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br Introduction The mammary tissue undergoes extensive morphological and

Introduction
The mammary tissue undergoes extensive morphological and phenotypic alterations during the pregnancy/lactation cycle forming a complex network of alveolar structures (Rosen et al., 1994; Macias and Hinck, 2012). This cellular architecture exhibits well defined A/B polarization established by the adherence and tight junction protein complexes. This polarized epithelial sheet with tight junction barrier consists of mature luminal epithelial tsa hdac functionally capable of synthesis and directional secretion of milk into the lumen of the mammary gland during lactation (Anderson et al., 2007).
While our understanding of the phenotypic differentiation of the mammary epithelial cells is still limited, however, signature molecules for various stem/progenitor cell populations have been described recently (Visvader and Stingl, 2014). Adult mammary glands maintain a population of stem cells which are capable of generating epithelial progenitor cells giving rise to terminally differentiated cells. Current knowledge indicates the complex nature of the mammary stem cell (MaSC) hierarchy (Fu et al., 2014; Shehata et al., 2012). Based on the expression pattern of cell surface markers EpCAM and CD49f, a differentiation model of MaSC was proposed: EpCAMlow/CD49fhi (bipotent progenitors)-EpCAMhi/CD49fhi (luminal progenitors)-EpCAMhi/CD49flow (mature luminal cells) (Fu et al., 2014; Shehata et al., 2012). The hormonal regulations and cellular mechanisms controlling these morphogenic/phenotypic events are not fully determined.
The hormone prolactin (PRL) is known to be indispensable in regulating the development of the mammary gland and promoting the terminal differentiation of mammary epithelial cells. PRL is known to mediate these effects through activation of the Jak2/Stat5 pathway. Indeed, genetically engineered knockout mice lacking either PRL, the PRL receptor, Jak2 or Stat5 showed limited mammary alveolar development and loss of lactation capacity, implicating a potential role for PRL in mammary alveolar development (Horseman et al., 1997; Ormandy et al., 1997; Wagner et al., 2004; Liu et al., 1997). Furthermore, we have previously shown that PRL signaling through Jak2 to induce re-epithelialization of mesenchymal breast cancer cells by suppressing the process of EMT further pointing to a potential role for PRL in regulating mammary epithelial morphogenesis/polarity (Nouhi et al., 2006).

Methods

Results

Discussion
Understanding mammary gland biology is of critical significance given the prevalence of breast cancer worldwide. To characterize mechanisms involved in regulating mammary morphogenesis, extensive studies have used ex vivo culture model of mammary epithelial cells on extracellular matrices in the presence of various hormonal and growth factors. These original studies showed that mammary epithelial cells to organize into functional acinar architecture resembling mammary alveoli. Information generated using these cellular model systems have highlighted the role of the ECM component like laminin (Streuli et al., 1991, 1995) and integrin (Lee and Streuli, 2014) as important regulators of mammary acini morphogenesis. Furthermore, Xian et.al has reported the development of mammary acini using HC11 cells cultured in Matrigel in the presence of EGF (Xian et al., 2005). However, there have been no studies examining explicitly the role of PRL hormone in regulating the various aspects of acini morphogenesis. Here we describe a new role for PRL as a crucial regulator of mammary epithelial A/B polarization and luminal cell fate determination.
While there is limited information with respect to physiological ligands inducing mammary acini morphogenesis, the literature presents several growth factors, oncogenes and signaling pathways that are involved in disrupting mammary cell polarity and acini formation. Indeed, it was shown that FGF (Xian et al., 2005); TGFβ (Ozdamar et al., 2005); Erbb2 (Aranda et al., 2006) and Ephrin B1 (Lee et al., 2008) as well as NFκB (Becker-Weimann et al., 2013) to interfere with mammary acini formation/organization. Thus, our results demonstrating an organizational role for PRL in mammary acini morphogenesis is highly significant. Indeed, our results demonstrate a novel regulatory PRL-dependent mechanism coordinating mammary acini organization.

tsa hdac br General discussion Our study demonstrates the use of faces

General discussion
Our study demonstrates the use of faces in central visual field as a viable tool for studying masking. Using a backward mask, we obtained peak masking at a non zero SOA (type B masking). Using a trailing mask, we obtained masking greater than that with a common onset common offset mask (SOA 0ms), demonstrating that the trailing portion of the mask was responsible for this effect. Our model, which was based on data from common onset masking with various portions of the trailing mask removed, as well as from backward making data, suggests that there is a specific period during the time course of visual processing, when the presence of a mask can exert itself. Our model also provides a framework within which backward and common onset masking operate through the same mechanisms.
There are, however, some important limitations to this model. For one, our model does not take into account offset transients, which have been shown to be associated with threshold elevations, at least in the context of masking by light (Crawford, 1947). The account given by Macknik and Livingstone (1998), who used bars as targets and mask, suggests that the disinhibitory rebound associated with a sharp luminance decrement of the mask (offset transient) is responsible for inhibiting the target. As our model does not take offset transients into account, it could be underestimating the masking effect of the offset transients introduced when a trail is interrupted. However, data from Experiment 2c shows that a series of pulsed masks (which introduced multiple transients) showed no increase in masking compared to an uninterrupted trail, a finding that held across a wide range of pulse frequencies. Nevertheless, it would be interesting to follow up this work to explore the potential role of transients in our paradigm (e.g. Sackur, 2011; Tapia, Breitmeyer, & Jacob, 2011).
Our model also predicts that backward masking will peak at an SOA of around 100ms, whereas our data suggest a peak quite a bit earlier (our baseline SOA runs in Experiment 3 showed a peak SOA of 58.3ms for a few participants). This discrepancy could be due to any number of the following reasons. First, our model was based on data from methodologically different experiments. While the common onset data was derived from the same observers, using the same method of calculating threshold elevations, the backward masking data in Experiment 1 was derived from a different set of observers, using a different method of calculating threshold elevations. Indeed, when combining the two data sets into a unified set of elevation thresholds, the peak SOA conditions from Experiment 1 showed slightly greater masking than the Full Trail condition from Experiment 2, while within Experiment 1, the peak SOA thresholds and Full Trail thresholds were virtually identical. Second, our model is a rather simple one, in that it posits a single tsa hdac across the entire trail duration, while in reality, there may be a number of distinct mechanisms each of which has its own integration window (see Breitmeyer and Ogmen (2006), p. 50). Third, our model only takes into account the magnocellular response of the mask, and does not model the influence of mask modulated parvocellular activity upon target visibility. It should also be noted that our model predicts unusually sharp backward masking functions (see Fig. 14), which is due to the narrow width of S(t).
Another important issue is that it is challenging to determine whether the increased masking found with a common onset trailing mask, relative to a common onset common offset mask, is due to the trailing portion’s ability to interfere with target processing for an extended period of time, or whether it is simply due to the extended trail being temporally integrated into a (perceptually) higher contrast mask. In other words, increasing mask duration may be equivalent to simply using a higher contrast mask that offsets with the target offset, within a limited integration window (Bloch’s Law). Increasing mask contrast relative to that of the target, while keeping mask and target durations fixed, has been shown to increase masking at an SOA of 0ms (Stewart & Purcell, 1974; Weisstein, 1972). Similarly, increasing mask duration, while keeping mask and target contrast fixed, also results in increased masking at an SOA of 0ms (Breitmeyer, 1978). Thus, it is difficult to say whether the increased masking we found with a common onset trailing mask is due to stronger sustained-on-sustained inhibition, or whether it is due to the trailing mask having more time to interfere with target processing (our model only takes into account the latter possibility). Indeed, this same question could be asked of the results of Bischof and Di Lollo (1995) study, which showed an increase in masking in central visual field as a function of mask duration. There is, however, some interesting data that suggest that the duration of a centrally presented contour mask is capable of driving masking independently of its (luminance x time) energy. Di Lollo, von Mühlenen, Enns, and Bridgeman (2004) showed that while masking remained fairly constant across brightness matched targets of varying durations (increasing target duration or increasing target luminance reduced masking substantially), the same was not true when it came to mask energy. That is, increasing the duration of a brightness matched mask produced a very similar masking function to that when the mask duration was increased with a fixed luminance, suggesting that mask duration is capable of driving masking. While this wasn’t common onset masking, the mask manipulations were done with a target duration of 10ms, and an ISI of 0ms, which is very close to a common onset paradigm. It should be noted, however, that in this study, the mask was a contour mask, whereas in our experiments, the mask was a full face. Because there is more contour overlap with the target in a full face mask, there may be a larger component of intrachannel sustained masking, or masking due to integration (luminance channels of the mask and target being shared due to spatial overlap), relative to a simple contour mask. As such, mask energy (luminance×time) may have a larger role to play with our stimuli. One way to further address this issue would be to more rigorously sample masking as a function of mask duration with different types of masking stimuli, as we are currently investigating in our lab.