Macrophage transactivation for chemokine production identified as a negative regulator of granulomatous inflammation using agent-based modeling

Cellular activation in trans by interferons, cytokines and chemokines is a commonly recognized mechanism to amplify immune effector function and limit pathogen spread. However, an optimal host response also requires that collateral damage associated with inflammation is limited. This may be particularly so in the case of granulomatous inflammation, where an excessive number and / or excessively florid granulomas can have significant pathological consequences. Here, we have combined transcriptomics, agent-based modeling and in vivo experimental approaches to study constraints on hepatic granuloma formation in a murine model of experimental leishmaniasis. We demonstrate that chemokine production by non-infected Kupffer cells in the Leishmania donovani-infected liver promotes competition with infected KCs for available iNKT cells, ultimately inhibiting the extent of granulomatous inflammation. We propose trans-activation for chemokine production as a novel broadly applicable mechanism that may operate early in infection to limit excessive focal inflammation

GSA Launches G3: Genes | Genomes | Genetics

We are proud to present the inaugural issue of G3: Genes | Genomes | Genetics, an open-access journal published by the Genetics Society of America (GSA). The journal’s team of over 60 associate editors and 4 section editors, all practicing scientists—your peers—have come together to form a new, open-access journal with a unique mission and vision. The Editorial Board of G3 taps the expertise of the community of geneticists in the widest sense, from microbes to humans, from individuals to populations, and from classic “wet lab” experimentation to the most recent innovations in bioinformatics

All the Brain\u27s a Stage for Serotonin: The Forgotten Story of Serotonin Diffusion across Cell Membranes

In the conventional model of serotonin neurotransmission, serotonin released by neurons in the midbrain raphe nuclei exerts its actions on forebrain neurons by interacting with a large family of post-synaptic receptors. The actions of serotonin are terminated by active transport of serotonin back into the releasing neuron, which is mediated by the serotonin reuptake transporter (SERT). Because SERT is expressed pre-synaptically and is widely thought to be the only serotonin transporter in the forebrain, the conventional model does not include serotonin transport into post-synaptic neurons. However, a large body of evidence accumulating since the 1970s has shown that serotonin, despite having a positive charge, can cross cell membranes through a diffusion-like process. Multiple low-affinity, high-capacity, sodium-independent transporters, widely expressed in the brain, allow the carrier-mediated diffusion of serotonin into forebrain neurons. The amount of serotonin crossing cell membranes through this mechanism under physiological conditions is considerable. Most prominent textbooks fail to include this alternative method of serotonin uptake in the brain, and even most neuroscientists are unaware of it. This failure has limited our understanding of a key regulator of serotonergic neurotransmission, impeded research on the potential intracellular actions of serotonin in post-synaptic neurons and glial cells, and may have impeded our understanding of the mechanism by which antidepressant medications reduce depressive symptoms

A Preliminary Model of the Hydrologic-Sociologic Flow System of an Urban Area

This report describes the first phase of a larger study which is directed toward the development of a general technique for analyzing and solving urban metropolitan hydrologic problems through a joint consideration of both the physical and social dimensions. This report is limited to the preliminary work of identification of social variables, the first steps in assigning mathematical values to them, and developing a mathematical format for these variables. In addition, the physical-hydrologic system is identified for purposes of clarifying the elements in that system. The ultimate objective of the entire study is directed toward discovering a theoretical and generally applicable mathematical model of both the physical and social dimensions involved in metropolitan flooding problems

G3, GENETICS, and the GSA: Two Journals, One Mission

With the June launch of its open-access journal G3: Genes | Genomes | Genetics, the Genetics Society of America (GSA) now offers two peer-edited journals. The missions of G3 and GENETICS are fundamentally the same: to provide a forum for timely communication of the latest findings in genetics, selected by editors who are the authors' peers. But the scopes of the two journals are different. Why offer two journals

Novel regulators of stem cell fates identified by a multivariate phenotype screen of small compounds on human embryonic stem cell colonies

Understanding the complex mechanisms that govern the fate decisions of human embryonic stem cells (hESCs) is fundamental to their use in cell replacement therapies. The progress of dissecting these mechanisms will be facilitated by the availability of robust high-throughput screening assays on hESCs. In this study, we report an image-based high-content assay for detecting compounds that affect hESC survival or pluripotency. Our assay was designed to detect changes in the phenotype of hESC colonies by quantifying multiple parameters, including the number of cells in a colony, colony area and shape, intensity of nuclear staining, and the percentage of cells in the colony that express a marker of pluripotency (TRA-1-60), as well as the number of colonies per well. We used this assay to screen 1040 compounds from two commercial compound libraries, and identified 17 that promoted differentiation, as well as 5 that promoted survival of hESCs. Among the novel small compounds we identified with activity on hESC are several steroids that promote hESC differentiation and the antihypertensive drug, pinacidil, which affects hESC survival. The analysis of overlapping targets of pinacidil and the other survival compounds revealed that activity of PRK2, ROCK, MNK1, RSK1, and MSK1 kinases may contribute to the survival of hESCs. (C) 2010 Elsevier B.V. All rights reserved

The effect of electrical stimulation on corticospinal excitability is dependent on application duration: a same subject pre-post test design

Background: In humans, corticospinal excitability is known to increase following motor electrical stimulation (ES) designed to mimic a voluntary contraction. However, whether the effect is equivalent with different application durations and whether similar effects are apparent for short and long applications is unknown. The aim of this study was to investigate whether the duration of peripheral motor ES influenced its effect on corticospinal excitability

Dinosaur tracks from the Kilmaluag Formation (Bathonian, Middle Jurassic) of Score Bay, Isle of Skye, Scotland, UK

Tracks of a juvenile theropod dinosaur with footprint lengths of between 2 and 9 cm as well as adults of the same ichnospecies with footprints of about 15–25 cm in length were found in the Bathonian (Middle Jurassic) Kilmaluag Formation of Score Bay, northwestern Trotternish Peninsula, Isle of Skye, Scotland, UK. Two footprint sizes occur together on the same bedding plane in the central portion of Score Bay, both in situ and on loose blocks. Another horizon containing footprints above this was also identified. The footprints from the lowest horizon were produced in a desiccated silty mud that was covered with sand. A close association of both adults and juveniles with similar travel direction indicated by the footprints may suggest post-hatching care in theropod dinosaurs. Other footprints, produced on a rippled sandy substrate, have been found on the slightly higher bedding plane at this locality. Loose blocks found 130 m to the northeast in the central part of Score Bay have not been correlated with any in situ sediments, but were preserved in a similar manner to those from the higher bedding plane. These tracks represent the youngest dinosaur remains yet found in Scotland