Cell-scale degradation of peritumoural extracellular matrix fibre network and its role within tissue-scale cancer invasion

Local cancer invasion of tissue is a complex, multiscale process which plays an essential role in tumour progression. Occurring over many different temporal and spatial scales, the first stage of invasion is the secretion of matrix degrading enzymes (MDEs) by the cancer cells that consequently degrade the surrounding extracellular matrix (ECM). This process is vital for creating space in which the cancer cells can progress and it is driven by the activities of specific matrix metalloproteinases (MMPs). In this paper, we consider the key role of two MMPs by developing further the novel two-part multiscale model introduced in [33] to better relate at micro-scale the two micro-scale activities that were considered there, namely, the micro-dynamics concerning the continuous rearrangement of the naturally oriented ECM fibres within the bulk of the tumour and MDEs proteolytic micro-dynamics that take place in an appropriate cell-scale neighbourhood of the tumour boundary. Focussing primarily on the activities of the membrane-tethered MT1-MMP and the soluble MMP-2 with the fibrous ECM phase, in this work we investigate the MT1-MMP/MMP-2 cascade and its overall effect on tumour progression. To that end, we will propose a new multiscale modelling framework by considering the degradation of the ECM fibres not only to take place at macro-scale in the bulk of the tumour but also explicitly in the micro-scale neighbourhood of the tumour interface as a consequence of the interactions with molecular fluxes of MDEs that exercise their spatial dynamics at the invasive edge of the tumour

Functional identity versus species richness: herbivory resistance in plant communities

The resistance of a plant community against herbivore attack may depend on plant species richness, with monocultures often much more severely affected than mixtures of plant species. Here, we used a plant–herbivore system to study the effects of selective herbivory on consumption resistance and recovery after herbivory in 81 experimental grassland plots. Communities were established from seed in 2002 and contained 1, 2, 4, 8, 16 or 60 plant species of 1, 2, 3 or 4 functional groups. In 2004, pairs of enclosure cages (1 m tall, 0.5 m diameter) were set up on all 81 plots. One randomly selected cage of each pair was stocked with 10 male and 10 female nymphs of the meadow grasshopper, Chorthippus parallelus. The grasshoppers fed for 2 months, and the vegetation was monitored over 1 year. Consumption resistance and recovery of vegetation were calculated as proportional changes in vegetation biomass. Overall, grasshopper herbivory averaged 6.8%. Herbivory resistance and recovery were influenced by plant functional group identity, but independent of plant species richness and number of functional groups. However, herbivory induced shifts in vegetation composition that depended on plant species richness. Grasshopper herbivory led to increases in herb cover at the expense of grasses. Herb cover increased more strongly in species-rich mixtures. We conclude that selective herbivory changes the functional composition of plant communities and that compositional changes due to selective herbivory depend on plant species richness

Degradation of Cdc25A by \u3b2-TrCP during S phase and in response to DNA damage

The Cdc25A phosphatase is essential for cell-cycle progression because of its function in dephosphorylating cyclin-dependent kinases. In response to DNA damage or stalled replication, the ATM and ATR protein kinases activate the checkpoint kinases Chk1 and Chk2, which leads to hyperphosphorylation of Cdc25A1\u20133. These events stimulate the ubiquitin-mediated pro- teolysis of Cdc25A1,4,5 and contribute to delaying cell-cycle progression, thereby preventing genomic instability1\u20137. Here we report that b-TrCP is the F-box protein that targets phosphory- lated Cdc25A for degradation by the Skp1/Cul1/F-box protein complex. Downregulation of b-TrCP1 and b-TrCP2 expression by short interfering RNAs causes an accumulation of Cdc25A in cells progressing through S phase and prevents the degradation of Cdc25A induced by ionizing radiation, indicating that b-TrCP may function in the intra-S-phase checkpoint. Consistent with this hypothesis, suppression of b-TrCP expression results in radioresistant DNA synthesis in response to DNA damage\u2014a phenotype indicative of a defect in the intra-S-phase checkpoint that is associated with an inability to regulate Cdc25A properly. Our results show that b-TrCP has a crucial role in mediating the response to DNA damage through Cdc25A degradation

Transplacental Passage of Interleukins 4 and 13?

The mechanisms by which prenatal events affect development of adult disease are incompletely characterized. Based on findings in a murine model of maternal transmission of asthma risk, we sought to test the role of the pro-asthmatic cytokines interleukin IL-4 and -13. To assess transplacental passage of functional cytokines, we assayed phosphorylation of STAT-6, a marker of IL-4 and -13 signaling via heterodimeric receptor complexes which require an IL-4 receptor alpha subunit. IL-4 receptor alpha−/− females were mated to wild-type males, and pregnant females were injected with supraphysiologic doses of IL-4 or 13. One hour after injection, the receptor heterozygotic embryos were harvested and tissue nuclear proteins extracts assayed for phosphorylation of STAT-6 by Western blot. While direct injection of embryos produced a robust positive control, no phosphorylation was seen after maternal injection with either IL-4 or -13, indicating that neither crossed the placenta in detectable amounts. The data demonstrate a useful approach to assay for transplacental passage of functional maternal molecules, and indicate that molecules other than IL-4 and IL-13 may mediate transplacental effects in maternal transmission of asthma risk

Recommendations for the design of therapeutic trials for neonatal seizures

Although seizures have a higher incidence in neonates than any other age group and are associated with significant mortality and neurodevelopmental disability, treatment is largely guided by physician preference and tradition, due to a lack of data from welldesigned clinical trials. There is increasing interest in conducting trials of novel drugs to treat neonatal seizures, but the unique characteristics of this disorder and patient population require special consideration with regard to trial design. The Critical Path Institute formed a global working group of experts and key stakeholders from academia, the pharmaceutical industry, regulatory agencies, neonatal nurse associations, and patient advocacy groups to develop consensus recommendations for design of clinical trials to treat neonatal seizures. The broad expertise and perspectives of this group were invaluable in developing recommendations addressing: (1) use of neonate-specific adaptive trial designs, (2) inclusion/exclusion criteria, (3) stratification and randomization, (4) statistical analysis, (5) safety monitoring, and (6) definitions of important outcomes. The guidelines are based on available literature and expert consensus, pharmacokinetic analyses, ethical considerations, and parental concerns. These recommendations will ultimately facilitate development of a Master Protocol and design of efficient and successful drug trials to improve the treatment and outcome for this highly vulnerable population

Responsible management: Engaging moral reflexive practice through threshold concepts

YesIn this conceptual paper we argue that, to date, principles of responsible management have not impacted practice as anticipated because of a disconnect between knowledge and practice. This disconnect means that an awareness of ethical concerns, by itself, does not help students take personal responsibility for their actions. We suggest that an abstract knowledge of principles has to be supplemented by an engaged understanding of the responsibility of managers and leaders to actively challenge irresponsible practices. We argue that a form of moral reflexive practice drawing on an understanding of threshold concepts is central to responsible management, and provides a gateway to transformative learning. Our conceptual argument leads to implications for management and professional education

Evidence of Increased Muscle Atrophy and Impaired Quality of Life Parameters in Patients with Uremic Restless Legs Syndrome

BACKGROUND: Restless Legs Syndrome is a very common disorder in hemodialysis patients. Restless Legs Syndrome negatively affects quality of life; however it is not clear whether this is due to mental or physical parameters and whether an association exists between the syndrome and parameters affecting survival. METHOD#ENTITYSTARTX003BF;LOGY/PRINCIPAL FINDINGS: Using the Restless Legs Syndrome criteria and the presence of Periodic Limb Movements in Sleep (PLMS/h >15), 70 clinically stable hemodialysis patients were assessed and divided into the RLS (n = 30) and non-RLS (n = 40) groups. Physical performance was evaluated by a battery of tests: body composition by dual energy X ray absorptiometry, muscle size and composition by computer tomography, while depression symptoms, perception of sleep quality and quality of life were assessed through validated questionnaires. In this cross sectional analysis, the RLS group showed evidence of thigh muscle atrophy compared to the non-RLS group. Sleep quality and depression score were found to be significantly impaired in the RLS group. The mental component of the quality of life questionnaire appeared significantly diminished in the RLS group, reducing thus the overall quality of life score. In contrast, there were no significant differences between groups in any of the physical performance tests, body and muscle composition. CONCLUSIONS: The low level of quality of life reported by the HD patients with Restless Legs Syndrome seems to be due mainly to mental health and sleep related aspects. Increased evidence of muscle atrophy is also observed in the RLS group and possibly can be attributed to the lack of restorative sleep

Soluble CD36 Ectodomain Binds Negatively Charged Diacylglycerol Ligands and Acts as a Co-Receptor for TLR2

BACKGROUND:Cluster of differentiation 36 (CD36) is a transmembrane glycoprotein involved in many biological processes, such as platelet biology, angiogenesis and in the aetiopathology of atherosclerosis and cardiovascular diseases. Toll-like receptors (TLRs) are one of the most important receptors of the innate immune system. Their main function is the recognition of conserved structure of microorganisms. This recognition triggers signaling pathways that activate transcription of cytokines and co-stimulatory molecules which participate in the generation of an immune response against microbes. In particular, TLR2 has been shown to recognize a broad range of ligands. Recently, we showed that CD36 serves as a co-receptor for TLR2 and enhances recognition of specific diacylglycerides derived from bacteria. METHODOLOGY/ PRINCIPAL FINDINGS:Here, we investigate the mechanism by which CD36 contributes to ligand recognition and activation of TLR2 signaling pathway. We show that the ectodomain of murine CD36 (mCD36ED) directly interacts with negatively charged diacylglycerol ligands, which explains the specificity and selectivity of CD36 as a TLR2 co-receptor. We also show that mCD36ED amplifies the pro-inflammatory response to lipoteichoic acid in macrophages of wild-type mice and restores the pro-inflammatory response of macrophages from mice deficient in CD36 (oblivious), but not from mice deficient in cluster of differentiation 14 (CD14) (heedless). CONCLUSION/ SIGNIFICANCE: These data indicate that the CD36 ectodomain is the only relevant domain for activation of TLR2 signaling pathway and that CD36 and CD14 have a non-redundant role for loading ligands onto TLR2 in the plasma-membrane. The pro-inflammatory role of soluble CD36 can be relevant in the activation of the immune response against pathogens, as well as in the progression of chronic diseases. Therefore, an increased level of soluble forms of CD36, which has been reported to be increased in type II diabetic patients, could accelerate atherosclerosis by increasing the pro-inflammatory response to diacylglycerol ligands

Ice sheets as a missing source of silica to the polar oceans

Ice sheets play a more important role in the global silicon cycle than previously appreciated. Input of dissolved and amorphous particulate silica into natural waters stimulates the growth of diatoms. Here we measure dissolved and amorphous silica in Greenland Ice Sheet meltwaters and icebergs, demonstrating the potential for high ice sheet export. Our dissolved and amorphous silica flux is 0.20 (0.06-0.79) Tmol year(-1), ∼50% of the input from Arctic rivers. Amorphous silica comprises >95% of this flux and is highly soluble in sea water, as indicated by a significant increase in dissolved silica across a fjord salinity gradient. Retreating palaeo ice sheets were therefore likely responsible for high dissolved and amorphous silica fluxes into the ocean during the last deglaciation, reaching values of ∼5.5 Tmol year(-1), similar to the estimated export from palaeo rivers. These elevated silica fluxes may explain high diatom productivity observed during the last glacial-interglacial period