Impulsive signaling model of cytoneme-based morphogen gradient formation

Morphogen protein gradients play a vital role in regulating spatial pattern formation during development. The most commonly accepted mechanism of protein gradient formation involves the diffusion and degradation of morphogens from a localized source. However, there is growing experimental evidence for a direct cell-to-cell signaling mechanism via thin actin-rich cellular extensions known as cytonemes. Recent modeling studies of cytoneme-based morphogenesis in invertebrates ignore the discrete nature of vesicular transport along cytonemes, focusing on deterministic continuum models. In this paper, we develop an impulsive signaling model of morphogen gradient formation in invertebrates, which takes into account the discrete and stochastic nature of vesicular transport along cytonemes. We begin by solving a first passage time problem with sticky boundaries to determine the expected time to deliver a vesicle to a target cell, assuming that there is a 'nucleation' time for injecting the vesicle into the cytoneme. We then use queuing theory to analyze the impulsive model of morphogen gradient formation in the case of multiple cytonemes and multiple targets. In particular, we determine the steady-state mean and variance of the morphogen distribution across a one-dimensional array of target cells. The mean distribution recovers the spatially decaying morphogen gradient of previous deterministic models. However, the burst-like nature of morphogen transport can lead to Fano factors greater than unity across the array of cells, resulting in significant fluctuations at more distant target sites

Bidirectional transport model of morphogen gradient formation via cytonemes

Morphogen protein gradients play an important role in the spatial regulation of patterning during embryonic development. The most commonly accepted mechanism for gradient formation is diffusion from a source combined with degradation. Recently, there has been growing interest in an alternative mechanism, which is based on the direct delivery of morphogens along thin, actin-rich cellular extensions known as cytonemes. In this paper, we develop a bidirectional motor transport model for the flux of morphogens along cytonemes, linking a source cell to a one-dimensional array of target cells. By solving the steady-state transport equations, we show how a morphogen gradient can be established, and explore how the mean velocity of the motors affects properties of the morphogen gradient such as accumulation time and robustness. In particular, our analysis suggests that in order to achieve robustness with respect to changes in the rate of synthesis of morphogen, the mean velocity has to be negative, that is, retrograde flow or treadmilling dominates. Thus the potential targeting precision of cytonemes comes at an energy cost. We then study the effects of non-uniformly allocating morphogens to the various cytonemes projecting from a source cell. This competition for resources provides a potential regulatory control mechanism not available in diffusion-based models

Cornering the unphysical vertex

In the classical pure spinor worldsheet theory of AdS5xS5 there are some vertex operators which do not correspond to any physical excitations. We study their flat space limit. We find that the BRST operator of the worldsheet theory in flat space-time can be nontrivially deformed without deforming the worldsheet action. Some of these deformations describe the linear dilaton background. But the deformation corresponding to the nonphysical vertex differs from the linear dilaton in not being worldsheet parity even. The nonphysically deformed worldsheet theory has nonzero beta-function at one loop. This means that the classical Type IIB SUGRA backgrounds are not completely characterized by requiring the BRST symmetry of the classical worldsheet theory; it is also necessary to require the vanishing of the one-loop beta-function.Comment: LaTeX 40pp; v2: explained the relation to the linear dilaton background (Section 6), changes in Introduction and Abstrac

Multifaceted empathy of healthy volunteers after single doses of MDMA: A pooled sample of placebo-controlled studies

Previous placebo-controlled experimental studies have shown that a single dose of MDMA can increase emotional empathy in the multifaceted empathy test (MET) without affecting cognitive empathy. Although sufficiently powered to detect main effects of MDMA, these studies were generally underpowered to also validly assess contributions of additional parameters, such as sex, drug use history, trait empathy and MDMA or oxytocin plasma concentrations. The present study examined the robustness of the MDMA effect on empathy and investigated the moderating role of these additional parameters. Participants ( n = 118) from six placebo-controlled within-subject studies and two laboratories were included in the present pooled analysis. Empathy (MET), MDMA and oxytocin plasma concentrations were assessed after oral administration of MDMA (single dose, 75 or 125 mg). Trait empathy was assessed using the interpersonal reactivity index. We confirmed that MDMA increased emotional empathy at both doses without affecting cognitive empathy. This MDMA-related increase in empathy was most pronounced during presentation of positive emotions as compared with negative emotions. MDMA-induced empathy enhancement was positively related to MDMA blood concentrations measured before the test, but independent of sex, drug use history and trait empathy. Oxytocin concentrations increased after MDMA administration but were not associated with behavioral effects. The MDMA effects on emotional empathy were stable across laboratories and doses. Sex did not play a moderating role in this effect, and oxytocin levels, trait empathy and drug use history were also unrelated. Acute drug exposure was of significant relevance in the MDMA-induced emotional empathy elevation

Search-and-capture model of cytoneme-mediated morphogen gradient formation

Morphogen protein gradients play an essential role in the spatial regulation of patterning during embryonic development. The most commonly accepted mechanism of protein gradient formation involves the diffusion and degradation of morphogens from a localized source. Recently, an alternative mechanism has been proposed, which is based on cell-to-cell transport via thin actin-rich cellular extensions known as cytonemes. Very little is currently known about the precise nature of the contacts between cytonemes and their target cells. Important unresolved issues include how cytoneme tips find their targets, how they are stabilized at their contact sites, and how vesicles are transferred to a receiving cell and subsequently internalized. It has been hypothesized that cytonemes find their targets via a random search process based on alternating periods of retraction and growth, perhaps mediated by some chemoattractant. This is an actin-based analog of the search-and-capture model of microtubules of the mitotic spindle searching for cytochrome binding sites (kinetochores) prior to separation of cytochrome pairs. In this paper we develop a search-and-capture model of cytoneme-based morphogenesis, in which nucleating cytonemes from a source cell dynamically grow and shrink along the surface of a one-dimensional array of target cells until making contact with one of the target cells. We analyze the first-passage-time problem for making contact and then use this to explore the formation of morphogen gradients under the mechanism proposed for Wnt in vertebrates. That is, we assume that morphogen is localized at the tip of a growing cytoneme, which is delivered as a “morphogen burst” to a target cell when the cytoneme makes temporary contact with a target cell before subsequently retracting. We show how multiple rounds of search-and-capture, morphogen delivery, cytoneme retraction, and nucleation events lead to the formation of a morphogen gradient. We proceed by formulating the morphogen bursting model as a queuing process, analogous to the study of translational bursting in gene networks. In order to analyze the expected times for cytoneme contact, we introduce an efficient method for solving first-passage-time problems in the presence of sticky boundaries, which exploits some classical concepts from probability theory, namely, stopping times and the strong Markov property. We end the paper by demonstrating how this method simplifies previous analyses of a well-studied problem in cell biology, namely, the search-and-capture model of microtubule-kinetochore attachment. Although the latter is completely unrelated to cytoneme-based morphogenesis from a biological perspective, it shares many of the same mathematical elements

Direct vs. synaptic coupling in a mathematical model of cytoneme-based morphogen gradient formation

In developmental biology, an important problem is understanding the mechanisms underlying the formation of morphogen concentration gradients. The most commonly hypothesized mechanism involves the diffusion and degradation of morphogens from a localized source. Recently, however, an alternative mechanism has been proposed, which is based on cell-to-cell contacts mediated by thin, actin-rich cellular extensions known as cytonemes. In this paper, we develop a one-dimensional advection-diffusion transport model of cytoneme-based morphogenesis. In particular, we compare two distinct types of contact between a cytoneme tip and a target cell: direct contact and indirect contact mediated by a synapse. First, we calculate the steady-state concentration profiles and show that synaptic contacts generate broader concentration profiles, thus allowing for longer-range interactions. We then consider two alternative methods for determining how quickly the system approaches steady-state: either calculating the accumulation time using Laplace transforms, or analyzing the discrete spectrum of the associated evolution operator. The latter is a nontrivial eigenvalue problem due to the nature of the boundary conditions. Finally, we extend the direct contact model to the case of a stochastically switching boundary at the cytoneme tip, in order to take into account the fact that cytonemes dynamically grow and shrink, resulting in more temporary contacts with target cells

Identifying the favored mutation in a positive selective sweep.

Most approaches that capture signatures of selective sweeps in population genomics data do not identify the specific mutation favored by selection. We present iSAFE (for "integrated selection of allele favored by evolution"), a method that enables researchers to accurately pinpoint the favored mutation in a large region (∼5 Mbp) by using a statistic derived solely from population genetics signals. iSAFE does not require knowledge of demography, the phenotype under selection, or functional annotations of mutations

Enterobacter nimipressuralis as a cause of pseudobacteremia

<p>Abstract</p> <p>Background</p> <p>The clinical significance of the <it>Enterobacter nimipressuralis </it>as human pathogens remains unclear.</p> <p>Case presentations</p> <p>The microbiologic culture monitoring system of sterile body fluids revealed on an episode of <it>Enterobacter cloacae </it>and <it>Enterobacter amnigenus </it>in blood culture results on the same day; the antibiotic sensitivity and MIC were nearly the same for both species. First patient was a healthy woman with postmenopausal syndrome, while second patient with herpes zoster. Both patients had febrile sensations without signs of bacteremia. <it>E. amnigenus </it>was also cultured from the unused package of salined cotton in the container through epidemiologic investigation. The cultured <it>Enterobacter </it>species were all identified as <it>E. nimipressuralis </it>through <it>hsp60 </it>gene sequencing and infrequent-restriction-site PCR (IRS-PCR).</p> <p>Conclusion</p> <p>When an unusual microorganisms such as <it>E. nimipressuralis </it>is isolated from blood of a patient with no clinical signs of sepsis, a pseudobacteremia should be suspected. When the antibiogram and MIC test results of bacterial cultures from two or more patients are nearly the same, although the species involved may appear different, it may be necessary to prove that they are the same species through molecular methods. The microbiologic cultures monitoring system will probably help to detect pseudobacteremia and other pseudo infections through reliable and fast identification.</p

European bone mineral density loci are also associated with BMD in East-Asian populations

Most genome-wide association (GWA) studies have focused on populations of European ancestry with limited assessment of the influence of the sequence variants on populations of other ethnicities. To determine whether markers that we have recently shown to associate with Bone Mineral Density (BMD) in Europeans also associate with BMD in East-Asians we analysed 50 markers from 23 genomic loci in samples from Korea (n = 1,397) and two Chinese Hong Kong sample sets (n = 3,869 and n = 785). Through this effort we identified fourteen loci that associated with BMD in East-Asian samples using a false discovery rate (FDR) of 0.05; 1p36 (ZBTB40, P = 4.3×10 -9), 1p31 (GPR177, P = 0.00012), 3p22 (CTNNB1, P = 0.00013), 4q22 (MEPE, P = 0.0026), 5q14 (MEF2C, P = 1.3×10 -5), 6q25 (ESR1, P = 0.0011), 7p14 (STARD3NL, P = 0.00025), 7q21 (FLJ42280, P = 0.00017), 8q24 (TNFRSF11B, P = 3.4×10 -5), 11p15 (SOX6, P = 0.00033), 11q13 (LRP5, P = 0.0033), 13q14 (TNFSF11, P = 7.5×10 -5), 16q24 (FOXL1, P = 0.0010) and 17q21 (SOST, P = 0.015). Our study marks an early effort towards the challenge of cataloguing bone density variants shared by many ethnicities by testing BMD variants that have been established in Europeans, in East-Asians. © 2010 Styrkarsdottir et al.published_or_final_versio

Investigating poultry trade patterns to guide avian influenza surveillance and control: a case study in Vietnam

Live bird markets are often the focus of surveillance activities monitoring avian influenza viruses (AIV) circulating in poultry. However, in order to ensure a high sensitivity of virus detection and effectiveness of management actions, poultry management practices features influencing AIV dynamics need to be accounted for in the design of surveillance programmes. In order to address this knowledge gap, a cross-sectional survey was conducted through interviews with 791 traders in 18 Vietnamese live bird markets. Markets greatly differed according to the sources from which poultry was obtained, and their connections to other markets through the movements of their traders. These features, which could be informed based on indicators that are easy to measure, suggest that markets could be used as sentinels for monitoring virus strains circulating in specific segments of the poultry production sector. AIV spread within markets was modelled. Due to the high turn-over of poultry, viral amplification was likely to be minimal in most of the largest markets. However, due to the large number of birds being introduced each day, and challenges related to cleaning and disinfection, environmental accumulation of viruses at markets may take place, posing a threat to the poultry production sector and to public health