk and subsequent burden is greater for females, lower ages and some anatomical areas. In the context of a national health system, Australia has various avenues to monitor radiation exposure levels, improve physician training and modify funding mechanisms to ensure individual and population medical radiation exposure is as low as reasonably achievable

Tail walking in a bottlenose dolphin community : the rise and fall of an arbitrary cultural 'fad'

M.B. was supported by multiple grants from Whale & Dolphin Conservation (WDC).Social learning of adaptive behaviour is widespread in animal populations, but the spread of arbitrary behaviours is less common. In this paper, we describe the rise and fall of a behaviour called tail walking, where a dolphin forces the majority of its body vertically out of the water and maintains the position by vigourously pumping its tail, in a community of Indo-Pacific bottlenose dolphins (Tursiops aduncus). The behaviour was introduced into the wild following the rehabilitation of a wild female individual, Billie, who was temporarily co-housed with trained dolphins in a dolphinarium. This individual was sighted performing the behaviour seven years after her 1988 release, as was one other female dolphin named Wave. Initial production of the behaviour was rare, but following Billie's death two decades after her release, Wave began producing the behaviour at much higher rates, and several other dolphins in the community were subsequently sighted performing the behaviour. Social learning is the most likely mechanism for the introduction and spread of this unusual behaviour, which has no known adaptive function. These observations demonstrate the potential strength of the capacity for spontaneous imitation in bottlenose dolphins, and help explain the origin and spread of foraging specializations observed in multiple populations of this genus.PostprintPeer reviewe

Radiological staging in breast cancer: which asymptomatic patients to image and how.

BACKGROUND: Approximately 4% of patients diagnosed with early breast cancer have occult metastases at presentation. Current national and international guidelines lack consensus on whom to image and how. METHODS: We assessed practice in baseline radiological staging against local guidelines for asymptomatic newly diagnosed breast cancer patients presenting to the Cambridge Breast Unit over a 9-year period. RESULTS: A total of 2612 patients were eligible for analysis; 91.7% were appropriately investigated. However in the subset of lymph node negative stage II patients, only 269 out of 354 (76.0%) investigations were appropriate. No patients with stage 0 or I disease had metastases; only two patients (0.3%) with stage II and or =4 positive lymph nodes), III and IV disease, respectively. CONCLUSION: These results prompted us to propose new local guidelines for staging asymptomatic breast cancer patients: only clinical stage III or IV patients require baseline investigation. The high specificity and convenience of computed tomography (chest, abdomen and pelvis) led us to recommend this as the investigation of choice in breast cancer patients requiring radiological staging

Analyzing Multi-key Security Degradation

Contains fulltext : 179039.pdf (preprint version ) (Closed access) Contains fulltext : 179039.pdf (Publisher’s version ) (Open Access)nul

Precision charging of microparticles in plasma via the Rayleigh instability for evaporating charged liquid droplets

In this paper we describe a novel method for delivering a precise, known amount of electric charge to a micron-sized solid target. Aerosolised microparticles passed through a plasma discharge will acquire significant electric charge. The fluid stability under evaporative stress is a key aspect that is core to the research. Initially stable charged aerosols subject to evaporation (i.e. a continually changing radius) may encounter the Rayleigh stability limit. This limit arises from the electrostatic and surface tension forces and determines the maximum charge a stable droplet can retain, as a function of radius. We demonstrate that even if the droplet charge is initially much less than the Rayleigh limit, the stability limit will be encountered as the droplet evaporates. The instability emission mechanism is strongly linked to the final charge deposited on the target, providing a mechanism that can be used to ensure a predictable charge deposit on a known encapsulated microparticle

Ploidy elicits a whole-genome dosage effect: growth of triploid Atlantic salmon is linked to the genetic origin of the second maternal chromosome set

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Isolation of a small molecule inhibitor of DNA base excision repair

The base excision repair (BER) pathway is essential for the removal of DNA bases damaged by alkylation or oxidation. A key step in BER is the processing of an apurinic/apyrimidinic (AP) site intermediate by an AP endonuclease. The major AP endonuclease in human cells (APE1, also termed HAP1 and Ref-1) accounts for >95% of the total AP endonuclease activity, and is essential for the protection of cells against the toxic effects of several classes of DNA damaging agents. Moreover, APE1 overexpression has been linked to radio- and chemo-resistance in human tumors. Using a newly developed high-throughput screen, several chemical inhibitors of APE1 have been isolated. Amongst these, CRT0044876 was identified as a potent and selective APE1 inhibitor. CRT0044876 inhibits the AP endonuclease, 3′-phosphodiesterase and 3′-phosphatase activities of APE1 at low micromolar concentrations, and is a specific inhibitor of the exonuclease III family of enzymes to which APE1 belongs. At non-cytotoxic concentrations, CRT0044876 potentiates the cytotoxicity of several DNA base-targeting compounds. This enhancement of cytotoxicity is associated with an accumulation of unrepaired AP sites. In silico modeling studies suggest that CRT0044876 binds to the active site of APE1. These studies provide both a novel reagent for probing APE1 function in human cells, and a rational basis for the development of APE1-targeting drugs for antitumor therapy

Brief communication: Lessons learned and experiences gained from building up a global survey on societal resilience to changing droughts

This paper describes the process of creating a global survey of experts to evaluate drought resilience indicators. The lessons learned include five main points: (1) the heterogeneity in the conceptual background should be minimized before the construction of the survey; (2) large numbers of indicators decrease the engagement of respondents through the survey, and ways to apportion indicators whilst maintaining reliability should be considered; (3) it is necessary to design the survey to balance response rate and accuracy; (4) the survey questions should have clear statements with a logical and flowing structure; and (5) reaching experts with different domain experience and representing different regions is difficult but crucial to minimize biased results.</p