Predicting Phenotypic Diversity and the Underlying Quantitative Molecular Transitions

During development, signaling networks control the formation of multicellular patterns. To what extent quantitative fluctuations in these complex networks may affect multicellular phenotype remains unclear. Here, we describe a computational approach to predict and analyze the phenotypic diversity that is accessible to a developmental signaling network. Applying this framework to vulval development in C. elegans, we demonstrate that quantitative changes in the regulatory network can render ~500 multicellular phenotypes. This phenotypic capacity is an order-of-magnitude below the theoretical upper limit for this system but yet is large enough to demonstrate that the system is not restricted to a select few outcomes. Using metrics to gauge the robustness of these phenotypes to parameter perturbations, we identify a select subset of novel phenotypes that are the most promising for experimental validation. In addition, our model calculations provide a layout of these phenotypes in network parameter space. Analyzing this landscape of multicellular phenotypes yielded two significant insights. First, we show that experimentally well-established mutant phenotypes may be rendered using non-canonical network perturbations. Second, we show that the predicted multicellular patterns include not only those observed in C. elegans, but also those occurring exclusively in other species of the Caenorhabditis genus. This result demonstrates that quantitative diversification of a common regulatory network is indeed demonstrably sufficient to generate the phenotypic differences observed across three major species within the Caenorhabditis genus. Using our computational framework, we systematically identify the quantitative changes that may have occurred in the regulatory network during the evolution of these species. Our model predictions show that significant phenotypic diversity may be sampled through quantitative variations in the regulatory network without overhauling the core network architecture. Furthermore, by comparing the predicted landscape of phenotypes to multicellular patterns that have been experimentally observed across multiple species, we systematically trace the quantitative regulatory changes that may have occurred during the evolution of the Caenorhabditis genus

Accuracy and repeatability of wrist joint angles in boxing using an electromagnetic tracking system

© 2019, The Author(s). The hand-wrist region is reported as the most common injury site in boxing. Boxers are at risk due to the amount of wrist motions when impacting training equipment or their opponents, yet we know relatively little about these motions. This paper describes a new method for quantifying wrist motion in boxing using an electromagnetic tracking system. Surrogate testing procedure utilising a polyamide hand and forearm shape, and in vivo testing procedure utilising 29 elite boxers, were used to assess the accuracy and repeatability of the system. 2D kinematic analysis was used to calculate wrist angles using photogrammetry, whilst the data from the electromagnetic tracking system was processed with visual 3D software. The electromagnetic tracking system agreed with the video-based system (paired t tests) in both the surrogate ( 0.9). In the punch testing, for both repeated jab and hook shots, the electromagnetic tracking system showed good reliability (ICCs > 0.8) and substantial reliability (ICCs > 0.6) for flexion–extension and radial-ulnar deviation angles, respectively. The results indicate that wrist kinematics during punching activities can be measured using an electromagnetic tracking system

The infuence of skin colour on the experience of ownership in the rubber hand illusion

Racial prejudice is associated with a fundamental distinction between "us" and "them"-a distinction linked to the perceived overlap between representations of the self and others. Implicit prejudice has been shown to reduce the intensity of White individuals' hand ownership sensation as induced by the Rubber Hand Illusion (RHI) with dark rubber hands. However, evidence for this link to implicit prejudice comes from self-report questionnaire data regarding the RHI. As an alternative, we assessed the onset time of the RHI. We hypothesized that onset time of the RHI would be higher for the black compared to the white RH, acting as the mediator between implicit prejudice and magnitude of the RH illusion and proprioceptive drift. As expected, participants took longer to incorporate the black RH and presented lower RH illusion magnitude and a smaller proprioceptive drift for the black RH. Mediation analysis revealed a significant indirect effect of implicit racial bias on proprioceptive drift and magnitude of illusion through onset time to illusion only for the black RH. These findings further illuminate the connection between implicit prejudice and embodied perception, suggesting new perspectives on how implicit biases operate.This work was supported by Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq; grant numbers: 466922/2014-0 and 401143/2014-7).info:eu-repo/semantics/publishedVersio

The Working After Cancer Study (WACS): a population-based study of middle-aged workers diagnosed with colorectal cancer and their return to work experiences

<p>Abstract</p> <p>Background</p> <p>The number of middle-aged working individuals being diagnosed with cancer is increasing and so too will disruptions to their employment. The aim of the Working After Cancer Study is to examine the changes to work participation in the 12 months following a diagnosis of primary colorectal cancer. The study will identify barriers to work resumption, describe limitations on workforce participation, and evaluate the influence of these factors on health-related quality of life.</p> <p>Methods/Design</p> <p>An observational population-based study has been designed involving 260 adults newly-diagnosed with colorectal cancer between January 2010 and September 2011 and who were in paid employment at the time they were diagnosed. These cancer cases will be compared to a nationally representative comparison group of 520 adults with no history of cancer from the general population. Eligible cases will have a histologically confirmed diagnosis of colorectal cancer and will be identified through the Queensland Cancer Registry. Data on the comparison group will be drawn from the Household, Income and Labour Dynamics in Australia (HILDA) Survey. Data collection for the cancer group will occur at 6 and 12 months after diagnosis, with work questions also asked about the time of diagnosis, while retrospective data on the comparison group will be come from HILDA Waves 2009 and 2010. Using validated instruments administered via telephone and postal surveys, data will be collected on socio-demographic factors, work status and circumstances, and health-related quality of life (HRQoL) for both groups while the cases will have additional data collected on cancer treatment and symptoms, work productivity and cancer-related HRQoL. Primary outcomes include change in work participation at 12 months, time to work re-entry, work limitations and change in HRQoL status.</p> <p>Discussion</p> <p>This study will address the reasons for work cessation after cancer, the mechanisms people use to remain working and existing workplace support structures and the implications for individuals, families and workplaces. It may also provide key information for governments on productivity losses.</p> <p>Study Registration</p> <p>Australian and New Zealand Clinical Trial Registry No. <a href="http://www.anzctr.org.au/ACTRN12611000530921.aspx">ACTRN12611000530921</a></p

The ability of thiourea to scavenge hydrogen peroxide and hydroxyl radicals during the intra-coronal bleaching of bloodstained root-filled teeth

The document attached has been archived with permission from the Australian Dental Association. An external link to the publisher’s copy is included.Background: Hydrogen peroxide, an agent used in the intra-coronal bleaching of root-filled teeth for over a century, has been shown to diffuse from the pulp chamber to the outer root surface. Furthermore, it has been demonstrated that destructive hydroxyl radicals, the by-products of the bleaching process, have been detected on the external root surface. The control of such diffusion may be of importance in minimizing the risk of invasive cervical resorption (ICR) which has been linked to intra-coronal bleaching of discoloured root-filled teeth using hydrogen peroxide. The aims of the present in vitro study are to quantify the diffusion of hydrogen peroxide and hydroxyl radicals to the outer root surface following intra-coronal bleaching, and to evaluate the ability of thiourea incorporated into the bleaching protocol to scavenge residual hydrogen peroxide and hydroxyl radicals. Methods: Thirty-five single rooted premolar teeth with intact cementum at the cemento-enamel junction were used in this project. Thirty teeth were stained with red blood cells and root-filled with gutta-percha and AH26. The five unstained teeth were root-filled and constituted a negative control (Group 1). The stained teeth were divided equally into the following experimental groups and subjected to various intra-coronal bleaching regimes: Group 2 – ‘walking bleach’ with 20μl 30 per cent w/w hydrogen peroxide; Group 3 – 20μl 30 per cent w/w hydrogen peroxide and thermocatalytically activated; Group 4 – 20μl acidified thiourea; Group 5 – 20μl acidified thiourea and 20μl 30 per cent w/w hydrogen peroxide; Group 6 – 20μl acidified thiourea and 20μl one per cent sodium hypochlorite; Group 7 – 20μl acidified thiourea, 20μl one per cent sodium hypochlorite and 20μl 30 per cent w/w hydrogen peroxide. The reaction products of the bleaching process were quantified at the outer root surface using high performance liquid chromatography and electrochemical detection (HPLC-ECD).Results: Results showed that hydrogen peroxide used alone in Groups 2 and 3 was able to be detected at the outer root surface in 100 per cent of the samples, and that the presence of the hydroxyl radical generated in both groups was detected in equal amounts (P<0.05). When thiourea was incorporated into the bleaching protocols in Groups 5–7, it was shown to scavenge both hydrogen peroxide and hydroxyl radicals to a significant degree (P<0.05). Conclusions: Acidulated thiourea is an effective scavenger of residual hydrogen peroxide and hydroxyl radicals generated during the intra-coronal bleaching of bloodstained root-filled teeth.DS Farmer, P Burcham, PD Mari

Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress

In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced reinstatement of drug seeking. Here, we first discuss the generality of stress-induced reinstatement to different drugs of abuse, different stressors, and different behavioral procedures. We also discuss neuropharmacological mechanisms, and brain areas and circuits controlling stress-induced reinstatement of drug seeking. We conclude by discussing results from translational human laboratory studies and clinical trials that were inspired by results from rat studies on stress-induced reinstatement. Our main conclusions are (1) The phenomenon of stress-induced reinstatement, first shown with an intermittent footshock stressor in rats trained to self-administer heroin, generalizes to other abused drugs, including cocaine, methamphetamine, nicotine, and alcohol, and is also observed in the conditioned place preference model in rats and mice. This phenomenon, however, is stressor specific and not all stressors induce reinstatement of drug seeking. (2) Neuropharmacological studies indicate the involvement of corticotropin-releasing factor (CRF), noradrenaline, dopamine, glutamate, kappa/dynorphin, and several other peptide and neurotransmitter systems in stress-induced reinstatement. Neuropharmacology and circuitry studies indicate the involvement of CRF and noradrenaline transmission in bed nucleus of stria terminalis and central amygdala, and dopamine, CRF, kappa/dynorphin, and glutamate transmission in other components of the mesocorticolimbic dopamine system (ventral tegmental area, medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens). (3) Translational human laboratory studies and a recent clinical trial study show the efficacy of alpha-2 adrenoceptor agonists in decreasing stress-induced drug craving and stress-induced initial heroin lapse

OrthoList: A Compendium of C. elegans Genes with Human Orthologs

C. elegans is an important model for genetic studies relevant to human biology and disease. We sought to assess the orthology between C. elegans and human genes to understand better the relationship between their genomes and to generate a compelling list of candidates to streamline RNAi-based screens in this model.We performed a meta-analysis of results from four orthology prediction programs and generated a compendium, "OrthoList", containing 7,663 C. elegans protein-coding genes. Various assessments indicate that OrthoList has extensive coverage with low false-positive and false-negative rates. Part of this evaluation examined the conservation of components of the receptor tyrosine kinase, Notch, Wnt, TGF-ß and insulin signaling pathways, and led us to update compendia of conserved C. elegans kinases, nuclear hormone receptors, F-box proteins, and transcription factors. Comparison with two published genome-wide RNAi screens indicated that virtually all of the conserved hits would have been obtained had just the OrthoList set (∼38% of the genome) been targeted. We compiled Ortholist by InterPro domains and Gene Ontology annotation, making it easy to identify C. elegans orthologs of human disease genes for potential functional analysis.We anticipate that OrthoList will be of considerable utility to C. elegans researchers for streamlining RNAi screens, by focusing on genes with apparent human orthologs, thus reducing screening effort by ∼60%. Moreover, we find that OrthoList provides a useful basis for annotating orthology and reveals more C. elegans orthologs of human genes in various functional groups, such as transcription factors, than previously described

A novel human skin chamber model to study wound infection ex vivo

Wound infections with multi-drug resistant bacteria increase morbidity and mortality and have considerable socioeconomic impact. They can lead to impaired wound healing, resulting in rising treatment costs. The aim of this study was to investigate an ex vivo human wound infection model. Human full-thickness skin from the operating room (OR) was placed into the Bo-Drum® and cultivated for 7 days in an air–liquid interphase. On day 8, the skin was inoculated with either (1) Pseudomonas aeruginosa, (2) Staphylococcus aureus (105 CFU, n = 3) or (3) carrier control. 1, 3 and 7 days after inoculation colony forming units in the tissue/media were determined and cytokine expression was quantified. A reliable and reproducible wound infection could be established for 7 days. At this timepoint, 1.8 × 108 CFU/g tissue of P. aeruginosa and 2 × 107 CFU/g tissue of S. aureus were detected. Immunohistochemical analysis demonstrated bacterial infection and epidermolysis in infected skin. RT-PCR analysis exhibited a significant induction of proinflammatory cytokines after infection. The BO-drum® is a robust, easy-to-use, sterilizable and reusable ex vivo full-skin culture system. For investigation of wound infection, treatment and healing, the BO-drum® presents a convenient model and may help to standardize wound research