CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice

Neuroinflammation and microglial activation are significant processes in Alzheimer's disease pathology. Recent genome-wide association studies have highlighted multiple immune-related genes in association with Alzheimer's disease, and experimental data have demonstrated microglial proliferation as a significant component of the neuropathology. In this study, we tested the efficacy of the selective CSF1R inhibitor JNJ-40346527 (JNJ-527) in the P301S mouse tauopathy model. We first demonstrated the anti-proliferative effects of JNJ-527 on microglia in the ME7 prion model, and its impact on the inflammatory profile, and provided potential CNS biomarkers for clinical investigation with the compound, including pharmacokinetic/pharmacodynamics and efficacy assessment by TSPO autoradiography and CSF proteomics. Then, we showed for the first time that blockade of microglial proliferation and modification of microglial phenotype leads to an attenuation of tau-induced neurodegeneration and results in functional improvement in P301S mice. Overall, this work strongly supports the potential for inhibition of CSF1R as a target for the treatment of Alzheimer's disease and other tau-mediated neurodegenerative diseases

Self-love and sociability: the ‘rudiments of commerce’ in the state of nature

Istvan Hont’s classic work on the theoretical links between the seventeenth-century natural jurists Hugo Grotius and Samuel Pufendorf and the eighteenth-century Scottish political economists remains a popular trope among intellectual and economic historians of various stamps. Despite this, a common criticism levelled at Hont remains his relative lack of engagement with the relationship between religion and economics in the early modern period. This paper challenges this aspect of Hont’s narrative by drawing attention to an alternative, albeit complementary, assessment of the natural jurisprudential heritage of eighteenth-century British political economy. Specifically, the article attempts to map on to Hont’s thesis the Christian Stoic interpretation of Grotius and Pufendorf which has gained greater currency in recent years. In doing so, the paper argues that Grotius and Pufendorf’s contributions to the ‘unsocial sociability’ debate do not necessarily lead directly to the Scottish school of political economists, as is commonly assumed. Instead, it contends that a reconsideration of Grotius and Pufendorf as neo-Stoic theorists, particularly via scrutiny of their respective adaptations of the traditional Stoic theory of oikeiosis, steers us towards the heart of the early English ‘clerical’ Enlightenment

Large-Scale Gene-Centric Meta-Analysis across 39 Studies Identifies Type 2 Diabetes Loci

To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom similar to 50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with similar to 2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 x 10(-9)) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p <2.4 x 10(-6)). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 x 10(-7)) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 x 10(-15)). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 x 10(-8)). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups

CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice

Neuroinflammation and microglial activation are significant processes in Alzheimer’s disease pathology. Recent genome-wide association studies have highlighted multiple immune-related genes in association with Alzheimer’s disease, and experimental data have demonstrated microglial proliferation as a significant component of the neuropathology. In this study, we tested the efficacy of the selective CSF1R inhibitor JNJ-40346527 (JNJ-527) in the P301S mouse tauopathy model. We first demonstrated the anti-proliferative effects of JNJ-527 on microglia in the ME7 prion model, and its impact on the inflammatory profile, and provided potential CNS biomarkers for clinical investigation with the compound, including pharmacokinetic/pharmacodynamics and efficacy assessment by TSPO autoradiography and CSF proteomics. Then, we showed for the first time that blockade of microglial proliferation and modification of microglial phenotype leads to an attenuation of tau-induced neurodegeneration and results in functional improvement in P301S mice. Overall, this work strongly supports the potential for inhibition of CSF1R as a target for the treatment of Alzheimer’s disease and other tau-mediated neurodegenerative diseases

The National Early Warning Score and its subcomponents recorded within ±24 hours of emergency medical admission are poor predictors of hospital-acquired acute kidney injury

YesBackground: Hospital-acquired Acute Kidney Injury (H-AKI) is a common cause of avoidable morbidity and mortality. Aim: To determine if the patients’ vital signs data as defined by a National Early Warning Score (NEWS), can predict H-AKI following emergency admission to hospital. Methods: Analyses of emergency admissions to York hospital over 24-months with NEWS data. We report the area under the curve (AUC) for logistic regression models that used the index NEWS (model A0), plus age and sex (A1), plus subcomponents of NEWS (A2) and two-way interactions (A3). Likewise for maximum NEWS (models B0,B1,B2,B3). Results: 4.05% (1361/33608) of emergency admissions had H-AKI. Models using the index NEWS had the lower AUCs (0.59 to 0.68) than models using the maximum NEWS AUCs (0.75 to 0.77). The maximum NEWS model (B3) was more sensitivity than the index NEWS model (A0) (67.60% vs 19.84%) but identified twice as many cases as being at risk of H-AKI (9581 vs 4099) at a NEWS of 5. Conclusions: The index NEWS is a poor predictor of H-AKI. The maximum NEWS is a better predictor but seems unfeasible because it is only knowable in retrospect and is associated with a substantial increase in workload albeit with improved sensitivity.The Health Foundatio

Inflammatory biomarkers in Alzheimer's disease plasma

Introduction:Plasma biomarkers for Alzheimer’s disease (AD) diagnosis/stratification are a“Holy Grail” of AD research and intensively sought; however, there are no well-established plasmamarkers.Methods:A hypothesis-led plasma biomarker search was conducted in the context of internationalmulticenter studies. The discovery phase measured 53 inflammatory proteins in elderly control (CTL;259), mild cognitive impairment (MCI; 199), and AD (262) subjects from AddNeuroMed.Results:Ten analytes showed significant intergroup differences. Logistic regression identified five(FB, FH, sCR1, MCP-1, eotaxin-1) that, age/APOε4 adjusted, optimally differentiated AD andCTL (AUC: 0.79), and three (sCR1, MCP-1, eotaxin-1) that optimally differentiated AD and MCI(AUC: 0.74). These models replicated in an independent cohort (EMIF; AUC 0.81 and 0.67). Twoanalytes (FB, FH) plus age predicted MCI progression to AD (AUC: 0.71).Discussion:Plasma markers of inflammation and complement dysregulation support diagnosis andoutcome prediction in AD and MCI. Further replication is needed before clinical translatio

INTEREST RATE SWAPS: THEIR USE IN FINANCING AGRICULTURE

Agricultural Finance,

Seagrass canopies and the performance of acoustic telemetry: Implications for the interpretation of fish movements

© 2020 The Author(s). Background: Acoustic telemetry has been used with great success to quantify the movements of marine fishes in open habitats, however research has begun to focus on patterns of movement and habitat usage within more structurally complex habitats. To date, there has been no detailed assessment of the performance of acoustic telemetry within seagrass, which forms a crucial nursery and foraging habitat for many fish species globally. Information on the detection range of acoustic receivers within seagrass is essential to guide receiver array design, particularly positioning systems. Here, we compare detection ranges for transmitters (Vemco V7) within and above the seagrass to determine impacts on the performance of a Vemco Positioning System (VPS). We also investigate the influence of environmental conditions (i.e. wind, time of day, background noise, atmospheric pressure and depth) on detection probability. Results: The performance of the VPS declined dramatically when the transmitters were positioned within the seagrass (positional accuracy = 2.69 m, precision = 0.9 m, system efficiency (i.e. the proportion of successful positions) = 5.9%) compared to above the canopy (positional accuracy = 2.21 m, precision = 0.45 m, system efficiency = 30.9%). The reduction in VPS efficiency when transmitters were within seagrass was caused by a decline in the detection range of receivers (range of 50% detections) from 85 to 40 m, as this limited the ability of the three receivers to simultaneously detect transmissions. Additionally, no detections were recorded for the transmitters within seagrass at a distance greater than 150 m from the receiver. Increasing wind speed from 0 to 50 km h-1 correlated with a 15% reduction in detections while detection probability decreased from 0.8 during the day to 0.55 at night, due to higher in-band noise (69 kHz). Conclusions: Our findings demonstrate that tagged fish ensconced within seagrass are unlikely to be detected by receivers or positioned by a VPS. Further, we demonstrate that wind conditions and the time of day create temporal variation in detection probability. These findings highlight the need for telemetry studies to perform in situ range testing and consider how fish use vegetated habitats such as seagrasses when positioning receivers and interpreting data.[Figure not available: see fulltext.

Application of the Acoustic Propagation Model to a deep-water cross-shelf curtain

A good understanding of acoustic coverage and temporal variation relative to environmental conditions is crucial for accurate interpretation of results from acoustic tracking studies and ensuing appropriate management recommendations.In their recent paper, Gjelland & Hedger (Methods in Ecology and Evolution, 2017) suggest that the general detection probability model proposed by Gjelland & Hedger (Methods in Ecology and Evolution, 2013, 4, 665–674) was not appropriately used in Huveneers et al. (Methods in Ecology and Evolution, 2016, 7, 825–835). The intent of the comparison in Huveneers et al. (2016) was to evaluate the Acoustic Propagation Model (APM) in a situation when parameterisation is not logistically feasible. This can be the case when reference tags have not been deployed, or when the distance between tagged animals and receivers cannot be accurately estimated or cannot be obtained under sufficiently varied weather conditions. Even when parameterisation is possible, there will be situations where the APM does not account for all factors affecting detection probability, e.g. deep-water receivers where density gradients can affect sound propagation.Re-parameterisation of the APM based on clarification in Gjelland & Hedger (2017) and application to a deep-water cross-shelf receiver array showed similar detection range to a logistic model until about ∼750 m distance, after which the APM resulted in unrealistically high detection probability estimates. The need for large amounts of data to parameterise the APM and achieve good statistical fit negates the value of the theoretical propagation model. Detection range can also be affected by a broad range of factors, many of which are not included within the APM. The complexity of the way different environmental factors can influence acoustic detections and the variability of environments in which acoustic tracking studies are undertaken make it challenging to develop a general model applicable across environments.We support further improvement of the APM and recommend the use of reference tags to collect necessary data to parameterise the APM and assess factors influencing detection probability