α5β1-Integrin promotes tension-dependent mammary epithelial cell invasion by engaging the fibronectin synergy site.

Tumors are fibrotic and characterized by abundant, remodeled, and cross-linked collagen that stiffens the extracellular matrix stroma. The stiffened collagenous stroma fosters malignant transformation of the tissue by increasing tumor cell tension to promote focal adhesion formation and potentiate growth factor receptor signaling through kinase. Importantly, collagen cross-linking requires fibronectin (FN). Fibrotic tumors contain abundant FN, and tumor cells frequently up-regulate the FN receptor α5β1 integrin. Using transgenic and xenograft models and tunable two- and three-dimensional substrates, we show that FN-bound α5β1 integrin promotes tension-dependent malignant transformation through engagement of the synergy site that enhances integrin adhesion force. We determined that ligation of the synergy site of FN permits tumor cells to engage a zyxin-stabilized, vinculin-linked scaffold that facilitates nucleation of phosphatidylinositol (3,4,5)-triphosphate at the plasma membrane to enhance phosphoinositide 3-kinase (PI3K)-dependent tumor cell invasion. The data explain why rigid collagen fibrils potentiate PI3K activation to promote malignancy and offer a perspective regarding the consistent up-regulation of α5β1 integrin and FN in many tumors and their correlation with cancer aggression

Carbamazepine-Induced Tics

A variety of movement disorders are known to occur in association with carbamazepine (CBZ) therapy in adults and children, but development of tics has been described infrequently and only in patients with underlying Tourette's syndrome or other movement disorders. We report 3 children with epilepsy who developed facial motor tics after initiation of CBZ for complex partial seizures. All 3 had documented CBZ blood levels in the therapeutic range at the time, and none had other symptoms or signs of clinical intoxication. Neurologic examinations were normal in 2 and showed developmental de lay of expressive language in the third. Brain imaging was normal in all. After development of the tics in 2, CBZ was continued at the same or higher dose, and the tics abated and then ceased spontaneously ≤6 months. In the third child, the tics ceased after CBZ discontinuation. These cases demonstrate that CBZ can induce simple motor tics in children. These idiosyncratic reactions may be transient and do not always necessitate drug discontinuation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66313/1/j.1528-1157.1993.tb02119.x.pd

Fluctuation scaling in complex systems: Taylor's law and beyond

Complex systems consist of many interacting elements which participate in some dynamical process. The activity of various elements is often different and the fluctuation in the activity of an element grows monotonically with the average activity. This relationship is often of the form "$fluctuations \approx const.\times average^\alpha$", where the exponent $\alpha$ is predominantly in the range $[1/2, 1]$. This power law has been observed in a very wide range of disciplines, ranging from population dynamics through the Internet to the stock market and it is often treated under the names \emph{Taylor's law} or \emph{fluctuation scaling}. This review attempts to show how general the above scaling relationship is by surveying the literature, as well as by reporting some new empirical data and model calculations. We also show some basic principles that can underlie the generality of the phenomenon. This is followed by a mean-field framework based on sums of random variables. In this context the emergence of fluctuation scaling is equivalent to some corresponding limit theorems. In certain physical systems fluctuation scaling can be related to finite size scaling.Comment: 33 pages, 20 figures, 2 tables, submitted to Advances in Physic

Primary Transgenic Bovine Cells and Their Rejuvenated Cloned Equivalents Show Transgene-Specific Epigenetic Differences

Cell-mediated transgenesis, based on somatic cell nuclear transfer (SCNT), provides the opportunity to shape the genetic make-up of cattle. Bovine primary fetal fibroblasts, commonly used cells for SCNT, have a limited lifespan, and complex genetic modifications that require sequential transfections can be challenging time and cost-wise. To overcome these limitations, SCNT is frequently used to rejuvenate the cell lines and restore exhausted growth potential. We have designed a construct to be used in a 2-step cassette exchange experiment. Our transgene contains a puromycin resistance marker gene and an enhanced green fluorescence protein (EGFP) expression cassette, both driven by a strong mammalian promoter, and flanked by loxP sites and sequences from the bovine β-casein locus. Several transgenic cell lines were generated by random insertion into primary bovine cell lines. Two of these original cell lines were rederived by SCNT and new primary cells, with the same genetic makeup as the original donors, were established. While the original cell lines were puromycin-resistant and had a characteristic EGFP expression profile, all rejuvenated cell lines were sensitive to puromycin, and displayed varied EGFP expression, indicative of various degrees of silencing. When the methylation states of individual CpG sites within the transgene were analyzed, a striking increase in transgene-specific methylation was observed in all rederived cell lines. The results indicate that original transgenic donor cells and their rejuvenated derivatives may not be equivalent and differ in the functionality of their transgene sequences

Network analysis of team communication in a busy emergency department

Background: The Emergency Department (ED) is consistently described as a high-risk environment for patients and clinicians that demands colleagues quickly work together as a cohesive group. Communication between nurses, physicians, and other ED clinicians is complex and difficult to track. A clear understanding of communications in the ED is lacking, which has a potentially negative impact on the design and effectiveness of interventions to improve communications. We sought to use Social Network Analysis (SNA) to characterize communication between clinicians in the ED. Methods. Over three-months, we surveyed to solicit the communication relationships between clinicians at one urban academic ED across all shifts. We abstracted survey responses into matrices, calculated three standard SNA measures (network density, network centralization, and in-degree centrality), and presented findings stratified by night/day shift and over time. Results: We received surveys from 82% of eligible participants and identified wide variation in the magnitude of communication cohesion (density) and concentration of communication between clinicians (centralization) by day/night shift and over time. We also identified variation in in-degree centrality (a measure of power/influence) by day/night shift and over time. Conclusions: We show that SNA measurement techniques provide a comprehensive view of ED communication patterns. Our use of SNA revealed that frequency of communication as a measure of interdependencies between ED clinicians varies by day/night shift and over time. © 2013 Patterson et al.; licensee BioMed Central Ltd

Identification and evaluation of risk of generalizability biases in pilot versus efficacy/effectiveness trials: A systematic review and meta-analysis

Background: Preliminary evaluations of behavioral interventions, referred to as pilot studies, predate the conduct of many large-scale efficacy/effectiveness trial. The ability of a pilot study to inform an efficacy/effectiveness trial relies on careful considerations in the design, delivery, and interpretation of the pilot results to avoid exaggerated early discoveries that may lead to subsequent failed efficacy/effectiveness trials. “Risk of generalizability biases (RGB)” in pilot studies may reduce the probability of replicating results in a larger efficacy/effectiveness trial. We aimed to generate an operational list of potential RGBs and to evaluate their impact in pairs of published pilot studies and larger, more well-powered trial on the topic of childhood obesity. Methods: We conducted a systematic literature review to identify published pilot studies that had a published larger-scale trial of the same or similar intervention. Searches were updated and completed through December 31st, 2018. Eligible studies were behavioral interventions involving youth (≤18 yrs) on a topic related to childhood obesity (e.g., prevention/treatment, weight reduction, physical activity, diet, sleep, screen time/sedentary behavior). Extracted information included study characteristics and all outcomes. A list of 9 RGBs were defined and coded: intervention intensity bias, implementation support bias, delivery agent bias, target audience bias, duration bias, setting bias, measurement bias, directional conclusion bias, and outcome bias. Three reviewers independently coded for the presence of RGBs. Multi-level random effects meta-analyses were performed to investigate the association of the biases to study outcomes. Results: A total of 39 pilot and larger trial pairs were identified. The frequency of the biases varied: delivery agent bias (19/39 pairs), duration bias (15/39), implementation support bias (13/39), outcome bias (6/39), measurement bias (4/39), directional conclusion bias (3/39), target audience bias (3/39), intervention intensity bias (1/39), and setting bias (0/39). In meta-analyses, delivery agent, implementation support, duration, and measurement bias were associated with an attenuation of the effect size of − 0.325 (95CI − 0.556 to − 0.094), − 0.346 (− 0.640 to − 0.052), − 0.342 (− 0.498 to − 0.187), and − 0.360 (− 0.631 to − 0.089), respectively. Conclusions Pre-emptive avoidance of RGBs during the initial testing of an intervention may diminish the voltage drop between pilot and larger efficacy/effectiveness trials and enhance the odds of successful translation

Phenoloxidase activity acts as a mosquito innate immune response against infection with semliki forest virus

Several components of the mosquito immune system including the RNA interference (RNAi), JAK/STAT, Toll and IMD pathways have previously been implicated in controlling arbovirus infections. In contrast, the role of the phenoloxidase (PO) cascade in mosquito antiviral immunity is unknown. Here we show that conditioned medium from the Aedes albopictus-derived U4.4 cell line contains a functional PO cascade, which is activated by the bacterium Escherichia coli and the arbovirus Semliki Forest virus (SFV) (Togaviridae; Alphavirus). Production of recombinant SFV expressing the PO cascade inhibitor Egf1.0 blocked PO activity in U4.4 cell- conditioned medium, which resulted in enhanced spread of SFV. Infection of adult female Aedes aegypti by feeding mosquitoes a bloodmeal containing Egf1.0-expressing SFV increased virus replication and mosquito mortality. Collectively, these results suggest the PO cascade of mosquitoes plays an important role in immune defence against arboviruses

Sea-level constraints on the amplitude and source distribution of Meltwater Pulse 1A.

During the last deglaciation, sea levels rose as ice sheets retreated. This climate transition was punctuated by periods of more intense melting; the largest and most rapid of these—Meltwater Pulse 1A—occurred about 14,500 years ago, with rates of sea-level rise reaching approximately 4 m per century1, 2, 3. Such rates of rise suggest ice-sheet instability, but the meltwater sources are poorly constrained, thus limiting our understanding of the causes and impacts of the event4, 5, 6, 7. In particular, geophysical modelling studies constrained by tropical sea-level records1, 8, 9 suggest an Antarctic contribution of more than seven metres, whereas most reconstructions10 from Antarctica indicate no substantial change in ice-sheet volume around the time of Meltwater Pulse 1A. Here we use a glacial isostatic adjustment model to reinterpret tropical sea-level reconstructions from Barbados2, the Sunda Shelf3 and Tahiti1. According to our results, global mean sea-level rise during Meltwater Pulse 1A was between 8.6 and 14.6 m (95% probability). As for the melt partitioning, we find an allowable contribution from Antarctica of either 4.1 to 10.0 m or 0 to 6.9 m (95% probability), using two recent estimates11, 12 of the contribution from the North American ice sheets. We conclude that with current geologic constraints, the method applied here is unable to support or refute the possibility of a significant Antarctic contribution to Meltwater Pulse 1A

Branch Mode Selection during Early Lung Development

Many organs of higher organisms, such as the vascular system, lung, kidney, pancreas, liver and glands, are heavily branched structures. The branching process during lung development has been studied in great detail and is remarkably stereotyped. The branched tree is generated by the sequential, non-random use of three geometrically simple modes of branching (domain branching, planar and orthogonal bifurcation). While many regulatory components and local interactions have been defined an integrated understanding of the regulatory network that controls the branching process is lacking. We have developed a deterministic, spatio-temporal differential-equation based model of the core signaling network that governs lung branching morphogenesis. The model focuses on the two key signaling factors that have been identified in experiments, fibroblast growth factor (FGF10) and sonic hedgehog (SHH) as well as the SHH receptor patched (Ptc). We show that the reported biochemical interactions give rise to a Schnakenberg-type Turing patterning mechanisms that allows us to reproduce experimental observations in wildtype and mutant mice. The kinetic parameters as well as the domain shape are based on experimental data where available. The developed model is robust to small absolute and large relative changes in the parameter values. At the same time there is a strong regulatory potential in that the switching between branching modes can be achieved by targeted changes in the parameter values. We note that the sequence of different branching events may also be the result of different growth speeds: fast growth triggers lateral branching while slow growth favours bifurcations in our model. We conclude that the FGF10-SHH-Ptc1 module is sufficient to generate pattern that correspond to the observed branching modesComment: Initially published at PLoS Comput Bio

Destabilization of the thermohaline circulation by transient perturbations to the hydrological cycle

We reconsider the problem of the stability of the thermohaline circulation as described by a two-dimensional Boussinesq model with mixed boundary conditions. We determine how the stability properties of the system depend on the intensity of the hydrological cycle. We define a two-dimensional parameters' space descriptive of the hydrology of the system and determine, by considering suitable quasi-static perturbations, a bounded region where multiple equilibria of the system are realized. We then focus on how the response of the system to finite-amplitude surface freshwater forcings depends on their rate of increase. We show that it is possible to define a robust separation between slow and fast regimes of forcing. Such separation is obtained by singling out an estimate of the critical growth rate for the anomalous forcing, which can be related to the characteristic advective time scale of the system.Comment: 37 pages, 8 figures, submitted to Clim. Dy