Evaluation of different flow stress laws coupled with a physical based ductile failure criterion for the modelling of the chip formation process of Ti-6Al-4V under broaching conditions

During the machining of Ti-6Al-4V the changing deformation mechanisms produce a complex microstructure of segmented chips, which directly influenced tool-wear and process stability. Numerical simulation could give an insight into the physical phenomena involved in chip segmentation, but its accuracy is directly related to the reliability of the input parameters. In this work, therefore, three different flow stress law were evaluated coupled with a physical based ductile failure criterion, which depends on stress triaxiality and temperature. To this end, the flow stress laws were implemented in the finite element software AdvantEdge by programming user-defined subroutines. The resulting FEM models were compared with orthogonal cutting experimental tests (tubular/linear), analyzing different fundamental outputs (machining forces, temperatures in the workpiece and chip morphology). All the FEM models showed good agreement with the experimental results

Caspase-8 binding to cardiolipin in giant unilamellar vesicles provides a functional docking platform for bid

Caspase-8 is involved in death receptor-mediated apoptosis in type II cells, the proapoptotic programme of which is triggered by truncated Bid. Indeed, caspase-8 and Bid are the known intermediates of this signalling pathway. Cardiolipin has been shown to provide an anchor and an essential activating platform for caspase-8 at the mitochondrial membrane surface. Destabilisation of this platform alters receptor-mediated apoptosis in diseases such as Barth Syndrome, which is characterised by the presence of immature cardiolipin which does not allow caspase-8 binding. We used a simplified in vitro system that mimics contact sites and/or cardiolipin-enriched microdomains at the outer mitochondrial surface in which the platform consisting of caspase-8, Bid and cardiolipin was reconstituted in giant unilamellar vesicles. We analysed these vesicles by flow cytometry and confirm previous results that demonstrate the requirement for intact mature cardiolipin for caspase-8 activation and Bid binding and cleavage. We also used confocal microscopy to visualise the rupture of the vesicles and their revesiculation at smaller sizes due to alteration of the curvature following caspase-8 and Bid binding. Biophysical approaches, including Laurdan fluorescence and rupture/tension measurements, were used to determine the ability of these three components (cardiolipin, caspase-8 and Bid) to fulfil the minimal requirements for the formation and function of the platform at the mitochondrial membrane. Our results shed light on the active functional role of cardiolipin, bridging the gap between death receptors and mitochondria

Innate control of actin nucleation determines two distinct migration behaviours in dendritic cells

Dendritic cell (DC) migration in peripheral tissues serves two main functions: antigen sampling by immature DCs, and chemokine-guided migration towards lymphatic vessels (LVs) on maturation. These migratory events determine the efficiency of the adaptive immune response. Their regulation by the core cell locomotion machinery has not been determined. Here, we show that the migration of immature DCs depends on two main actin pools: a RhoA mDial-dependent actin pool located at their rear, which facilitates forward locomotion; and a Cdc42 Arp2/3-dependent actin pool present at their front, which limits migration but promotes antigen capture. Following TLR4 MyD88-induced maturation, Arp2/3-dependent actin enrichment at the cell front is markedly reduced. Consequently, mature DCs switch to a faster and more persistent mDial-dependent locomotion mode that facilitates chemotactic migration to LVs and lymph nodes. Thus, the differential use of actin-nucleating machineries optimizes the migration of immature and mature DCs according to their specific function

The impact of ambient temperature on mortality among the urban population in Skopje, Macedonia during the period 1996–2000

BACKGROUND: This study assesses the relationship between daily numbers of deaths and variations in ambient temperature within the city of Skopje, R. Macedonia. METHODS: The daily number of deaths from all causes, during the period 1996–2000, as well as those deaths from cardiovascular diseases, occurring within the city of Skopje were related to the average daily temperature on the same day using Multiple Regression statistical analyses. Temperature was measured within the regression model as two complementary variables: 'Warm' and 'Cold'. Excess winter mortality was calculated as winter deaths (deaths occurring in December to March) minus the average of non-winter deaths (April to July of the current year and August to November of the previous year). RESULTS: In this study the average daily total of deaths was 7% and 13% greater in the cold when compared to the whole period and warm period respectively. The same relationship was noticed for deaths caused by cardiovascular diseases. The Regression Beta Coefficient (b = -0.19) for the total mortality as a function of the temperature in Skopje during the period 1996–2000 was statistically significant with negative connotation as was the circulatory mortality due to average temperature (statistically significant regression Beta coefficient (b = -0.24)). A measure of this increase is provided, on an annual basis, in the form of the excess winter mortality figure. CONCLUSION: Mortality with in the city of Skopje displayed a marked seasonality, with peaks in the winter and relative troughs in the summer

Nonparametric Simulation of Signal Transduction Networks with Semi-Synchronized Update

Simulating signal transduction in cellular signaling networks provides predictions of network dynamics by quantifying the changes in concentration and activity-level of the individual proteins. Since numerical values of kinetic parameters might be difficult to obtain, it is imperative to develop non-parametric approaches that combine the connectivity of a network with the response of individual proteins to signals which travel through the network. The activity levels of signaling proteins computed through existing non-parametric modeling tools do not show significant correlations with the observed values in experimental results. In this work we developed a non-parametric computational framework to describe the profile of the evolving process and the time course of the proportion of active form of molecules in the signal transduction networks. The model is also capable of incorporating perturbations. The model was validated on four signaling networks showing that it can effectively uncover the activity levels and trends of response during signal transduction process

Effects of apparent temperature on daily mortality in Lisbon and Oporto, Portugal

<p>Abstract</p> <p>Background</p> <p>Evidence that elevated temperatures can lead to increased mortality is well documented, with population vulnerability being location specific. However, very few studies have been conducted that assess the effects of temperature on daily mortality in urban areas in Portugal.</p> <p>Methods</p> <p>In this paper time-series analysis was used to model the relationship between mean apparent temperature and daily mortality during the warm season (April to September) in the two largest urban areas in Portugal: Lisbon and Oporto. We used generalized additive Poisson regression models, adjusted for day of week and season.</p> <p>Results</p> <p>Our results show that in Lisbon, a 1°C increase in mean apparent temperature is associated with a 2.1% (95%CI: 1.6, 2.5), 2.4% (95%CI: 1.7, 3.1) and 1.7% (95%CI: 0.1, 3.4) increase in all-causes, cardiovascular, and respiratory mortality, respectively. In Oporto the increase was 1.5% (95%CI: 1.0, 1.9), 2.1% (95%CI: 1.3, 2.9) and 2.7% (95%CI: 1.2, 4.3) respectively. In both cities, this increase was greater for the group >65 years.</p> <p>Conclusion</p> <p>Even without extremes in apparent temperature, we observed an association between temperature and daily mortality in Portugal. Additional research is needed to allow for better assessment of vulnerability within populations in Portugal in order to develop more effective heat-related morbidity and mortality public health programs.</p

Pneumococcal meningitis: Clinical-pathological correlations (meningene-path)

Pneumococcal meningitis is associated with substantial mortality and morbidity. We systematically assessed brain histopathology of 31 patients who died of pneumococcal meningitis from a nationwide study (median age 67 years; 21 (67 %) were male) using a pathology score including inflammation and vascular damage. Of the 27 patients with known time from the admission to death, 14 patients died within 7 days of admission and 13 after 7 days of admission. Eleven of 25 (44 %) patients had been treated with adjunctive dexamethasone therapy. Observed pathological processes were inflammation of medium-large arteries in 30 brains (97 %), cerebral haemorrhage in 24 (77 %), cerebritis in 24 (77 %), thrombosis in 21 (68 %), infarction in 19 (61 %) and ventriculitis in 19 (of 28 cases, 68 %). Inflammation of medium-large arteries led to obstruction of the vascular lumen in 14 (of 31 cases, 45 %). Vascular inflammation was associated with infarction and thrombosis of brain parenchymal vessels. Hippocampal dentate gyrus apoptosis between patients treated with and without dexamethasone was similar (p = 0.66); however, dexamethasone treated patients had higher total pathology score than non-dexamethasone treated patients (p = 0.003). Our study shows that vascular damage is key in the process of brain damage in pneumococcal meningitis. Data and material of this study will be made open-access for translational research in pneumococcal meningitis (MeninGene-Path)

mTOR independent regulation of macroautophagy by Leucine Rich Repeat Kinase 2 via Beclin-1

Leucine rich repeat kinase 2 is a complex enzyme with both kinase and GTPase activities, closely linked to the pathogenesis of several human disorders including Parkinson’s disease, Crohn’s disease, leprosy and cancer. LRRK2 has been implicated in numerous cellular processes; however its physiological function remains unclear. Recent reports suggest that LRRK2 can act to regulate the cellular catabolic process of macroautophagy, although the precise mechanism whereby this occurs has not been identi ed. To investigate the signalling events through which LRRK2 acts to in uence macroautophagy, the mammalian target of rapamycin (mTOR)/Unc-51-like kinase 1 (ULK1) and Beclin-1/phosphatidylinositol 3-kinase (PI3K) pathways were evaluated in astrocytic cell models in the presence and absence of LRRK2 kinase inhibitors. Chemical inhibition of LRRK2 kinase activity resulted in the stimulation of macroautophagy in a non-canonical fashion, independent of mTOR and ULK1, but dependent upon the activation of Beclin 1-containing class III PI3-kinase

Information Routing Driven by Background Chatter in a Signaling Network

Living systems are capable of processing multiple sources of information simultaneously. This is true even at the cellular level, where not only coexisting signals stimulate the cell, but also the presence of fluctuating conditions is significant. When information is received by a cell signaling network via one specific input, the existence of other stimuli can provide a background activity –or chatter– that may affect signal transmission through the network and, therefore, the response of the cell. Here we study the modulation of information processing by chatter in the signaling network of a human cell, specifically, in a Boolean model of the signal transduction network of a fibroblast. We observe that the level of external chatter shapes the response of the system to information carrying signals in a nontrivial manner, modulates the activity levels of the network outputs, and effectively determines the paths of information flow. Our results show that the interactions and node dynamics, far from being random, confer versatility to the signaling network and allow transitions between different information-processing scenarios

A Widespread Distribution of Genomic CeMyoD Binding Sites Revealed and Cross Validated by ChIP-Chip and ChIP-Seq Techniques

Identifying transcription factor binding sites genome-wide using chromatin immunoprecipitation (ChIP)-based technology is becoming an increasingly important tool in addressing developmental questions. However, technical problems associated with factor abundance and suitable ChIP reagents are common obstacles to these studies in many biological systems. We have used two completely different, widely applicable methods to determine by ChIP the genome-wide binding sites of the master myogenic regulatory transcription factor HLH-1 (CeMyoD) in C. elegans embryos. The two approaches, ChIP-seq and ChIP-chip, yield strongly overlapping results revealing that HLH-1 preferentially binds to promoter regions of genes enriched for E-box sequences (CANNTG), known binding sites for this well-studied class of transcription factors. HLH-1 binding sites were enriched upstream of genes known to be expressed in muscle, consistent with its role as a direct transcriptional regulator. HLH-1 binding was also detected at numerous sites unassociated with muscle gene expression, as has been previously described for its mouse homolog MyoD. These binding sites may reflect several additional functions for HLH-1, including its interactions with one or more co-factors to activate (or repress) gene expression or a role in chromatin organization distinct from direct transcriptional regulation of target genes. Our results also provide a comparison of ChIP methodologies that can overcome limitations commonly encountered in these types of studies while highlighting the complications of assigning in vivo functions to identified target sites