Modifiable risk-factors for keratinocyte cancers in Australia: a case-control study

Keratinocyte cancer is the most common malignancy in Caucasians. The aim of this study was to investigate risk-factors responsible for development of keratinocyte cancer in Australia. A case-control study was conducted, including 112 cases of squamous cell carcinoma (SCC), 95 cases of basal cell carcinoma (BCC) and 122 controls. Freckling during adolescence (SCC: odds ratio (OR) 1.04, p < 0.01; BCC: OR 1.05, p < 0.01), propensity to sunburn (SCC: OR 2.75, p = 0.01, BCC: OR 2.68 p = 0.01) and high cumulative sun-exposure (SCC: OR 2.43, p = 0.04; BCC: OR 2.36 p = 0.04) were independent risk-factors for both SCC and BCC. This study provides further evidence that a sun-sensitive phenotype and excessive sun-exposure during adulthood contribute to the risk of developing keratinocyte cancer. Wearing a hat, long-sleeved shirts, and sunscreen did not significantly reduce the risk of keratinocyte cancer in this study

Bridging the gap between systems biology and medicine

Systems biology has matured considerably as a discipline over the last decade, yet some of the key challenges separating current research efforts in systems biology and clinically useful results are only now becoming apparent. As these gaps are better defined, the new discipline of systems medicine is emerging as a translational extension of systems biology. How is systems medicine defined? What are relevant ontologies for systems medicine? What are the key theoretic and methodologic challenges facing computational disease modeling? How are inaccurate and incomplete data, and uncertain biologic knowledge best synthesized in useful computational models? Does network analysis provide clinically useful insight? We discuss the outstanding difficulties in translating a rapidly growing body of data into knowledge usable at the bedside. Although core-specific challenges are best met by specialized groups, it appears fundamental that such efforts should be guided by a roadmap for systems medicine drafted by a coalition of scientists from the clinical, experimental, computational, and theoretic domains

IκB kinase 2 determines oligodendrocyte loss by non-cell-autonomous activation of NF-κB in the central nervous system

The IκB kinase complex induces nuclear factor kappa B activation and has recently been recognized as a key player of autoimmunity in the central nervous system. Notably, IκB kinase/nuclear factor kappa B signalling regulates peripheral myelin formation by Schwann cells, however, its role in myelin formation in the central nervous system during health and disease is largely unknown. Surprisingly, we found that brain-specific IκB kinase 2 expression is dispensable for proper myelin assembly and repair in the central nervous system, but instead plays a fundamental role for the loss of myelin in the cuprizone model. During toxic demyelination, inhibition of nuclear factor kappa B activation by conditional ablation of IκB kinase 2 resulted in strong preservation of central nervous system myelin, reduced expression of proinflammatory mediators and a significantly attenuated glial response. Importantly, IκB kinase 2 depletion in astrocytes, but not in oligodendrocytes, was sufficient to protect mice from myelin loss. Our results reveal a crucial role of glial cell-specific IκB kinase 2/nuclear factor kappa B signalling for oligodendrocyte damage during toxic demyelination. Thus, therapies targeting IκB kinase 2 function in non-neuronal cells may represent a promising strategy for the treatment of distinct demyelinating central nervous system disease

Dust Devil Sediment Transport: From Lab to Field to Global Impact

The impact of dust aerosols on the climate and environment of Earth and Mars is complex and forms a major area of research. A difficulty arises in estimating the contribution of small-scale dust devils to the total dust aerosol. This difficulty is due to uncertainties in the amount of dust lifted by individual dust devils, the frequency of dust devil occurrence, and the lack of statistical generality of individual experiments and observations. In this paper, we review results of observational, laboratory, and modeling studies and provide an overview of dust devil dust transport on various spatio-temporal scales as obtained with the different research approaches. Methods used for the investigation of dust devils on Earth and Mars vary. For example, while the use of imagery for the investigation of dust devil occurrence frequency is common practice for Mars, this is less so the case for Earth. Modeling approaches for Earth and Mars are similar in that they are based on the same underlying theory, but they are applied in different ways. Insights into the benefits and limitations of each approach suggest potential future research focuses, which can further reduce the uncertainty associated with dust devil dust entrainment. The potential impacts of dust devils on the climates of Earth and Mars are discussed on the basis of the presented research results

Screening out irrelevant cell-based models of disease

The common and persistent failures to translate promising preclinical drug candidates into clinical success highlight the limited effectiveness of disease models currently used in drug discovery. An apparent reluctance to explore and adopt alternative cell-and tissue-based model systems, coupled with a detachment from clinical practice during assay validation, contributes to ineffective translational research. To help address these issues and stimulate debate, here we propose a set of principles to facilitate the definition and development of disease-relevant assays, and we discuss new opportunities for exploiting the latest advances in cell-based assay technologies in drug discovery, including induced pluripotent stem cells, three-dimensional (3D) co-culture and organ-on-a-chip systems, complemented by advances in single-cell imaging and gene editing technologies. Funding to support precompetitive, multidisciplinary collaborations to develop novel preclinical models and cell-based screening technologies could have a key role in improving their clinical relevance, and ultimately increase clinical success rates

Modification of Noradrenaline Release in Pithed Spontaneously Hypertensive Rats by I 1 -Binding Sites in Addition to ␣ 2 -Adrenoceptors

ABSTRACT It is known that moxonidine acts as an agonist at presynaptic ␣ 2 -adrenoceptors of the postganglionic sympathetic nerve terminals and leads to a reduction in noradrenaline release. In addition, it is conceivable that I 1 -binding sites located in other regions of the pre-and postganglionic sympathetic neurons are involved in this effect. Our aim was to investigate whether and to what extent activation of the I 1 -binding sites contributes to the moxonidine-induced inhibition of noradrenaline release. Noradrenaline release was induced in pithed spontaneously hypertensive rats (pretreated with phenoxybenzamine/desipramine at 10/0.5 mg/kg) by stimulation of sympathetic overflow from the spinal cord. Noradrenaline overflow was reduced using moxonidine (0.18, 0.6, and 1.8 mg/kg) by 39.4, 70.4, or 78.7%, respectively, even when all ␣ 1 -/␣ 2 -adrenoceptors were blocked effectively by phenoxybenzamine. In contrast, the I 1 -antagonist efaroxan (0.1, 1, and 3 mg/kg) increased noradrenaline overflow from 453 (control) to 1710, 1999, or 2754 pg/ml, suggesting an autoreceptor-like function of I 1 -binding sites. In consequence, moxonidine (0.18, 0.6, and 1.8 mg/kg) reduced the increase in noradrenaline overflow in efaroxan-treated animals (1 mg/kg) by 22.7, 41.7, and 50.5%, respectively. Agmatine (6 and 60 mg/kg), an endogenous agonist at I 1 -binding sites, reduced noradrenaline overflow (Ϫ36 or 53%), even under ␣ 2 -adrenoceptor blockade. When 2-endo-amino-3-exoisopropylbicyclo[2.2.1]heptane (AGN192403) (10 mg/kg) was injected, a selective blocker of I 1 -binding sites, noradrenaline overflow was not influenced by agmatine. It is concluded that moxonidine reduces noradrenaline overflow by acting at I 1 -binding sites in addition to its agonistic property at ␣ 2 -adrenoceptors. The exact location of the I 1 -binding sites on the pre-or postsynaptic sympathetic neurons is unknown, but the location in the pre-or postsynaptic membrane of the sympathetic ganglion is the most plausible explanation. Clonidine and the related compounds moxonidine and rilmenidine that induce inhibition of noradrenaline release from sympathetic neurons are second line antihypertensives. Recently, the presynaptic ␣ 2 -adrenoceptor mediating an inhibition of noradrenaline release from sympathetic nerves at which these compounds act was subclassified as the ␣ 2A -and ␣ 2

Non-coding RNA detection methods combined to improve usability, reproducibility and precision

<p>Abstract</p> <p>Background</p> <p>Non-coding RNAs gain more attention as their diverse roles in many cellular processes are discovered. At the same time, the need for efficient computational prediction of ncRNAs increases with the pace of sequencing technology. Existing tools are based on various approaches and techniques, but none of them provides a reliable ncRNA detector yet. Consequently, a natural approach is to combine existing tools. Due to a lack of standard input and output formats combination and comparison of existing tools is difficult. Also, for genomic scans they often need to be incorporated in detection workflows using custom scripts, which decreases transparency and reproducibility.</p> <p>Results</p> <p>We developed a Java-based framework to integrate existing tools and methods for ncRNA detection. This framework enables users to construct transparent detection workflows and to combine and compare different methods efficiently. We demonstrate the effectiveness of combining detection methods in case studies with the small genomes of <it>Escherichia coli</it>, <it>Listeria monocytogenes </it>and <it>Streptococcus pyogenes</it>. With the combined method, we gained 10% to 20% precision for sensitivities from 30% to 80%. Further, we investigated <it>Streptococcus pyogenes </it>for novel ncRNAs. Using multiple methods--integrated by our framework--we determined four highly probable candidates. We verified all four candidates experimentally using RT-PCR.</p> <p>Conclusions</p> <p>We have created an extensible framework for practical, transparent and reproducible combination and comparison of ncRNA detection methods. We have proven the effectiveness of this approach in tests and by guiding experiments to find new ncRNAs. The software is freely available under the GNU General Public License (GPL), version 3 at <url>http://www.sbi.uni-rostock.de/moses</url> along with source code, screen shots, examples and tutorial material.</p