Infinitely-fast diffusion in Single-File Systems

We have used Dynamic Monte Carlo (DMC) methods and analytical techniques to analyze Single-File Systems for which diffusion is infinitely-fast. We have simplified the Master Equation removing the fast reactions and we have introduced a DMC algorithm for infinitely-fast diffusion. The DMC method for fast diffusion give similar results as the standard DMC with high diffusion rates. We have investigated the influence of characteristic parameters, such as pipe length, adsorption, desorption and conversion rate constants on the steady-state properties of Single-File Systems with a reaction, looking at cases when all the sites are reactive and when only some of them are reactive. We find that the effect of fast diffusion on single-file properties of the system is absent even when diffusion is infinitely-fast. Diffusion is not important in these systems. Smaller systems are less reactive and the occupancy profiles for infinitely-long systems show an exponential behavior.Comment: 8 pages, 5 figure

Scaling behavior in steady-state contractile actomyosin network flow

Contractile actomyosin network flows are crucial for many cellular processes including cell division and motility, morphogenesis and transport. How local remodeling of actin architecture tunes stress production and dissipation and regulates large-scale network flow remains poorly understood. Here, we generate contractile actomyosin networks with rapid turnover in vitro, by encapsulating cytoplasmic Xenopus egg extracts into cell-sized 'water-in-oil' droplets. Within minutes, the networks reach a dynamic steady-state with continuous inward flow. The networks exhibit homogenous, density-independent contraction for a wide range of physiological conditions, indicating that the myosin-generated stress driving contraction is proportional to the effective network viscosity. We further find that the contraction rate approximately scales with the network turnover rate, but this relation breaks down in the presence of excessive crosslinking or branching. Our findings suggest that cells use diverse biochemical mechanisms to generate robust, yet tunable, actin flows by regulating two parameters: turnover rate and network geometry

The actin-bundling protein, PLS3, is part of the mechanoresponsive machinery that regulates osteoblast mineralization

Plastin-3 (PLS3) is a calcium-sensitive actin-bundling protein that has recently been linked to the development of childhood-onset osteoporosis. Clinical data suggest that PLS3 mutations lead to a defect in osteoblast function, however the underlying mechanism remains elusive. To investigate the role of PLS3 in bone mineralization, we generated MC3T3-E1 preosteoblast cells that are stably depleted of PLS3. Analysis of osteogenic differentiation of control and PLS3 knockdown (PLS3 KD) cells showed that depletion of PLS3 does not alter the first stage of osteoblast mineralization in which a collagen matrix is deposited, but severely affects the subsequent mineralization of that matrix. During this phase, osteoblasts heavily rely on mechanosensitive signaling pathways to sustain mineral deposition in response to increasing stiffness of the extracellular matrix (ECM). PLS3 prominently localizes to focal adhesions (FAs), which are intricately linked to mechanosensation. In line with this, we observed that depletion of PLS3 rendered osteoblasts unresponsive to changes in ECM stiffness and showed the same cell size, FA lengths and number of FAs when plated on soft (6 kPa

Universality and scaling behavior of RG gauge actions

We study universality and scaling properties of RG gauge actions (Iwasaki and DBW2). In the first part we consider the critical temperature T_{c} and compute the reference energy scale r_{0} for critical couplings \beta_{c} corresponding to N_{t}=3,4,6,8. The universality of T_{c}r_{0} between Iwasaki and Wilson action is confirmed and the scaling behavior of the Iwasaki action is found to be better than the one for the Wilson action. The results for the DBW2 action show larger lattice artefacts. A continuum value T_{c}r_{0}=0.7498(50) is extracted. We compute also the glueball masses for the states 0^{++} and 2^{++}, investigate the scaling of m_{0^{++}}r_{0} and m_{2^{++}}r_{0} and point out practical problems which are due to the violation of positivity present in the RG actions.Comment: 36 page

Exploring Outcomes to Consider in Economic Evaluations of Health Promotion Programs: What Broader Non-Health Outcomes Matter Most?

Background Attention is increasing on the consideration of broader non-health outcomes in economic evaluations. It is unknown which non-health outcomes are valued as most relevant in the context of health promotion. The present study fills this gap by investigating the relative importance of non-health outcomes in a health promotion context. Method We investigated the relative importance of ten non-health outcomes of health promotion programs not commonly captured in QALYs. Preferences were elicited from a sample of the Dutch general public (N = 549) by means of a ranking task. These preferences were analyzed using Borda scores and rank-ordered logit models. Results The relative order of preference (from most to least important) was: self-confidence, insights into own (un)healthy behavior, perceived life control, knowledge about a certain health problem, social support, relaxation, better educational achievements, increased labor participation and work productivity, social participation, and a reduction in criminal behavior. The weight given to a particular non-health outcome was affected by the demographic variables age, gender, income, and education. Furthermore, in an open question, respondents mentioned a number of other relevant non-health outcomes, which we classified into outcomes relevant for the individual, the direct social environment, and for society as a whole. Conclusion The study provides valuable insights in the non-health outcomes that are considered as most important by the Dutch general population. Ideally, researchers should include the most important non-health outcomes in economic evaluations of health promotio

Structural basis for mutation-induced destabilization of profilin 1 in ALS

Mutations in profilin 1 (PFN1) are associated with amyotrophic lateral sclerosis (ALS); however, the pathological mechanism of PFN1 in this fatal disease is unknown. We demonstrate that ALS-linked mutations severely destabilize the native conformation of PFN1 in vitro and cause accelerated turnover of the PFN1 protein in cells. This mutation-induced destabilization can account for the high propensity of ALS-linked variants to aggregate and also provides rationale for their reported loss-of-function phenotypes in cell-based assays. The source of this destabilization is illuminated by the X-ray crystal structures of several PFN1 proteins, revealing an expanded cavity near the protein core of the destabilized M114T variant. In contrast, the E117G mutation only modestly perturbs the structure and stability of PFN1, an observation that reconciles the occurrence of this mutation in the control population. These findings suggest that a destabilized form of PFN1 underlies PFN1-mediated ALS pathogenesis

Atlantic circulation changes across a stadial-interstadial transition

We combine consistently dated benthic carbon isotopic records distributed over the entire Atlantic Ocean with numerical simulations performed by a glacial configuration of the Norwegian Earth System Model with active ocean biogeochemistry, in order to interpret the observed Cibicides &delta;13C changes at the stadial-interstadial transition corresponding to the end of Heinrich Stadial 4 (HS4) in terms of ocean circulation and remineralization changes. We show that the marked increase in Cibicides &delta;13C observed at the end of HS4 between ~2000 and 4200 m in the Atlantic can be explained by changes in nutrient concentrations as simulated by the model in response to the halting of freshwater input in the high latitude glacial North Atlantic. Our model results show that this Cibicides &delta;13C signal is associated with changes in the ratio of southern-sourced (SSW) versus northern-sourced (NSW) water masses at the core sites, whereby SSW is replaced by NSW as a consequence of the resumption of deep water formation in the northern North Atlantic and Nordic Seas after the freshwater input is halted. Our results further suggest that the contribution of ocean circulation changes to this signal increases from ~40 % at 2000 m to ~80 % at 4000 m. Below ~4200 m, the model shows little ocean circulation change but an increase in remineralization across the transition marking the end of HS4. The simulated lower remineralization during stadials than interstadials is particularly pronounced in deep subantarctic sites, in agreement with the decrease in the export production of carbon to the deep Southern Ocean during stadials found in previous studies.</p

Exploring Topology Conserving Gauge Actions for Lattice QCD

We explore gauge actions for lattice QCD, which are constructed such that the occurrence of small plaquette values is strongly suppressed. By choosing strong bare gauge couplings we arrive at values for the physical lattice spacings of O(0.1 fm). Such gauge actions tend to confine the Monte Carlo history to a single topological sector. This topological stability facilitates the collection of a large set of configurations in a specific sector, which is profitable for numerical studies in the epsilon-regime. The suppression of small plaquette values is also expected to be favourable for simulations with dynamical quarks. We use a local Hybrid Monte Carlo algorithm to simulate such actions, and we present numerical results for the static potential, the physical scale, the topological stability and the kernel condition number of the overlap Dirac operator. In addition we discuss the question of reflection positivity for a class of such gauge actions.Comment: 28 pages, 8 figure

Cancer Cell Expression of Autotaxin Controls Bone Metastasis Formation in Mouse through Lysophosphatidic Acid-Dependent Activation of Osteoclasts

Bone metastases are highly frequent complications of breast cancers. Current bone metastasis treatments using powerful anti-resorptive agents are only palliative indicating that factors independent of bone resorption control bone metastasis progression. Autotaxin (ATX/NPP2) is a secreted protein with both oncogenic and pro-metastatic properties. Through its lysosphospholipase D (lysoPLD) activity, ATX controls the level of lysophosphatidic acid (LPA) in the blood. Platelet-derived LPA promotes the progression of osteolytic bone metastases of breast cancer cells. We asked whether ATX was involved in the bone metastasis process. We characterized the role of ATX in osteolytic bone metastasis formation by using genetically modified breast cancer cells exploited on different osteolytic bone metastasis mouse models.Intravenous injection of human breast cancer MDA-B02 cells with forced expression of ATX (MDA-B02/ATX) to immunodeficiency BALB/C nude mice enhanced osteolytic bone metastasis formation, as judged by increased bone loss, tumor burden, and a higher number of active osteoclasts at the metastatic site. Mouse breast cancer 4T1 cells induced the formation of osteolytic bone metastases after intracardiac injection in immunocompetent BALB/C mice. These cells expressed active ATX and silencing ATX expression inhibited the extent of osteolytic bone lesions and decreased the number of active osteoclasts at the bone metastatic site. In vitro, osteoclast differentiation was enhanced in presence of MDA-B02/ATX cell conditioned media or recombinant autotaxin that was blocked by the autotaxin inhibitor vpc8a202. In vitro, addition of LPA to active charcoal-treated serum restored the capacity of the serum to support RANK-L/MCSF-induced osteoclastogenesis.Expression of autotaxin by cancer cells controls osteolytic bone metastasis formation. This work demonstrates a new role for LPA as a factor that stimulates directly cancer growth and metastasis, and osteoclast differentiation. Therefore, targeting the autotaxin/LPA track emerges as a potential new therapeutic approach to improve the outcome of patients with bone metastases