Senescence can play an essential role in modelling and estimation of vector based epidemiological indicators: demographical approach

In the paper basic epidemiological indicators, produced by an aging population of vectors, are calculated. In the study we follow two lines: calculations for demographically structured population and individual life-history approach. We discuss the advantages and limitations of these approaches and compare the results of our calculations with epidemiological indicators obtained for non-aging population of vectors.Gibraltar, age effect, disease control, gerontology

Discovering predictive variables when evolving cognitive models

A non-dominated sorting genetic algorithm is used to evolve models of learning from different theories for multiple tasks. Correlation analysis is performed to identify parameters which affect performance on specific tasks; these are the predictive variables. Mutation is biased so that changes to parameter values tend to preserve values within the population's current range. Experimental results show that optimal models are evolved, and also that uncovering predictive variables is beneficial in improving the rate of convergence

An organotypic slice culture to study the formation of calyx of Held synapses in-vitro.

The calyx of Held, a large axo-somatic relay synapse containing hundreds of presynaptic active zones, is possibly the largest nerve terminal in the mammalian CNS. Studying its initial growth in-vitro might provide insights into the specification of synaptic connection size in the developing brain. However, attempts to maintain calyces of Held in organotypic cultures have not been fruitful in past studies. Here, we describe an organotypic slice culture method in which calyces of Held form in-vitro. We made coronal brainstem slices with an optimized slice angle using newborn mice in which calyces have not yet formed; the presynaptic bushy cells were genetically labeled using the Math5 promoter. After six to nine days of culturing, we readily observed large Math5-positive nerve terminals in the medial nucleus of the trapezoid body (MNTB), but not in the neighboring lateral superior olive nucleus (LSO). These calyx-like synapses expressed the Ca2+- sensor Synaptotagmin-2 (Syt-2) and the Ca2+ binding protein Parvalbumin (PV), two markers of developing calyces of Held in vivo. Application of the BMP inhibitor LDN-193189 significantly inhibited the growth of calyx synapses, demonstrating the feasibility of long-term pharmacological manipulation using this organotypic culture method. These experiments provide a method for organotypic culturing of calyces of Held, and show that the formation of calyx-like synapses onto MNTB neurons can be preserved in-vitro. Furthermore, our study adds pharmacological evidence for a role of BMP-signaling in the formation of large calyx of Held synapses

Modulation of Osteoblastic Cell Efferocytosis by Bone Marrow Macrophages

Apoptosis occurs at an extraordinary rate in the human body and the effective clearance of dead cells (efferocytosis) is necessary to maintain homeostasis and promote healing, yet the contribution and impact of this process in bone is unclear. Bone formation requires that bone marrow stromal cells (BMSCs) differentiate into osteoblasts which direct matrix formation and either become osteocytes, bone lining cells, or undergo apoptosis. A series of experiments were performed to identify the regulators and consequences of macrophage efferocytosis of apoptotic BMSCs (apBMSCs). Bone marrow derived macrophages treated with the anti‐inflammatory cytokine interleukin‐10 (IL‐10) exhibited increased efferocytosis of apBMSCs compared to vehicle treated macrophages. Additionally, IL‐10 increased anti‐inflammatory M2‐like macrophages (CD206+), and further enhanced efferocytosis within the CD206+ population. Stattic, an inhibitor of STAT3 phosphorylation, reduced the IL‐10‐mediated shift in M2 macrophage polarization and diminished IL‐10‐directed efferocytosis of apBMSCs by macrophages implicating the STAT3 signaling pathway. Cell culture supernatants and RNA from macrophages co‐cultured with apoptotic bone cells showed increased secretion of monocyte chemotactic protein 1/chemokine (C‐C motif) ligand 2 (MCP‐1/CCL2) and transforming growth factor beta 1 (TGF‐β1) and increased ccl2 gene expression. In conclusion, IL‐10 increases M2 macrophage polarization and enhances macrophage‐mediated engulfment of apBMSCs in a STAT3 phosphorylation‐dependent manner. After engulfment of apoptotic bone cells, macrophages secrete TGF‐β1 and MCP‐1/CCL2, factors which fuel the remodeling process. A better understanding of the role of macrophage efferocytosis as it relates to normal and abnormal bone turnover will provide vital information for future therapeutic approaches to treat bone related diseases. J. Cell. Biochem. 117: 2697–2706, 2016. © 2016 Wiley Periodicals, Inc.The process of efferocytosis (clearance of apoptotic cells) has been characterized in various tissues but the role of efferocytosis in the bone microenvironment is unclear. Bone marrow macrophage efferocytosis of apoptotic osteoblastic cells was enhanced by interleukin‐10 in a STAT‐3 dependent manner and resulted in increased production of TGF‐β1 and CCL‐2. The process of efferocytosis is likely important in bone remodeling and osseous wound healing.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134491/1/jcb25567.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134491/2/jcb25567_am.pd

Stress-related anhedonia is associated with ventral striatum reactivity to reward and transdiagnostic psychiatric symptomatology

BACKGROUND: Early life stress (ELS) is consistently associated with increased risk for subsequent psychopathology. Individual differences in neural response to reward may confer vulnerability to stress-related psychopathology. Using data from the ongoing Duke Neurogenetics Study, the present study examined whether reward-related ventral striatum (VS) reactivity moderates the relationship between retrospectively reported ELS and anhedonic symptomatology. We further assessed whether individual differences in reward-related VS reactivity were associated with other depressive symptoms and problematic alcohol use via stress-related anhedonic symptoms and substance use-associated coping. METHOD: Blood oxygen level-dependent functional magnetic resonance imaging (fMRI) was collected while participants (n = 906) completed a card-guessing task, which robustly elicits VS reactivity. ELS, anhedonic symptoms, other depressive symptoms, coping behavior, and alcohol use behavior were assessed with self-report questionnaires. Linear regressions were run to examine whether VS reactivity moderated the relationship between ELS and anhedonic symptoms. Structural equation models examined whether this moderation was indirectly associated with other depression symptoms and problematic alcohol use through its association with anhedonia. RESULTS: Analyses of data from 820 participants passing quality control procedures revealed that the VS × ELS interaction was associated with anhedonic symptoms (p = 0.011). Moreover, structural equation models indirectly linked this interaction to non-anhedonic depression symptoms and problematic alcohol use through anhedonic symptoms and substance-related coping. CONCLUSIONS: These findings suggest that reduced VS reactivity to reward is associated with increased risk for anhedonia in individuals exposed to ELS. Such stress-related anhedonia is further associated with other depressive symptoms and problematic alcohol use through substance-related coping

The Impact II, a Very High-Resolution Quadrupole Time-of-Flight Instrument (QTOF) for Deep Shotgun Proteomics

Hybrid quadrupole time-of-flight (QTOF) mass spectrometry is one of the two major principles used in proteomics. Although based on simple fundamentals, it has over the last decades greatly evolved in terms of achievable resolution, mass accuracy, and dynamic range. The Bruker impact platform of QTOF instruments takes advantage of these developments and here we develop and evaluate the impact II for shotgun proteomics applications. Adaption of our heated liquid chromatography system achieved very narrow peptide elution peaks. The impact II is equipped with a new collision cell with both axial and radial ion ejection, more than doubling ion extraction at high tandem MS frequencies. The new reflectron and detector improve resolving power compared with the previous model up to 80%, i.e. to 40,000 at m/z 1222. We analyzed the ion current from the inlet capillary and found very high transmission (>80%) up to the collision cell. Simulation and measurement indicated 60% transfer into the flight tube. We adapted MaxQuant for QTOF data, improving absolute average mass deviations to better than 1.45 ppm. More than 4800 proteins can be identified in a single run of HeLa digest in a 90 min gradient. The workflow achieved high technical reproducibility (R2 > 0.99) and accurate fold change determination in spike-in experiments in complex mixtures. Using label-free quantification we rapidly quantified haploid against diploid yeast and characterized overall proteome differences in mouse cell lines originating from different tissues. Finally, after high pH reversed-phase fractionation we identified 9515 proteins in a triplicate measurement of HeLa peptide mixture and 11,257 proteins in single measurements of cerebellum-the highest proteome coverage reported with a QTOF instrument so far

Non-contact infrared temperature measurements in dry permafrost boreholes

While planning the COAST Expedition to the Siberian Laptev Sea in 2005, the question of how to make a short equilibrium temperature measurement in a dry borehole arose. As a result, an infrared borehole tool was developed and used in three dry boreholes (up to 60.2 m deep) in the coastal transition zone from terrestrial to sub-sea permafrost near Mamontovy Klyk in the western Laptev Sea. A depth versus temperature profile was acquired with equilibration times of 50 × 10−3 s at each depth interval. Comparison with a common resistor string revealed an offset due to limitations of accuracy of the infrared technique and the influence of the probe's massive steel housing. Therefore it was necessary to calibrate the infrared sensor with a high precision temperature logger in each borehole. The results of the temperature measurements show a highly dynamic transition zone with temperature gradients up to −0.092°C/m and heat flow of −218 mW/m. A period of submergence of only 600 years the drilled sub-sea permafrost is approaching the overlying seawater temperature at −1.61°C with a temperature gradient of 0.021°C/m and heat flow of 49 mW/m. Further offshore, 11 km from the coastline, a temperature gradient of 0.006°C/m and heat flow of 14 mW/m occur. Thus the sub-sea permafrost in the Mamontovy Klyk region has reached a critical temperature for the presence of interstitial ice. The aim of this article is to give a brief feasibility study of infrared downhole temperature measurements and to present experiences and results of its successful application

Disseminated Low Grade Glioma in Children and Young Adults

Background: Disseminated low-grade gliomas [d-LGG] in children, teenagers and young adults [TYA] are rare and the treatment outcome is worse than for than for those with localised disease. We present a retrospective institutional and ethical review board approved report of d-LGG in children and TYA treated at the London Cancer Paediatric & Adolescent Neuro-Oncology Service. Purpose: Between 1998 and 2014, 36 patients with d-LGG either at diagnosis or during follow up were identified. Anonymized data were retrospectively collected from the hospital databases and included patient demographics, modality of diagnosis, treatment received, recurrences or disease progression and outcome. Results: The median age of our cohort was 4.5 years and median follow up was 6 years. 60% had disseminated disease at diagnosis; pilocytic astrocytoma was the commonest histological subtype (n=18, 50%). Chemotherapy was the most common treatment modality utilised. The 6-year overall survival for those with localised disease with dissemination during follow-up and disseminated disease at presentation were 77.9% and 76.1% respectively. Progression free survival at 1, 2 and 3 years were 64.3%, 50% and 21.4% and 57.3, 43% and 38.2% respectively. Conclusion: Children with d-LGG treated have a poor outcome. A significant proportion of patients have multiple recurrences or disease progressions. There appears to be no difference in OS in those who had disseminated disease at diagnosis compared to those who developed disseminated disease at a later time point during follow up. Prospective international studies with molecular genetic profiling will help clarify the best treatment approach for this group of patients