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

Plasticity in nest site choice behavior in response to hydric conditions in a reptile

Natural selection is expected to select for and maintain maternal behaviors associated with choosing a nest site that promotes successful hatching of offspring, especially in animals that do not exhibit parental care such as reptiles. In contrast to temperature effects, we know little about how soil moisture contributes to successful hatching and particularly how it shapes nest site choice behavior in nature. The recent revelation of exceptionally deep nesting in lizards under extreme dry conditions underscored the potential for the hydric environment in shaping the evolution of nest site choice. But if deep nesting is an adaptation to dry conditions, is there a plastic component such that mothers would excavate deeper nests in drier years? We tested this hypothesis by excavating communal warrens of a large, deep-nesting monitor lizard (Varanus panoptes), taking advantage of four wet seasons with contrasting rainfall amounts. We found 75 nests during two excavations, including 45 nests after a 4-year period with larger wet season rainfall and 30 nests after a 4-year period with smaller wet season rainfall. Mothers nested significantly deeper in years associated with drier nesting seasons, a finding best explained as a plastic response to soil moisture, because differences in both the mean and variance in soil temperatures between 1 and 4 m deep are negligible. Our data are novel for reptiles in demonstrating plasticity in maternal behavior in response to hydric conditions during the time of nesting. The absence of evidence for other ground-nesting reptile mothers adjusting nest depth in response to a hydric-depth gradient is likely due to the tradeoff between moisture and temperature with changing depth; most ground-nesting reptile eggs are deposited at depths of ~ 2–25 cm—nesting deeper within or outside of that range of depths to achieve higher soil moisture would also generally create cooler conditions for embryos that need adequate heat for successful development. In contrast, extreme deep nesting in V. panoptes allowed us to disentangle temperature and moisture. Broadly, our data suggest that ground-nesting reptiles can assess soil moisture and respond by adjusting the depth of the nest, but may not, due to the cooling effect of nesting deeper. Our results, within the context of previous work, provide a more complete picture of how mothers can promote hatching success through adjustments in nest site choice behavior

Are agri‐environment schemes successful in delivering conservation grazing management on saltmarsh?

1.Grasslands occur around the globe and, in temperate regions, their natural management by fire, drought and wild herbivores has largely been replaced by grazing with domestic livestock. Successful management for agriculture is not always suitable for conservation and can have a detrimental effect on biodiversity. Conservation grazing of saltmarshes, delivered through agri‐environment schemes, may provide a solution to counteract biodiversity loss by providing farmers with financial incentives to graze these internationally important coastal wetlands more sensitively. 2.To assess whether conservation grazing is being achieved, and whether agri‐environment schemes are effective in delivering this management, we conducted a national survey on English saltmarshes, scoring the management on each site as optimal, suboptimal or detrimental in terms of suitability for achieving conservation aims for five aspects of grazing: presence, stock type, intensity, timing and habitat impact. 3.Although most saltmarshes suitable for grazing in England were grazed, conservation grazing was not being achieved. Sites under agri‐environment management for longer did score higher and approached optimal levels in terms of grazing intensity in one region, but sites with agri‐environment agreements were no more likely to be grazed at optimal conservation levels than sites without them overall, indicating that agri‐environment schemes, in their current form, are an ineffective delivery mechanism for conservation grazing on saltmarsh. 4.The low specificity of agri‐environment prescription wording may contribute to this failure, with prescriptions either being vague or specifying suboptimal or detrimental management objectives, particularly for grazing intensity, timing and stock type. These objectives are often set too high or too low, during unsuitable periods, or using stock types inappropriate for achieving conservation aims. 5.Synthesis and applications. Our national survey indicates that agri‐environment schemes are not currently delivering conservation grazing on English saltmarshes. Agri‐environment schemes are the only mechanism through which such grazing can be implemented on a national scale, so improving their effectiveness is a priority. Policymakers, researchers and managers need to work together to ensure better translation of conservation guidelines into schemes, increasing the specificity of management prescriptions and improving understanding of the need for management measures. A more detailed and reliable system of auditing to ensure that management activities are taking place would be beneficial, or alternatively moving to a results‐based scheme where payments are made on desirable outcomes rather than on evidence of management

Geophysical surveys of the East Kirkton Limestone, Visean, West Lothian, Scotland

ABSTRACT: Magnetic and resistivity geophysical surveys conducted across the only known exposure of the East Kirkton Limestone have produced new information upon its extent. This is important to determine because of its unique faunal assemblage and possible hot spring deposition, suggesting a potential for precious metal mineralisation. Magnetic anomalies are attributed to basalts within the Bathgate Hills Volcanic Formation. Modelling of the magnetic data demonstrates a general dip to the west of about 25°, and the presence of significant local faulting. Modelling of vertical electrical sounding data shows the East Kirkton sequence (the limestone and associated beds) to be a low resistivity layer within the more highly resistive volcanic sequence. The East Kirkton sequence is seen to deepen to the west, and also to the north probably by faulting. Therefore the present exposure is the only near surface occurrence of the East Kirkton Limestone locally, but within the area of the survey no lateral limits to the formation are observed. KEY WORDS: Geophysics, hot springs, magnetic surveys, mineralisation, resistivity surveys, Lower Carboniferous. The East Kirkton quarry at Bathgate Bedding planes seen at outcrop dip at 15-25° to the W. Various hypotheses exist regarding the extent of the East Kirkton Limestone beyond the quarry: (1) it continues N beneath a thin glacial cover as shown on the one-inch geological map (Scotland Sheet 31); (2) subcrop to the N is limited due to faulting at the N end of the known exposure (Stephenson & Monro 1986); or (3) the sequence was deposited in an isolated lagoon forming only a small lens of sediment (Geikie 1861). Magnetic and resistivity surveys were undertaken to determine the structure and extent of the EKS in the vicinity of the quarry. Exploration was undertaken mostly W (down dip) and to the N. Housing development prevented work to the S. The results are of use in future prospecting of the East Kirkton Limestone for precious metal mineralisation Geophysical approach Our aim was to determine the subsurface structure of the EKS using the East Kirkton quarry as a reference point. Given the presence of basaltic lavas and clastic volcanics above and below the sedimentary sequence, it was anticipated that there would be a strong contrast of magnetic and electrical resistivity properties between the EKS and volcanics. Borehole information was made available by the National Museums of Scotland, permitting calibration of the geophysical results but only to rather limited depths (typically 10 m, maximum 33 m). Magnetometer survey The total magnetic field intensity was measured along 12 E-W traverses across the quarry and its projected continuation along strike to the N. The contoured results are plotted in Magnetic susceptibility measurements of bore hole samples Using these values, a model profile across the East Kirkton quarry was determined using the GRA VMAG computer program. The model was constructed along line Z, a dip line crossing the anomaly immediately W of the quarry The one-inch geological map shows the EKS to be underlain by basalts Resistivity survey Four electrical resistivity vertical soundings were conducted using expanding Wenner arrays (VES1-VES3 of At East Kirkton we attribute generally low, but highly variable, resistivities modelled at surface to soils and/or boulder clay. At depth the main resistivity contrast was expected to be between the highly resistive volcanics of the Bathgate Hills Volcanic Formation and the low resistivity of the mixed sedimentary EKS. Resistivities of much less than 100 ohm-m modelled at depth can be correlated with the EKS. High resistivities (480 ohm-m) above the EKS on VES1 and VES2 are correlated with the lower of two basalts of the magnetic model. High resistivities (typically over 400 ohm-m) beneath the EKS are consistent with the presence of volcanic rocks. The following points arise from the resistivity results: (1) Comparison of VES1 and VES2 confirms the significant westward deepening of the EKS shown by.the magnetic interpretation. (2) VES1, VES3 and VES4 are located broadly along strike from each other, but show the sub-EKS volcanics to deepen northwards. This was confirmed by the constant separation traverse. Thus the EKS may thicken. The resolution of the resistivity data does not permit us to distinguish between a northward deepening due to folding or faulting

Innovation in assessment: building student confidence in preparation for unfamiliar assessment methods

Innovative assessment methods in which students are active participants promote deeper learning. A group debate and a webfolio were implemented as methods of assessment in the 2015 undergraduate midwifery curriculum, with the assessment tools being evaluated by students. Thematic analysis of the evaluations showed students enjoyed undertaking innovative methods of assessment, they developed confidence and engaged meaningfully with the content to be assessed. Students also commented they developed multiple skills required for future professional practice as a midwife. Thorough preparation of students to undertake an innovative method of assessment however is vital in fostering student confidence

Blood spots as an alternative to whole blood collection and the effect of a small monetary incentive to increase participation in genetic association studies

<p>Abstract</p> <p>Background</p> <p>Collection of buccal cells from saliva for DNA extraction offers a less invasive and convenient alternative to venipuncture blood collection that may increase participation in genetic epidemiologic studies. However, dried blood spot collection, which is also a convenient method, offers a means of collecting peripheral blood samples from which analytes in addition to DNA can be obtained.</p> <p>Methods</p> <p>To determine if offering blood spot collection would increase participation in genetic epidemiologic studies, we conducted a study of collecting dried blood spot cards by mail from a sample of female cancer cases (n = 134) and controls (n = 256) who were previously selected for a breast cancer genetics study and declined to provide a venipuncture blood sample. Participants were also randomized to receive either a $2.00 bill or no incentive with the blood spot collection kits.</p> <p>Results</p> <p>The average time between the venipuncture sample refusal and recruitment for the blood spot collection was 4.4 years. Thirty-seven percent of cases and 28$2.00 incentive vs. 26% for no incentive, p = 0.6), it was significantly associated with participation among the breast cancer cases (48% vs. 27%, respectively, p = 0.01). There did not appear to be any bias in response since no differences between cases and controls and incentive groups were observed when examining several demographic, work history and radiation exposure variables.</p> <p>Conclusion</p> <p>This study demonstrates that collection of dried blood spot cards in addition to venipuncture blood samples may be a feasible method to increase participation in genetic case-control studies.</p

Rivastigmine: an open-label, observational study of safety and effectiveness in treating patients with Alzheimer's disease for up to 5 years

BACKGROUND: Rivastigmine, a butyl- and acetylcholinesterase inhibitor, is approved for symptomatic treatment of Alzheimer's disease (AD). Data supporting the safety and efficacy of second-generation cholinesterase inhibitors, such as rivastigmine, are available for treatment up to 1 year, with limited data up to 2 1/2 years. The purpose of this report is to present safety and effectiveness data for rivastigmine therapy in patients with mild to moderately severe AD receiving treatment for up to 5 years. METHODS: An observational approach was used to study 37 patients with originally mild to moderate AD receiving rivastigmine as a therapy for AD in an open-label extension (ENA713, B352 Study Group, 1998). RESULTS: The initial trial demonstrated rivastigmine was well-tolerated and effective in terms of cognition, global functioning and activities of daily living. In this open label extension, high-dose rivastigmine therapy was safe and well tolerated over a 5-year period. Two thirds of the participants still enrolled at week 234 were in the original high-dose rivastigmine group during the double-blind phase, suggesting that early therapy may confer some benefit in delaying long-term progression of symptoms. CONCLUSIONS: Long-term cholinesterase inhibition therapy with rivastigmine was well tolerated, with no dropouts due to adverse effects past the initial titration period. Early initiation of treatment, with titration to high-dose therapy, may have an advantage in delaying progression of the illness

Climate and predation dominate juvenile and adult recruitment in a turtle with temperature-dependent sex determination

Conditions experienced early in life can influence phenotypes in ecologically important ways, as exemplified by organisms with environmental sex determination. For organisms with temperature-dependent sex determination (TSD), variation in nest temperatures induces phenotypic variation that could impact population growth rates. In environments that vary over space and time, how does this variation influence key demographic parameters (cohort sex ratio and hatchling recruitment) in early life stages of populations exhibiting TSD? We leverage a 17-year data set on a population of painted turtles, Chrysemys picta, to investigate how spatial variation in nest vegetation cover and temporal variation in climate influence early life-history demography. We found that spatial variation in nest cover strongly influenced nest temperature and sex ratio, but was not correlated with clutch size, nest predation, total nest failure, or hatching success. Temporal variation in climate influenced percentage of total nest failure and cohort sex ratio, but not depredation rate, mean clutch size, or mean hatching success. Total hatchling recruitment in a year was influenced primarily by temporal variation in climate-independent factors, number of nests constructed, and depredation rate. Recruitment of female hatchlings was determined by stochastic variation in nest depredation and annual climate and also by the total nest production. Overall population demography depends more strongly on annual variation in climate and predation than it does on the intricacies of nest-specific biology. Finally, we demonstrate that recruitment of female hatchlings translates into recruitment of breeding females into the population, thus linking climate (and other) effects on early life stages to adult demographics

Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden

Abstract Background It has traditionally been thought that the pathological accumulation of tau in Alzheimer's disease and other tauopathies facilitates neurodegeneration, which in turn leads to cognitive impairment. However, recent evidence suggests that tau tangles are not the entity responsible for memory loss, rather it is an intermediate tau species that disrupts neuronal function. Thus, efforts to discover therapeutics for tauopathies emphasize soluble tau reductions as well as neuroprotection. Results Here, we found that neuroprotection alone caused by methylene blue (MB), the parent compound of the anti-tau phenothiaziazine drug, Rember&#8482;, was insufficient to rescue cognition in a mouse model of the human tauopathy, progressive supranuclear palsy (PSP) and fronto-temporal dementia with parkinsonism linked to chromosome 17 (FTDP17): Only when levels of soluble tau protein were concomitantly reduced by a very high concentration of MB, was cognitive improvement observed. Thus, neurodegeneration can be decoupled from tau accumulation, but phenotypic improvement is only possible when soluble tau levels are also reduced. Conclusions Neuroprotection alone is not sufficient to rescue tau-induced memory loss in a transgenic mouse model. Development of neuroprotective agents is an area of intense investigation in the tauopathy drug discovery field. This may ultimately be an unsuccessful approach if soluble toxic tau intermediates are not also reduced. Thus, MB and related compounds, despite their pleiotropic nature, may be the proverbial "magic bullet" because they not only are neuroprotective, but are also able to facilitate soluble tau clearance. Moreover, this shows that neuroprotection is possible without reducing tau levels. This indicates that there is a definitive molecular link between tau and cell death cascades that can be disrupted.http://deepblue.lib.umich.edu/bitstream/2027.42/78314/1/1750-1326-5-45.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78314/2/1750-1326-5-45.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/78314/3/1750-1326-5-45-S1.PDFPeer Reviewe