Cross-Talk between the Cellular Redox State and the Circadian System in Neurospora

The circadian system is composed of a number of feedback loops, and multiple feedback loops in the form of oscillators help to maintain stable rhythms. The filamentous fungus Neurospora crassa exhibits a circadian rhythm during asexual spore formation (conidiation banding) and has a major feedback loop that includes the FREQUENCY (FRQ)/WHITE COLLAR (WC) -1 and -2 oscillator (FWO). A mutation in superoxide dismutase (sod)-1, an antioxidant gene, causes a robust and stable circadian rhythm compared with that of wild-type (Wt). However, the mechanisms underlying the functions of reactive oxygen species (ROS) remain unknown. Here, we show that cellular ROS concentrations change in a circadian manner (ROS oscillation), and the amplitudes of ROS oscillation increase with each cycle and then become steady (ROS homeostasis). The ROS oscillation and homeostasis are produced by the ROS-destroying catalases (CATs) and ROS-generating NADPH oxidase (NOX). cat-1 is also induced by illumination, and it reduces ROS levels. Although ROS oscillation persists in the absence of frq, wc-1 or wc-2, its homeostasis is altered. Furthermore, genetic and biochemical evidence reveals that ROS concentration regulates the transcriptional function of WCC and a higher ROS concentration enhances conidiation banding. These findings suggest that the circadian system engages in cross-talk with the cellular redox state via ROS-regulatory factors

Kinetic Analysis of Substrate Utilization by Native and TNAP-, NPP1-, or PHOSPHO1-Deficient Matrix Vesicles

During the process of endochondral bone formation, chondrocytes and osteoblasts mineralize their extracellular matrix by promoting the formation of hydroxyapatite seed crystals in the sheltered interior of membrane-limited matrix vesicles (MVs). Here, we have studied phosphosubstrate catalysis by osteoblast-derived MVs at physiologic pH, analyzing the hydrolysis of ATP, ADP, and PPi by isolated wild-type (WT) as well as TNAP-, NPP1- and PHOSPHO1-deficient MVs. Comparison of the catalytic efficiencies identified ATP as the main substrate hydrolyzed by WT MVs. The lack of TNAP had the most pronounced effect on the hydrolysis of all physiologic substrates. The lack of PHOSPHO1 affected ATP hydrolysis via a secondary reduction in the levels of TNAP in PHOSPHO1-deficient MVs. The lack of NPP1 did not significantly affect the kinetic parameters of hydrolysis when compared with WT MVs for any of the substrates. We conclude that TNAP is the enzyme that hydrolyzes both ATP and PPi in the MV compartment. NPP1 does not have a major role in PPi generation from ATP at the level of MVs, in contrast to its accepted role on the surface of the osteoblasts and chondrocytes, but rather acts as a phosphatase in the absence of TNAP. © 2010 American Society for Bone and Mineral Research

A High-Level Language for Rule-Based Modelling

Rule-based languages such as Kappa excel in their support for handling the combinatorial complexities prevalent in many biological systems, including signalling pathways. But Kappa provides little structure for organising rules, and large models can therefore be hard to read and maintain. This paper introduces a high-level, modular extension of Kappa called LBS-κ. We demonstrate the constructs of the language through examples and three case studies: a chemotaxis switch ring, a MAPK cascade, and an insulin signalling pathway. We then provide a formal definition of LBS-κ through an abstract syntax and a translation to plain Kappa. The translation is implemented in a compiler tool which is available as a web application. We finally demonstrate how to increase the expressivity of LBS-κ through embedded scripts in a general-purpose programming language, a technique which we view as generally applicable to other domain specific languages

Accelerating functional gene discovery in osteoarthritis.

Osteoarthritis causes debilitating pain and disability, resulting in a considerable socioeconomic burden, yet no drugs are available that prevent disease onset or progression. Here, we develop, validate and use rapid-throughput imaging techniques to identify abnormal joint phenotypes in randomly selected mutant mice generated by the International Knockout Mouse Consortium. We identify 14 genes with functional involvement in osteoarthritis pathogenesis, including the homeobox gene Pitx1, and functionally characterize 6 candidate human osteoarthritis genes in mouse models. We demonstrate sensitivity of the methods by identifying age-related degenerative joint damage in wild-type mice. Finally, we phenotype previously generated mutant mice with an osteoarthritis-associated polymorphism in the Dio2 gene by CRISPR/Cas9 genome editing and demonstrate a protective role in disease onset with public health implications. We hope this expanding resource of mutant mice will accelerate functional gene discovery in osteoarthritis and offer drug discovery opportunities for this common, incapacitating chronic disease

Interaction between valence of empathy and familiarity: is it difficult to empathize with the positive events of a stranger?

Background: Empathy in humans is thought to have evolved via social interactions caused by the formation of social groups. Considering the role of empathy within a social group, there might be a difference between emotional empathy for strangers and familiar others belonging to the same social group. In this study, we used the global field power (GFP) index to investigate empathic brain activity during observation of a cue indicating either a negative or positive image viewed by a stranger or close friend. Methods: Sixteen healthy participants observed a partner performing an emotional gambling task displayed on a monitor. After the partner\u27s choice-response, a frowning or smiling face symbol was simultaneously presented to the participant\u27s monitor while a negative or positive emotional image was presented to the partner\u27s monitor. All participants observed a control condition (CT) showing a computer trial, a stranger-observation condition (SO) showing the trial of a stranger, and a friend-observation condition (FO) to observe the trial of a close friend. During these observations, participants\u27 event-related potentials (ERPs) were recorded to calculate GFP, and after the task, a subjective assessment of their feelings was measured. Results: Positive emotion was significantly larger under the FO compared to the CT and the SO. Significantly larger negative emotion was found under the SO and FO compared to the CT. In response to a positive cue, significantly larger GFP during 300 to 600 ms was observed under the FO compared to the CT and SO. In response to a negative cue, significantly larger GFP was observed under the FO and SO compared to the CT. A significantly larger GFP under the SO was found in response to only a negative cue. Topographic map analysis suggested that these differences were related to frontal-occipital dynamics. GFP was significantly correlated with empathic trait. Conclusion: These results revealed that familiarity with another person has different effects depending on the valence of empathy. Negative empathy, including the danger perception function, might easily occur even among strangers, whereas positive empathy related to nursing and supporting an inner group does not happen easily with strangers

Light regulation of metabolic pathways in fungi

Light represents a major carrier of information in nature. The molecular machineries translating its electromagnetic energy (photons) into the chemical language of cells transmit vital signals for adjustment of virtually every living organism to its habitat. Fungi react to illumination in various ways, and we found that they initiate considerable adaptations in their metabolic pathways upon growth in light or after perception of a light pulse. Alterations in response to light have predominantly been observed in carotenoid metabolism, polysaccharide and carbohydrate metabolism, fatty acid metabolism, nucleotide and nucleoside metabolism, and in regulation of production of secondary metabolites. Transcription of genes is initiated within minutes, abundance and activity of metabolic enzymes are adjusted, and subsequently, levels of metabolites are altered to cope with the harmful effects of light or to prepare for reproduction, which is dependent on light in many cases. This review aims to give an overview on metabolic pathways impacted by light and to illustrate the physiological significance of light for fungi. We provide a basis for assessment whether a given metabolic pathway might be subject to regulation by light and how these properties can be exploited for improvement of biotechnological processes

Autistic children's language imitation shows reduced sensitivity to ostracism

In dialogue, speakers tend to imitate, or align with, a partner’s language choices. Higher levels of alignment facilitate communication and can be elicited by affiliation goals. Since autistic children have interaction and communication impairments, we investigated whether a failure to display affiliative language imitation contributes to their conversational difficulties. We measured autistic children’s lexical alignment with a partner, following an ostracism manipulation which induces affiliative motivation in typical adults and children. While autistic children demonstrated lexical alignment, we observed no affiliative influence on ostracised children’s tendency to align, relative to controls. Our results suggest that increased language imitation—a potentially valuable form of social adaptation—is unavailable to autistic children, which may reflect their impaired affective understanding