A Putative Multiple-Demand System in the Macaque Brain.

UNLABELLED: In humans, cognitively demanding tasks of many types recruit common frontoparietal brain areas. Pervasive activation of this "multiple-demand" (MD) network suggests a core function in supporting goal-oriented behavior. A similar network might therefore be predicted in nonhuman primates that readily perform similar tasks after training. However, an MD network in nonhuman primates has not been described. Single-cell recordings from macaque frontal and parietal cortex show some similar properties to human MD fMRI responses (e.g., adaptive coding of task-relevant information). Invasive recordings, however, come from limited prespecified locations, so they do not delineate a macaque homolog of the MD system and their positioning could benefit from knowledge of where MD foci lie. Challenges of scanning behaving animals mean that few macaque fMRI studies specifically contrast levels of cognitive demand, so we sought to identify a macaque counterpart to the human MD system using fMRI connectivity in 35 rhesus macaques. Putative macaque MD regions, mapped from frontoparietal MD regions defined in humans, were found to be functionally connected under anesthesia. To further refine these regions, an iterative process was used to maximize their connectivity cross-validated across animals. Finally, whole-brain connectivity analyses identified voxels that were robustly connected to MD regions, revealing seven clusters across frontoparietal and insular cortex comparable to human MD regions and one unexpected cluster in the lateral fissure. The proposed macaque MD regions can be used to guide future electrophysiological investigation of MD neural coding and in task-based fMRI to test predictions of similar functional properties to human MD cortex. SIGNIFICANCE STATEMENT: In humans, a frontoparietal "multiple-demand" (MD) brain network is recruited during a wide range of cognitively demanding tasks. Because this suggests a fundamental function, one might expect a similar network to exist in nonhuman primates, but this remains controversial. Here, we sought to identify a macaque counterpart to the human MD system using fMRI connectivity. Putative macaque MD regions were functionally connected under anesthesia and were further refined by iterative optimization. The result is a network including lateral frontal, dorsomedial frontal, and insular and inferior parietal regions closely similar to the human counterpart. The proposed macaque MD regions can be useful in guiding electrophysiological recordings or in task-based fMRI to test predictions of similar functional properties to human MD cortex

Short-term CD8+ T Cell Depletion Results in Decreased Large Artery Stiffness Via Decreased Collagen Content in Old Mice

Cardiovascular disease is the leading cause of death in the United States. Advanced age is associated with large artery stiffness, partially due to increased collagen deposition within the aorta. Previously we have found that T cells accumulate in the aortas of old animals. A large proportion of these cells are CD8+ and produce inflammatory cytokines. We have previously demonstrated that CD8+ T cell depletion results in improved large artery stiffness. However, the mechanisms by which CD8+ depletion improves large artery stiffness are unclear. Therefore, we sought to determine whether CD8+ T cell depletion in old mice results in blunted aortic collagen deposition compared to old CD8+ intact mice. PURPOSE: To test the hypothesis that old CD8+ T cell depleted mice would exhibit blunted collagen deposition and collagen gene expression in the aorta compared to old CD8+ T cell intact mice. METHODS: Old (22-24mo) mice (n=5-12) were injected every 5 days with anti-CD8+ or isotype (control) antibodies for 28 days. On the 28th day, the mice were euthanized, a 5mm section of the aorta was saved for histology and the remaining aorta was cleaned and saved for qPCR analysis. Aortas were paraffin embedded, sectioned, and stained using picrosirius red to assess collagen content. Collagen content was quantified using ImageJ. Aorta collagen gene expression was assessed by qPCR. Group differences were assessed by independent samples t test. Data is presented as mean ± SEM (normalized to old Isotype; Units Arbitrary (AU)). RESULTS: Old CD8+ depleted mice exhibited blunted collagen deposition in both the medial (Control: 1.00±0.06 AU, Anti-CD8:0.78±0.07 AU; p=0.02) and adventitial (Control: 1.00±0.05 AU, Anti-CD8:0.81±0.05 AU; p=0.01) layers of the aorta compared to isotype controls. However, there were no differences in the expression of genes responsible for collagen creation, Col1a1 (Control: 1.00±0.28 AU, Anti-CD8: 1.68±0.53AU, p=0.15) and Col3a1(Control: 1.00±0.46 AU, Anti-CD8: 0.89±0.35 AU, p=0.42). CONCLUSION: Short-term manipulation of CD8+ T cells results in blunted aortic collagen deposition but has no effect on collagen gene expression compared to old controls. The specific mechanisms in which old CD8+ T cells influence collagen deposition are unknown

Dynamic compression can inhibit chondrogenesis of mesenchymal stem cells.

The objective of this study was to investigate the influence of dynamic compressive loading on chondrogenesis of mesenchymal stem cells (MSCs) in the presence of TGF-beta3. Isolated porcine MSCs were suspended in 2% agarose and subjected to intermittent dynamic compression (10% strain) for a period of 42 days in a dynamic compression bioreactor. After 42 days in culture, the free-swelling specimens exhibited more intense alcian blue staining for proteoglycans, while immunohistochemical analysis revealed increased collagen type II immunoreactivity. Glycosaminoglycan (GAG) content increased with time for both free-swelling and dynamically loaded constructs, and by day 42 it was significantly higher in both the core (2.5+/-0.21%w/w vs. 0.94+/-0.03%w/w) and annulus (1.09+/-0.09%w/w vs. 0.59+/-0.08%w/w) of free-swelling constructs compared to dynamically loaded constructs. This result suggests that further optimization is required in controlling the biomechanical and/or the biochemical environment if such stimuli are to have beneficial effects in generating functional cartilaginous tissue

Sub-Antarctic and High Antarctic Notothenioid Fishes: Ecology and Adaptational Biology Revealed by the ICEFISH 2004 Cruise of RVIB Nathaniel B. Palmer

The goal of the ICEFISH 2004 cruise, which was conducted on board RVIB Nathaniel B. Palmer and traversed the transitional zones linking the South Atlantic to the Southern Ocean, was to compare the evolution, ecology, adaptational biology, community structure, and population dynamics of Antarctic notothenioid fishes relative to the cool/temperate notothenioids of the sub-Antarctic. To place this work in a comprehensive ecological context, cruise participants surveyed the benthos and geology of the biogeographic provinces and island shelves on either side of the Antarctic Polar Front (or Antarctic Convergence). Genome-enabled comparison of the responses of cold-living and temperate notothenioids to heat stress confirmed the sensitivity of the former to a warming Southern Ocean. Successful implementation of the international and interdisciplinary ICEFISH research cruise provides a model for future exploration of the sub-Antarctic sectors of the Indian and Pacific Oceans

Coupling Freshly Isolated CD44(+) Infrapatellar Fat Pad-Derived Stromal Cells with a TGF-β3 Eluting Cartilage ECM-Derived Scaffold as a Single-Stage Strategy for Promoting Chondrogenesis.

An alternative strategy to the use of in vitro expanded cells in regenerative medicine is the use of freshly isolated stromal cells, where a bioactive scaffold is used to provide an environment conducive to proliferation and tissue-specific differentiation in vivo. The objective of this study is to develop a cartilage extracellular matrix (ECM)-derived scaffold that could facilitate the rapid proliferation and chondrogenic differentiation of freshly isolated stromal cells. By freeze-drying cryomilled cartilage ECM of differing concentrations, it is possible to produce scaffolds with a range of pore sizes. The migration, proliferation, and chondrogenic differentiation of infrapatellar fat pad-derived stem cells (FPSCs) depend on the concentration/porosity of these scaffolds, with greater sulphated glycosaminoglycan (sGAG) accumulation observed in scaffolds with larger-sized pores. It is then sought to determine if freshly isolated fat pad-derived stromal cells, seeded onto a transforming growth factor (TGF)-β3 eluting ECM-derived scaffold, could promote chondrogenesis in vivo. While a more cartilage-like tissue could be generated using culture expanded FPSCs compared to nonenriched freshly isolated cells, fresh CD44(+) stromal cells are capable of producing a tissue in vivo that stained strongly for sGAGs and type II collagen. These findings open up new possibilities for in-theatre cell-based therapies for joint regeneration

Functional reorganisation and recovery following cortical lesions: A preliminary study in macaque monkeys.

Damage following traumatic brain injury or stroke can often extend beyond the boundaries of the initial insult and can lead to maladaptive cortical reorganisation. On the other hand, beneficial cortical reorganisation leading to recovery of function can also occur. We used resting state FMRI to investigate how cortical networks in the macaque brain change across time in response to lesions to the prefrontal cortex, and how this reorganisation correlated with changes in behavioural performance in cognitive tasks. After prelesion testing and scanning, two monkeys received a lesion to regions surrounding the left principal sulcus followed by periodic testing and scanning. Later, the animals received another lesion to the opposite hemisphere and additional testing and scanning. Following the first lesion, we observed both a behavioural impairment and decrease in functional connectivity, predominantly in frontal-frontal networks. Approximately 8 weeks later, performance and connectivity patterns both improved. Following the second lesion, we observed a further behavioural deficit and decrease in connectivity that showed little recovery. We discuss how different mechanisms including alternate behavioural strategies and reorganisation of specific prefrontal networks may have led to improvements in behaviour. Further work will be needed to confirm these mechanisms.This work was supported by the MRC intramural program MC-A060-5PQ10 (MA, DM, JD, AB), an MRC Career Development Award G0800329 (AM)

Antipsychotic dose escalation as a trigger for Neuroleptic Malignant Syndrome (NMS): literature review and case series report

Background: “Neuroleptic malignant syndrome” (NMS) is a potentially fatal idiosyncratic reaction to any medication which affects the central dopaminergic system. Between 0.5% and 1% of patients exposed to antipsychotics develop the condition. Mortality rates may be as high as 55% and many risk factors have been reported. Although rapid escalation of antipsychotic dose is thought to be an important risk factor, to date it has not been the focus of a published case series or scientifically defined. <p/>Aims: To identify cases of NMS and review risk factors for its development with a particular focus on rapid dose escalation in the 30 days prior to onset. <p/>Methodology: A review of the literature on rapid dose escalation was undertaken and a pragmatic definition of “rapid dose escalation” was made. NMS cases were defined using DSM-IV criteria and systematically identified within a secondary care mental health service. A ratio of titration rate was calculated for each NMS patient and “rapid escalators” and “non rapid escalators” were compared. <p/>Results: 13 cases of NMS were identified. A progressive mean dose increase 15 days prior to the confirmed episode of NMS was observed (241.7mg/day during days 1-15 to 346.9mg/day during days 16-30) and the mean ratio of dose escalation for NMS patients was 1.4. Rapid dose escalation was seen in 5/13 cases and non rapid escalators had markedly higher daily cumulative antipsychotic dose compared to rapid escalators. <p/>Conclusions: Rapid dose escalation occurred in less than half of this case series (n=5, 38.5%), although there is currently no consensus on the precise definition of rapid dose escalation. Cumulative antipsychotic dose – alongside other known risk factors - may also be important in the development of NMS

The first GCT camera for the Cherenkov Telescope Array

The Gamma Cherenkov Telescope (GCT) is proposed to be part of the Small Size Telescope (SST) array of the Cherenkov Telescope Array (CTA). The GCT dual-mirror optical design allows the use of a compact camera of diameter roughly 0.4 m. The curved focal plane is equipped with 2048 pixels of ~0.2{\deg} angular size, resulting in a field of view of ~9{\deg}. The GCT camera is designed to record the flashes of Cherenkov light from electromagnetic cascades, which last only a few tens of nanoseconds. Modules based on custom ASICs provide the required fast electronics, facilitating sampling and digitisation as well as first level of triggering. The first GCT camera prototype is currently being commissioned in the UK. On-telescope tests are planned later this year. Here we give a detailed description of the camera prototype and present recent progress with testing and commissioning.Comment: In Proceedings of the 34th International Cosmic Ray Conference (ICRC2015), The Hague, The Netherlands. All CTA contributions at arXiv:1508.0589

High blood pressure and risk of dementia : a two-sample Mendelian randomization study in the UK biobank

This work was supported by Janssen Research and Development , LLC (of Johnson & Johnson).Background: Findings from randomized controlled trials have yielded conflicting results on the association between blood pressure (BP) and dementia traits. We tested the hypothesis that a causal relationship exists between systolic BP (SBP) and/or diastolic BP (DBP) and risk of Alzheimer's disease (AD). Methods: We performed a generalized summary Mendelian randomization (GSMR) analysis using summary statistics of a genome-wide association study meta-analysis of 299,024 individuals of SBP or DBP as exposure variables against three different outcomes: 1) AD diagnosis (International Genomics of Alzheimer's Project), 2) maternal family history of AD (UK Biobank), and 3) paternal family history of AD (UK Biobank). Finally, a combined meta-analysis of 368,440 individuals that included these three summary statistics was used as final outcome. Results: GSMR applied to the International Genomics of Alzheimer's Project dataset revealed a significant effect of high SBP lowering the risk of AD (βGSMR = −0.19, p =.04). GSMR applied to the maternal family history of AD UK Biobank dataset (SBP [βGSMR = −0.12, p =.02], DBP [βGSMR = −0.10, p =.05]) and to the paternal family history of AD UK Biobank dataset (SBP [βGSMR = −0.16, p =.02], DBP [βGSMR = −0.24, p = 7.4 × 10−4]) showed the same effect. A subsequent combined meta-analysis confirmed the overall significant effect for the other SBP analyses (βGSMR = −0.14, p =.03). The DBP analysis in the combined meta-analysis also confirmed a DBP effect on AD (βGSMR = −0.14, p =.03). Conclusions: A causal effect exists between high BP and a reduced late-life risk of AD. The results were obtained through careful consideration of confounding factors and the application of complementary MR methods on independent cohorts.Peer reviewe