Response dynamics of phosphorelays suggest their potential utility in cell signalling

Phosphorelays are extended two-component signalling systems found in diverse bacteria, lower eukaryotes and plants. Only few of these systems are characterized, and we still lack a full understanding of their signalling abilities. Here, we aim to achieve a global understanding of phosphorelay signalling and its dynamical properties. We develop a generic model, allowing us to systematically analyse response dynamics under different assumptions. Using this model, we find that the steady-state concentration of phosphorylated protein at the final layer of a phosphorelay is a linearly increasing, but eventually saturating function of the input. In contrast, the intermediate layers can display ultrasensitivity. We find that such ultrasensitivity is a direct result of the phosphorelay biochemistry; shuttling of a single phosphate group from the first to the last layer. The response dynamics of the phosphorelay results in tolerance of cross-talk, especially when it occurs as cross-deactivation. Further, it leads to a high signal-to-noise ratio for the final layer. We find that a relay length of four, which is most commonly observed, acts as a saturating point for these dynamic properties. These findings suggest that phosphorelays could act as a mechanism to reduce noise and effects of cross-talk on the final layer of the relay and enforce its input–response relation to be linear. In addition, our analysis suggests that middle layers of phosphorelays could embed thresholds. We discuss the consequence of these findings in relation to why cells might use phosphorelays along with enzymatic kinase cascades

Depicting a protein's two faces: GPCR classification by phylogenetic tree‐based HMMs

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/116379/1/feb2s0014579303011128.pd

The use of mobile phones for skin tumor screening

A lot of importance is attributed to mobile telemedicine these days, a topic that encompasses a wide and ever growing range of applications. Small, handheld devices such as camera mobile phones have come into every day use providing technically sophisticated tasks on a user-friendly level and can therefore be easily used in various fields of telemedicine. Dermatology is a perfect candidate for the use of telemedicine tools in general, as well as mobile devices in particular. The unique aspect of mobile teledermatology is that this system represents a filtering, or triage system, allowing a sensitive approach for the management of patients with emergent skin diseases. In order to investigate the feasibility of teleconsultation using a new generation of cellular phones, a clinical study to evaluate the accuracy of online diagnosis of skin tumours was conducted. Teledermoscopy represents a recent development of teledermatology that might add up additional information in the diagnosis of pigmented skin lesions. Teledermatology, mobile as well as stationary, can advance the reliability of diagnosis by expert consultations without expensive and time-consuming relocations. Consequently, the quality of patient's care can be raised and the costs of the health care system can be reduced

Teledermatological monitoring of leg ulcers in cooperation with home care nurses

Objectives: To examine the feasibility and acceptance of teledermatology for wound management for patients with leg ulcers by home care nurses and evaluate the reduction of costs and the acceptance of teledermatology by patients and home care nurses

Distribution of subsequent primary invasive melanomas following a first primary invasive OR in situ Melanoma Queensland, Australia, 1982-2010

IMPORTANCE: Melanoma survivors are known to have a highly elevated risk of subsequent primary melanomas. OBJECTIVE: To determine the relative risk of subsequent primary invasive melanomas following a first primary invasive or in situ melanoma, with a focus on body site. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort studywas conducted using population-based administrative data for melanoma diagnoses collected by the Queensland Cancer Registry, Queensland, Australia. Deidentified records of all cases of melanoma among Queensland residents during the period 1982-2005 were obtained and reviewed to December 31, 2010. There were 39 668 eligible cases of first primary invasive melanoma and 22 845 cases of first primary in situ melanoma. MAIN OUTCOMES AND MEASURES: Standardized incidence ratios (SIRs), a proxy measure for relative risk, were calculated by dividing the observed number of subsequent primary invasive melanomas by the product of the strata-specific incidence rates that occurred in the general population and the cumulative time at risk for the cohort. Synchronous subsequent melanomas (diagnosed within 60 days of the first primary melanoma) were excluded. Differences between SIRs were assessed using multivariate negative binomial regression adjusted for sex, age group, time to second diagnosis, and body site and expressed in terms of adjusted SIR ratios with corresponding 95%CIs. RESULTS: There were 5358 subsequent primary invasive melanomas diagnosed, resulting in SIRs of 5.42 (95%CI, 5.23-5.61) and 4.59 (4.37-4.82) for persons with a first primary invasive or in situ melanoma, respectively. The SIRs remained elevated throughout the follow-up period. In general, subsequent primary invasive melanomas were more likely to occur at the same body site as the initial invasive or in situ melanoma. The largest relative risk was for females with a first primary invasive melanoma on the head followed by a subsequent primary invasive melanoma also on the head (SIR, 13.32; 95%CI, 10.28-16.98). CONCLUSIONS AND RELEVANCE: Melanoma survivors require ongoing surveillance, with particular attention required for the body site of the initial lesion. Clinical practice guidelines have recognized the importance of monitoring for people with invasive melanoma; the results of the present study highlight the need for similar levels of supervision for those with a diagnosis of in situ melanoma

Gastrointestinal stenting: Current status and imaging features

AbstractThe use of stents in the gastrointestinal tract has been subjected to major changes. Initially, the use of stents was restricted to malignant strictures in patients with metastatic disease. But thanks to reduction of the morbidity and mortality rates, they are now used with curative intention and in patients with benign diseases after careful selection. However, for patients presenting with colon obstruction due to an advanced colon carcinoma, the mortality and morbidity are still high. The purpose of this review is to provide an overview of indications, techniques and further developments of the stents in the gastrointestinal tract and to highlight the predominant role of multidetector row computed tomography (MDCT) in the detection of potential complications

STRONG: metagenomics strain resolution on assembly graphs

We introduce STrain Resolution ON assembly Graphs (STRONG), which identifies strains de novo, from multiple metagenome samples. STRONG performs coassembly, and binning into metagenome assembled genomes (MAGs), and stores the coassembly graph prior to variant simplification. This enables the subgraphs and their unitig per-sample coverages, for individual single-copy core genes (SCGs) in each MAG, to be extracted. A Bayesian algorithm, BayesPaths, determines the number of strains present, their haplotypes or sequences on the SCGs, and abundances. STRONG is validated using synthetic communities and for a real anaerobic digestor time series generates haplotypes that match those observed from long Nanopore reads

ADC normalization: A promising research track for diffusion-weighted MR imaging of the abdomen

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Three roots of melanoma

Segura et al1 describe morphologic features of melanomas with a nodular component using in vivo reflectance-mode confocal microscopy (RCM) and correlate these RCM findings with histopathologic findings. The most striking observation made by the investigators is the remarkable difference in epidermal involvement between nodular melanoma (NM) and superficial spreading melanoma (SSM) with a nodular component. At RCM, SSMs frequently showed epidermal disarrangement and pagetoid infiltration, whereas NMs exhibited a preserved epidermal pattern and few pagetoid cells.1 This new observation provides fertile ground for revisiting the conventional concept of melanoma development. We propose an alternative hypothesis based on recent observations made in stem cell research and demonstrate how this hypothesis can better account for the observed clinical and epidemiologic differences between melanoma subtypes

Evolution of Taxis Responses in Virtual Bacteria: Non-Adaptive Dynamics

Bacteria are able to sense and respond to a variety of external stimuli, with responses that vary from stimuli to stimuli and from species to species. The best-understood is chemotaxis in the model organism Escherichia coli, where the dynamics and the structure of the underlying pathway are well characterised. It is not clear, however, how well this detailed knowledge applies to mechanisms mediating responses to other stimuli or to pathways in other species. Furthermore, there is increasing experimental evidence that bacteria integrate responses from different stimuli to generate a coherent taxis response. We currently lack a full understanding of the different pathway structures and dynamics and how this integration is achieved. In order to explore different pathway structures and dynamics that can underlie taxis responses in bacteria, we perform a computational simulation of the evolution of taxis. This approach starts with a population of virtual bacteria that move in a virtual environment based on the dynamics of the simple biochemical pathways they harbour. As mutations lead to changes in pathway structure and dynamics, bacteria better able to localise with favourable conditions gain a selective advantage. We find that a certain dynamics evolves consistently under different model assumptions and environments. These dynamics, which we call non-adaptive dynamics, directly couple tumbling probability of the cell to increasing stimuli. Dynamics that are adaptive under a wide range of conditions, as seen in the chemotaxis pathway of E. coli, do not evolve in these evolutionary simulations. However, we find that stimulus scarcity and fluctuations during evolution results in complex pathway dynamics that result both in adaptive and non-adaptive dynamics depending on basal stimuli levels. Further analyses of evolved pathway structures show that effective taxis dynamics can be mediated with as few as two components. The non-adaptive dynamics mediating taxis responses provide an explanation for experimental observations made in mutant strains of E. coli and in wild-type Rhodobacter sphaeroides that could not be explained with standard models. We speculate that such dynamics exist in other bacteria as well and play a role linking the metabolic state of the cell and the taxis response. The simplicity of mechanisms mediating such dynamics makes them a candidate precursor of more complex taxis responses involving adaptation. This study suggests a strong link between stimulus conditions during evolution and evolved pathway dynamics. When evolution was simulated under conditions of scarce and fluctuating stimulus conditions, the evolved pathway contained features of both adaptive and non-adaptive dynamics, suggesting that these two types of dynamics can have different advantages under distinct environmental circumstances