A Novel Biosynthetic Gene Cluster Across the Species Complex Is Important for Pathogenicity in Onion.

Onion center rot is caused by at least four species of genus (, , , and subsp). Critical onion pathogenicity determinants for were recently described, but whether those determinants are common among other onion-pathogenic species remains unknown. In this work, we report onion pathogenicity determinants in subsp and We identified two distinct secondary metabolite biosynthetic gene clusters present separately in different strains of onion-pathogenic subsp.

Identifying prognostic structural features in tissue sections of colon cancer patients using point pattern analysis.

Diagnosis and prognosis of cancer are informed by the architecture inherent in cancer patient tissue sections. This architecture is typically identified by pathologists, yet advances in computational image analysis facilitate quantitative assessment of this structure. In this article, we develop a spatial point process approach to describe patterns in cell distribution within tissue samples taken from colorectal cancer (CRC) patients.

Evidences of strong sources of DFe and DMn in Ryder Bay, Western Antarctic Peninsula.

The spatial distribution, biogeochemical cycling and external sources of dissolved iron and dissolved manganese (DFe and DMn) were investigated in Ryder Bay, a small coastal embayment of the West Antarctic Peninsula, during Austral summer (2013 and 2014). Dissolved concentrations were measured throughout the water column at 11 stations within Ryder Bay. The concentration ranges of DFe and DMn were large, between 0.

Towards the elimination of paediatric tuberculosis in high-income, immigrant-receiving countries: a 25-year conventional and molecular epidemiological case study.

The epidemiology of tuberculosis (TB) in high-income countries is increasingly dictated by immigration. The influence of this trend on paediatric TB and TB elimination are not well defined. We undertook a 25-year conventional and molecular epidemiologic study of paediatric TB in Alberta, one of four major immigrant-receiving provinces in Canada.

NRF2 Regulates HER1 Signaling Pathway to Modulate the Sensitivity of Ovarian Cancer Cells to Lapatinib and Erlotinib.

NF-E2-related factor 2 (NRF2) regulates the transcription of a battery of metabolic and cytoprotective genes. NRF2 and epidermal growth factor receptors (EGFRs/HERs) are regulators of cellular proliferation and determinants of cancer initiation and progression. NRF2 and HERs confer cancers with resistance to several therapeutic agents.

Kinetic modelling of in vitro data of PI3K, mTOR1, PTEN enzymes and on-target inhibitors Rapamycin, BEZ235, and LY294002.

The phosphatidylinositide 3-kinases (PI3K) and mammalian target of rapamycin-1 (mTOR1) are two key targets for anti-cancer therapy. Predicting the response of the PI3K/AKT/mTOR1 signalling pathway to targeted therapy is made difficult because of network complexities. Systems biology models can help explore those complexities but the value of such models is dependent on accurate parameterisation.

A novel mechanism of action of HER2 targeted immunotherapy is explained by inhibition of NRF2 function in ovarian cancer cells.

Nuclear erythroid related factor-2 (NRF2) is known to promote cancer therapeutic detoxification and crosstalk with growth promoting pathways. HER2 receptor tyrosine kinase is frequently overexpressed in cancers leading to uncontrolled receptor activation and signaling. A combination of HER2 targeting monoclonal antibodies shows greater anticancer efficacy than the single targeting antibodies, however, its mechanism of action is largely unclear.

A signaling visualization toolkit to support rational design of combination therapies and biomarker discovery: SiViT.

Targeted cancer therapy aims to disrupt aberrant cellular signalling pathways. Biomarkers are surrogates of pathway state, but there is limited success in translating candidate biomarkers to clinical practice due to the intrinsic complexity of pathway networks. Systems biology approaches afford better understanding of complex, dynamical interactions in signalling pathways targeted by anticancer drugs.

NRF2 Regulates HER2 and HER3 Signaling Pathway to Modulate Sensitivity to Targeted Immunotherapies.

NF-E2 related factor-2 (NRF2) is an essential transcription factor for multiple genes encoding antioxidants and detoxification enzymes. NRF2 is implicated in promoting cancer therapeutic resistance by its detoxification function and crosstalk with proproliferative pathways. However, the exact mechanism of this intricate connectivity between NRF2 and growth factor induced proliferative pathway remains elusive.

Quantitative analysis of NRF2 pathway reveals key elements of the regulatory circuits underlying antioxidant response and proliferation of ovarian cancer cells.

Cells are constantly exposed to Reactive Oxygen Species (ROS) produced both endogenously to meet physiological requirements and from exogenous sources. While endogenous ROS are considered as important signalling molecules, high uncontrollable ROS are detrimental. It is unclear how cells can achieve a balance between maintaining physiological redox homeostasis and robustly activate the antioxidant system to remove exogenous ROS.

Systems analysis of drug-induced receptor tyrosine kinase reprogramming following targeted mono- and combination anti-cancer therapy.

The receptor tyrosine kinases (RTKs) are key drivers of cancer progression and targets for drug therapy. A major challenge in anti-RTK treatment is the dependence of drug effectiveness on co-expression of multiple RTKs which defines resistance to single drug therapy. Reprogramming of the RTK network leading to alteration in RTK co-expression in response to drug intervention is a dynamic mechanism of acquired resistance to single drug therapy in many cancers.

Evidence for the use of dry needling and physiotherapy in the management of cervicogenic or tension-type headache: a systematic review.

Background: There is good evidence in the literature supporting physiotherapy in the management of some forms of headache. Dry needling of myofascial trigger points is becoming an increasingly common approach despite a paucity of research evidence supporting its use. The purpose of this review was to determine the evidence supporting the use of dry needling in addition to conventional physiotherapy in the management of tension-type and cervicogenic headache.

Customizing the therapeutic response of signaling networks to promote antitumor responses by drug combinations.

Drug resistance, de novo and acquired, pervades cellular signaling networks (SNs) from one signaling motif to another as a result of cancer progression and/or drug intervention. This resistance is one of the key determinants of efficacy in targeted anti-cancer drug therapy. Although poorly understood, drug resistance is already being addressed in combination therapy by selecting drug targets where SN sensitivity increases due to combination components or as a result of de novo or acquired mutations.

Feedforward and feedback regulation of the MAPK and PI3K oscillatory circuit in breast cancer.

Although the theoretical possibility of oscillations in MAPK signalling has long been described, experimental validation has proven more elusive. In this study we observed oscillations in MAPK and PI3K signalling in breast cancer cells in response to epidermal growth factor receptor-family stimulation. Using systems level analysis with a kinetic model, we demonstrate that receptor amplification, loss of transcriptional feedback, or pathway crosstalk, are responsible for oscillations in MAPK and PI3K signalling.

Engineering simulations for cancer systems biology.

Computer simulation can be used to inform in vivo and in vitro experimentation, enabling rapid, low-cost hypothesis generation and directing experimental design in order to test those hypotheses. In this way, in silico models become a scientific instrument for investigation, and so should be developed to high standards, be carefully calibrated and their findings presented in such that they may be reproduced. Here, we outline a framework that supports developing simulations as scientific instruments, and we select cancer systems biology as an exemplar domain, with a particular focus on cellular signalling models.

Characterising the tumour morphological response to therapeutic intervention: an ex vivo model.

In cancer, morphological assessment of histological tissue samples is a fundamental part of both diagnosis and prognosis. Image analysis offers opportunities to support that assessment through quantitative metrics of morphology. Generally, morphometric analysis is carried out on two-dimensional tissue section data and so only represents a small fraction of any tumour.

Features of the reversible sensitivity-resistance transition in PI3K/PTEN/AKT signalling network after HER2 inhibition.

Systems biology approaches that combine experimental data and theoretical modelling to understand cellular signalling network dynamics offer a useful platform to investigate the mechanisms of resistance to drug interventions and to identify combination drug treatments. Extending our work on modelling the PI3K/PTEN/AKT signalling network (SN), we analyse the sensitivity of the SN output signal, phospho-AKT, to inhibition of HER2 receptor. We model typical aberrations in this SN identified in cancer development and drug resistance: loss of PTEN activity, PI3K and AKT mutations, HER2 overexpression, and overproduction of GSK3β and CK2 kinases controlling PTEN phosphorylation.

Modelling of healthcare-associated infections: a study on the dynamics of pathogen transmission by using an individual-based approach.

Prevention and control of Healthcare Associated Infections (HAIs) has become a high priority for most healthcare organizations. Mathematical models can provide insights into the dynamics of nosocomial infections and help to evaluate the effect of infection control measures. The model presented in this paper adopts an individual-based and stochastic approach to investigate MRSA outbreaks in a hospital ward.

Modelling fungal colonies and communities: challenges and opportunities.

This contribution, based on a Special Interest Group session held during IMC9, focuses on physiological based models of filamentous fungal colony growth and interactions. Fungi are known to be an important component of ecosystems, in terms of colony dynamics and interactions within and between trophic levels. We outline some of the essential components necessary to develop a fungal ecology: a mechanistic model of fungal colony growth and interactions, where observed behaviour can be linked to underlying function; a model of how fungi can cooperate at larger scales; and novel techniques for both exploring quantitatively the scales at which fungi operate; and addressing the computational challenges arising from this highly detailed quantification.

Compensatory effects in the PI3K/PTEN/AKT signaling network following receptor tyrosine kinase inhibition.

Overcoming de novo and acquired resistance to anticancer drugs that target signaling networks is a formidable challenge for drug design and effective cancer therapy. Understanding the mechanisms by which this resistance arises may offer a route to addressing the insensitivity of signaling networks to drug intervention and restore the efficacy of anticancer therapy. Extending our recent work identifying PTEN as a key regulator of Herceptin sensitivity, we present an integrated theoretical and experimental approach to study the compensatory mechanisms within the PI3K/PTEN/AKT signaling network that afford resistance to receptor tyrosine kinase (RTK) inhibition by anti-HER2 monoclonal antibodies.

Cancer systems biology.

Cancer is a complex and heterogeneous disease, not only at a genetic and biochemical level, but also at a tissue, organism, and population level. Multiple data streams, from reductionist biochemistry in vitro to high-throughput "-omics" from clinical material, have been generated with the hope that they encode useful information about phenotype and, ultimately, tumour behaviour in response to drugs. While these data stand alone in terms of the biology they represent, there is the enticing prospect that if incorporated into systems biology models, they can help understand complex systems behaviour and provide a predictive framework as an additional tool in understanding how tumours change and respond to treatment over time.

A novel ataxia-telangiectasia mutated autoregulatory feedback mechanism in murine embryonic stem cells.

Ataxia-telangiectasia mutated (ATM) is known to play a central role in effecting the DNA damage response that protects somatic cells from potentially harmful mutations, and in this role it is a key anti-cancer agent. However, it also promotes repair of therapeutic damage (e.g.

Modelling interactions in fungi.

Indeterminate organisms have received comparatively little attention in theoretical ecology and still there is much to be understood about the origins and consequences of community structure. The fungi comprise an entire kingdom of life and epitomize the indeterminate growth form. While interactions play a significant role in shaping the community structure of indeterminate organisms, to date most of our knowledge relating to fungi comes from observing interaction outcomes between two species in two-dimensional arena experiments.

Prolactin upregulates its receptors and inhibits lipolysis and leptin release in male rat adipose tissue.

Prolactin (PRL) is recognized as a metabolic regulator during lactation, but little information exists on its actions in male adipose tissue. We examined whether PRL affects the expression of its receptors (PRLR), lipolysis, and adipokine secretion in male rats. Both long and short PRLR isoforms were induced 40-50-fold during differentiation of epididymal preadipocytes, with a 10-fold higher expression of the long isoform.