The samples were later rinsed in salt water, which floated most of the plastic to the surface for removal. Using a dissecting microscope, plastic was removed from preserved natural material, and then sorted by rinsing through Tyler sieves into six size classes: 0.355–0.499 mm, 0.500–0.709 mm, 0.710–0.999 mm, 1.00–2.79 mm, 2.80–4.749 mm, >4.75 mm. Individual pieces of plastic were divided into categories; fragment, polystyrene fragment, pellet, polypropylene/monofilament line, film; and then counted. The area sampled was calculated

by using onboard knotmeter data to measure the actual length of sea surface trawled in the 60-min period. The tow length multiplied by the width of the trawl provided the area sampled, allowing particle weight and abundance per km2 to be calculated. Using the Beaufort Scale (Beer, 1996), the sea state was calculated using wave height observed by three crewmembers and decided selleck chemicals by consensus. Forty six out of 48 net tows (96%) contained plastic marine pollution, with no plastic found in two of the eastern-most samples (Fig. 1). Fig. 1 shows excellent correspondence between tracer distribution assessed by the model (shaded gray areas) and the observed count of plastic particles (color dots). For the comparisons in Fig. 2 and Fig. 3, the model has been scaled using the integral

values, summed over all stations. Visual evaluation shows good correspondence between the observations (bars in Fig. 2 and Fig. 3) and the model (solid lines), all demonstrating Selleckchem AUY922 bell-shape distributions along the

transect. Correlation coefficients were found equal to 0.45 and 0.44, respectively. Somewhat wider model “bells” and their southeastern shift by a few stations may be due the difference between the multi-year mean, assessed by the model, and quasi-instantaneous state of the system, sampled during the 2 months of the expedition. The average abundance was 26,898 pieces km−2, and the average weight was 70.96 g km−2. 85.6% of the total count and 88.8% of the total weight were collected between 97°09′W (sample 17) and 111°91′W (sample 32), representing the center third of the sampling transect (Fig. 2 and Fig. 3). Plastic particles were found in each of the six size classes, and of the five type categories all were found except for foam, which did not occur in any of the 48 samples (Table 1). The two size classes representing particles 1.00–4.749 mm 3-mercaptopyruvate sulfurtransferase accounted for 55% of the total particle count and 72% of the total weight (Table 1). Plastic fragments by far dominated the microplastics collected in this study, both by count and by weight. Pellets were found in relatively low abundances, but due to their large individual weight made up 9.6% of the total microplastics weight. Lines and thin films were relatively abundant, but constituted less weight than the pellets. As shown in Fig. 2 and Fig. 3, the sample 22, collected at 29°04′S, 101°73′W, contained 1102 pieces and a total weight of 2.

A total of forty-three participants responded, however three questionnaires were incomplete. The sample included qualified physiotherapists (n = 31) and students (n = 12), of whom 18 (42%) were male and 25 (58%) female. The number of years experience in musculoskeletal physiotherapy ranged from 2 months to 29 years (mean: 10 years 10 months, median: 10 years 2 months) and the number of years qualified ranged from 1 year 3 months–37 years (mean: 13 years 10 months, median: 12 years 2 months). The majority of respondents reported including the following topics in their clinical encounter before raising the KCQ: i) a general

greeting (n = 39); ii) an introduction of their name (n = 38) and role (n = 31); iii) an explanation of what would be involved in the consultation (n = 31); iv) confirmation of referrer selleck chemicals llc details (n = 28); and v) a check of the patient’s personal details (n = 32), and preferred name (n = 33). Additionally, 16% (n = 7) reported mentioning parking and directions, and 30%

(n = 13) the weather. The preferred phrasing of the KCQ in an initial clinical encounter was “Do you Proteases inhibitor want to just tell me a little bit about (your ‘problem presentation’) first of all?” (score: 83). Preferences for the KCQs are summarised in Table 1. When clinicians were asked for their own preference for opening a clinical encounter (i.e. not from the audio-recordings), a shared theme that arose was to explicitly ask about the patients’ presenting problems and why they had come to physiotherapy in their own words. The themes participants identified as ‘missing’ from

the questionnaire included: a check to see if patients had seen a physiotherapist before; establishing whether patients understood Phospholipase D1 why they had been referred; and their understanding of the role of physiotherapy. In the follow-up consultations, clinicians reported greeting the patient (n = 38), giving a summary of the previous clinical encounters findings (n = 20), and explaining what would be involved in the follow-up consultation (n = 20) prior to asking them about their problem presentation. Additionally, 14% (n = 6) of respondents reported mentioning parking, 5% (n = 2) directions and 37% (n = 16) weather, before the KCQ. An additional topic respondents deemed important to bring up was to check how the patient felt after their initial physiotherapy session. The preferred phrasing of the KCQ by physiotherapists in a follow-up clinical encounter was “How have you been since I last saw you?” (score: 158). Preferences of KCQs in the follow-up encounters are summarised in Table 2. When asked if they had any other preferred ways of opening the encounters, a theme emerged of asking directly about the patient’s symptoms. From the 42 audio-recorded initial consultations, 19% (n = 8) of the KCQs were open, 17% (n = 7) were open-focused and 64% (n = 27) were closed. Open questions elicited on average a 22.

The function of this incretin mimetic is to inhibit the action of DPPIV, thus improving the glycaemic control by prolonging the action of glucagon-like peptide-1 (GLP1) and gastric inhibitory polypeptide (GIP). Moreover, the MK0431 can still stimulate the recovery and the maintenance of pancreatic cells.12, 13, 14, 16, 17, 18 and 19 The salivary gland may be considered similar

to pancreas in some aspects.20 Accordingly, there is evidence indicating Icotinib molecular weight a relationship between insulin production and the salivary tissues. Although the salivary glands are typically exocrine, He et al. demonstrated endocrine secretions related to these tissues. Sánchez García et al., observed that insulin levels found in saliva were similar to plasma levels under normal conditions and suggested that the insulin might be a product of the salivary glands.21 and 22 Thus, knowing this relationship between salivary glands and pancreas, the therapy with MK0431 can lead as yet to the recovery of salivary tissues, similar to the observed in pancreatic cells. However, doubts still exist regarding the efficacy of this treatment in recovery of tissues damaged

by type 1 diabetes. Therefore, this study evaluated the treatment with MK0431 in salivary glands of spontaneously diabetic mice, focusing mainly on the possible therapeutic and hypoglycaemic effects of this dipeptide peptidase IV inhibitor in the recovery of these salivary tissues. Twenty 15-week-old female NOD mice, weighing on average 25 g, were divided into two groups: 10 diabetic Nintedanib in vitro NOD mice (group I) and 10 also

diabetic Isotretinoin NOD mice (group II). The animals were obtained from the Animal House of State University of Campinas (CEMIB-UNICAMP) and were kept under standard conditions of housing, feeding and treatment at the Sector of Laboratory Animal Experimentation (SEA), Department of Morphology and Basic Pathology, Faculty of Medicine of Jundiaí, Brazil. Blood glucose (mg/dL) was measured weekly in all animals with a blood glucose meter (Accu-Chek Performa, Roche, Switzerland). After characterization of the diabetic condition, animals of both groups presented glucose levels higher than 300 mg/dL.23 Then, the animals of group II received MK0431 mixed in pelleted diet (11 g/kg) similar to Lamont and Drucker24 for a period of 4 weeks.17 In order to simulate the experimental conditions of treated group, animals of the group I were manipulated in the same way and received pelleted diet and water ad libitum, however, without hypoglycaemic agents. After treatment, the animals were anaesthetised (imp.) with a mixture of ketamine hydrochloride (130 mg/kg, Francotar, Virbac, Brazil) and xylazine hydrochloride (6.8 mg/kg, 2% Virbaxyl, Virbac, Brazil) and salivary gland samples were collected for analyses by transmitted and polarized light microscopy.

Supportive, it Screening Library ic50 was shown that the biosynthesis of secondary metabolites in Microcystis aeruginosa PCC 7806 occurs essentially during the light period and that they may interact with the diurnal part of the central metabolism ( Straub et al., 2011). Even diverse

marine microbial species can respond synchronously as found by genome-wide transcription profiles of coherent microbial populations followed over two days ( Ottesen et al., 2013). Thus, multispecies metabolic processes are coordinated in time shaping marine biogeochemical cycles ( Ottesen et al., 2013). Still it is unknown whether each species population responds independently to the same environmental cues using its own timing and signaling system or whether species populations are also affected by inter-species communication

( Ottesen et al., 2013). Small signaling molecules may play an important role for a coordinated multispecies response ( Ng and Bassler, 2009). However, FDA-approved Drug Library cost there are diverse timing systems around and elucidation of molecular mechanisms and putative inter-species communication will provide further insight into marine population dynamics. Cyanobacteria potentially are able to switch off the internal clock under certain environmental conditions. For example, S. elongatus showed the highest fitness at low temperature when circadian gene expression was suppressed post-transcriptionally ( Xu et al., 2013). Furthermore, it has been shown that MED4 has lost the protein KaiA and therefore very probably possesses an hourglass-like timing mechanism. Consequently, the trade-off between the benefit and the costs of a circadian clock may vary within different species of Cyanobacteria. However, rhythms of metabolism, in particular redox

rhythms, have been discovered in almost all model organisms ranging from Archaea (Halobacterium salinarum NRC-1), Cyanobacteria (S. elongatus), Plants (Arabidopsis) to Mammals (mouse) and are suggested to be the most ancient and widely used timing mechanism ( Edgar et al., 2012). The authors of this study also infer that organisms with redox rhythms will always exhibit also a circadian rhythm. Megestrol Acetate Very recently, temperature-dependent metabolic rhythms shorter than 24 h, so called ultradian rhythms, have been observed for a cyanobacterium, Cyanothece, when grown under continuous light suggesting ultradian and circadian timing mechanisms to run in a single cell ( Cerveny et al., 2013). It remains an open question whether these rhythms will hold true for all Cyanobacteria. This study was supported by the DFG to I.M.A. and A.W. (AX 84/1-1 and Wi2014/5-1). “
“Pseudomonads demonstrate considerable metabolic diversity and are consequently able to colonize a wide range of niches. The Pseudomonas monteilii species was first identified by Elomari ( Elomari et al., 1997). Most P.

In Experiment FB (top-left panel), TT is generally lower by 0.2–0.8 °C throughout the tropics, except for the strong localized warmings off the Central America and Baja California and the weak warming in the southeastern Pacific. In the regional experiments, locally-generated δTδT’s tend Bosutinib concentration to be dominated by negative signals because T0zzT0zz tends to be negative above the pycnocline (Section 3.2.2; Fig. 4b). As discussed above, the locally-generated signals converge to the equator and propagate eastward along it. In the eastern-equatorial Pacific (EEPO), the

pycnocline rises near the surface so that upper-pycnocline water impacts TT there. Therefore, the part of the remotely-generated signals that impact δTδT in the EEPO are those that lie on the upper pycnocline. As a single measure of the impact of δκbδκb in the EEPO, we use δTδT averaged over the Niño-3 region ( δTN3;150°W– 90°W,5°S– 5°N). For solution FB, δTN3=-0.35°C. Individual contributions of the regional solutions to equatorial δTδT differ considerably, owing to the different, local, background

temperature and salinity VRT752271 cost structures that generate them and their different ways of propagation. The largest contributions to negative δTN3δTN3 come from Solutions ESE and ENE (bottom and upper-middle right panels of Fig. 9), a consequence of their forcing regions having the largest overlap with the Niño-3 region. Interestingly, negative contributions from Solution EQE and EQW are much smaller, because the locally forced negative anomaly is balanced by the underlying, positive one that rises into the upper 50 m there (Fig. 8b). The contributions from Solutions ESW and ENW (bottom and upper-middle left panels of Fig. 9) are small because their near-surface, negative dynamical signals do not much propagate

to the eastern equatorial Pacific, and their positive dynamical signals partially cancel their negative spiciness signals (right panels of Fig. B.3b and Fig. B.4b). In Solutions NE (top-right panel of Fig. 9) and NW (not shown), there is a systematic warming   of TT in the EEPO, a consequence of the dynamical, warming signal rising to the surface there ( Fig. 7b and Fig. B.2b). In contrast, in Solutions SE and SW (not shown) δTδT in the EEPO is weak because FAD their positive dynamical signal is balanced by a strong negative spiciness signal ( Fig. 6b and Fig. B.1b). The contribution from Solution SE is weakly negative because the negative spiciness signal dominates, and that from SW is weakly positive because the spiciness is somewhat weaker and dynamical signal is somewhat stronger ( Appendix B.1). It was surprising to us that the contributions to equatorial TT differ so much among the regional solutions, and that altogether they tend to cool, rather than warm, TT in the EEPO.

Angesichts des engen Zusammenhangs zwischen Proteinaggregation, Metallionen und Neurodegeneration ist es äußerst naheliegend anzunehmen, dass Metalle die Pathophysiologie der HK modulieren könnten. Um Metalle zu identifizieren, die pathophysiologische Bedeutung für HK haben und somit möglicherweise das Alter bei Krankheitsausbruch, IWR-1 clinical trial den Schweregrad und die Neuropathologie beeinflussen könnten, führten Bowman und Kollegen mithilfe einer Striatum-Zelllinie als HK-Modell ein Screening im Hinblick auf einen Zusammenhang zwischen der Krankheit und verschiedenen Giftstoffen durch [157]. Dabei testeten sie das Potenzial von Mn2+, Fe3+, Cu2+, Zn2+, Pb2+, Cd2+, Co2+ und Ni2+, das Überleben von Zellen

einer etablierten, durch Knock-in immortalisierten Striatum-Zelllinie aus der Maus zu modifizieren, die entweder Wildtyp-HTT (STHdhQ7/Q7) oder HTT mit Poly-Q-Expansion (STHdhQ111/Q111) exprimiert

[158], [159], [160], [161], [162], [163] and [164]. Cobimetinib cell line Mit dieser Studie wurde eine neue Gen-Umwelt-Interaktion zwischen der Expression des mutierten HTT und Mn aufgedeckt. Insbesondere senkte akute Exposition der kultivierten Striatum-Zellen gegenüber Mn unerwarteterweise die Verwundbarkeit der Zellen, die das mutierte (STHdhQ111/Q111) exprimierten, durch die zytotoxische Wirkung von Mn im Vergleich zu den Zellen mit dem Wildtyp-Protein (STHdhQ7/Q7) [165]. Darüber hinaus war der in den STHdhQ7/Q7- und den STHdhQ111/Q111-Zellen durch GFAAS bestimmte Gesamtgehalt an Mn nach Mn-Exposition in den Zellen mit dem mutierten Protein signifikant niedriger als in Zellen mit dem Wildtyp. Des Weiteren wurde ADAM7 die Annahme einer Interaktion zwischen

dem mutierten HTT und Mn in vivo durch Experimente mit dem YAC128Q-Mausmodell für HK gestützt. Diese Tiere akkumulieren nach subkutaner Injektion von Mn weniger Mn im Striatum als Wildtyp-Tiere [165] and [166]. Schließlich war der basale Mn-Gehalt signifikant niedriger in Zellen mit mutiertem als mit Wildtyp-Protein, was auch für die mittels CFMEA bestimmte Aufnahme von Mn galt [91]. Die Aufdeckung einer Krankheits-Giftstoff-Interaktion zwischen dem HTT mit Glutamin-Expansion und Mn ist von Bedeutung; sie zeigt, dass es wichtig ist zu klären, auf welche Weise das mutierte HTT-Protein den Mn-Transport und Transportersysteme moduliert, so dass sich eine verringerte Suszeptibilität gegenüber der Toxizität von Mn ergibt. Mn-Überladung wurde auch als Ursache der ALS diskutiert. Diesen Zusammenhang hat Voss erstmals beschrieben, der den Fall eines Mn-Schmelzers aus Deutschland dokumentierte, der an berufsbedingtem Manganismus und bulbärer ALS litt [167]. Danach wurde über einen Mn-Minenarbeiter aus Kuba berichtet, der ebenfalls an berufsbedingten Manganismus litt, Symptome einer Motoneuron-Erkrankung zeigte und sich nach Behandlung erholte [168].

Such a variant would have to be tested to determine whether cytoplasmic expression still confers the beneficial secretion-enhancing effects of full-length cytFkpA. As a consequence of the inability of overexpressed heterologous U0126 molecular weight proteins to fold properly in a timely fashion, misfolded proteins can be deposited in the form of cytoplasmic or periplasmic

inclusion bodies or they can be driven towards degradation (Georgiou et al., 1986, Betton et al., 1998 and Baneyx and Mujacic, 2004) Therefore, we isolated insoluble fractions of E. coli cells expressing XPA23 or ING1 Fabs, in the absence of cytFkpA, but we were unable to detect any Fab species by Western blot analysis (unpublished data), suggesting that no Fab was localized in inclusion bodies. Thus, we cannot support the notion that co-expression of cytFkpA increases the amount of functional Fab by means of improving its solubility. We hypothesize that misfolded or unfolded antibody fragment species serve as substrates for proteolytic degradation, instead of associating into inclusion bodies. We also demonstrate that co-expression of cytFkpA together with the kappa light chain-containing ING1 Fab expressed on a single tricistronic vector results in an improvement of functional Fab

secretion relative to expression in the absence of cytFkpA. Similarly, it previously was shown that the amounts of single chain antibodies expressed in

the periplasm of E. coli upon the co-expression Selleckchem SCH727965 of Skp were also increased when expression of both proteins was driven from a dicistronic vector ( Hayhurst and Harris, 1999). After observing the benefit of cytFkpA co-expression on Fab secretion, we evaluated its contribution to the antibody discovery process by incorporating the same expression platform with cytFkpA into phage panning selection and screening assays. The isolation of ideal lead candidates requires the design of methodologies allowing efficient screening of the libraries and exploitation of the vast repertoire of different library members. The choice of antibody formats (mostly scFv and Fab), the protein expression yields, the sequence ID-8 diversity, the levels of display (i.e. on phage or yeast), and the ease and quality of in vitro screening are just a few of the factors that can impact the quality of antibody libraries (Mondon et al., 2008). In fact, it can be increasingly challenging to design screening assays that allow the identification of high-affinity library members and distinguish them from high-expressing clones since they are both able to display efficiently. Poorly expressed, functional library members are underrepresented and as a consequence, fail to be selected during screening. Thus, it is of paramount importance to maximize the solubility and functional expression of antibody library members.

Therefore, PF-01367338 in vivo in our cohort, sporting activity may have played a substantially larger role in the determination of cortical bone parameters when compared to muscle strength, suggesting that impact loading is a stronger

predictor of cortical parameters, while muscle strength may be a stronger predictor of trabecular outcomes (e.g. Tb.BMD, Tb.Th — trabecular bone mineral density and trabecular thickness, respectively). Both muscle strength and sporting activity were significant predictors of failure load at the distal tibia in the female cohort, but muscle strength accounted for approximately 13% more of the variance in failure load than sporting activity. When investigating the distal tibia of the male cohort, sporting activity accounted for 30% of the variance in failure load, while muscle strength accounted for none. These

seemingly opposite results may have arisen due to sex differences in the variability of muscle strength parameters. Specifically, the variability in knee extension torque was substantially higher in men than women, which NSC 683864 cell line may have influenced our ability to detect a relationship between muscle strength and bone quality in men. This data is in contrast with Nikander et al. [3] who showed that loading modality, but not muscle power or muscle strength, was a predictor of bone strength index at the distal tibia in female athletes (male athletes were not investigated). A possible explanation for the discrepancy is that the bone strength index used by Nikander et al. (density-weighted polar section modulus) is an indicator of bone’s resistance to torsion and bending, while the failure load that we estimated is purely a compressive property. Thus, it is difficult to directly compare the results of the two studies. As stated previously, our results generally indicate that sporting activity involving impact loading is associated with augmented bone quality in both female and male athletes. One single, but perhaps major discrepancy found

in this study was that of female swimmers having significantly higher Ct.BMD at the distal tibia than soccer players after adjusting Resveratrol for age, height, and body mass. We observed a similar trend in males, but the difference across groups was not statistically significant. This finding may suggest that the lack of impact loading in swimming is associated with lower intracortical remodeling, which agrees with previous work [12] and [56] that showed both young and old female athletes have lower Ct.BMD at the tibial shaft than non-athletic controls. Furthermore, Rantalainen et al. [56] showed the trend that young high-impact and odd-impact female athletes exhibit lower Ct.BMD by pQCT than swimmers (not statistically significant), and Ct.BMD of swimmers is not different from controls.

coli bacteria were less sensitive with a growth inhibition of 48 ± 8.5% at 5000 ppm. The presence of light did not significantly increase the toxicity. Increase of the particle size to 930 nm or 60,000 nm did not influence toxicity ( Adams et al., 2006). Silica particles (10–20 nm, purity 99.5%, obtained as dry powder from American Elements, USA), stabilised with a non-toxic dispersant (100 mg Dispex A40/L) did not inhibit oxygen uptake by yeast cells up to

the highest tested concentration of 1000 mg/L; however, some damage of the cell membrane was found Pictilisib nmr (Garcia-Saucedo et al., 2011). Fumed and porous type SiO2 particles (purchased from Sigma Corp., USA) with specific surface areas of 349.71 and 644.44 m2/g, and primary particle sizes of 7 nm (fumed) and 10 nm

(porous type), respectively Everolimus nmr (aggregate sizes not reported), did not affect DNA integrity (as measured in the Comet assay), nor growth or reproduction parameters in Daphnia magna at the only tested concentration of 1 mg/L. An increase in the mortality rate of D. magna was observed after a 96 h-treatment with fumed material (mortality rate 10 ± 8.16%) and porous type material (15 ± 4.08%; controls 5 ± 4.08%). In larvae of the aquatic midge Chironomus riparius, an increase in mortality was observed after exposure to the porous-type SiO2 particles, but growth indicators were not significantly changed ( Lee et al., 2009). Because of the high variability in the results reported by Lee et al. (2009), and because only one dose level (1 mg/L) was tested and therefore no dose–response relationship

can be established, the relevance of these findings is doubtful. Fujiwara et al. (2008) report a non-linear, but size-dependent growth inhibition of algae (Chlorella kessleri) after a 96 h exposure to suspensions of Na2O stabilised SiO2 nanoparticles (Catalloid; 5, 26 and 78 nm). The pH of the culture medium was adjusted to 7.7. The 96 h-EC50 values were 0.8 ± 0.6%, 7.1 ± 2.8%, and 9.1 ± 4.7% for materials with primary particle sizes of 5, 26 and 78 nm, indicating an overall very low level of toxicity, even after exposure concentrations that by CYTH4 far exceed current standard testing guideline recommendations. Toxicity was independent of illumination with light. The size of cells increased in the presence of 5 nm particles, and, to a lesser extent in the presence of materials composed of 26 and 78 nm-sized primary particles (as shown by flow cytometry). Coagulation of cells was observed after exposure to the material containing 5 nm particles (1.02%; test conditions not specified further). In a study reported by Ji et al. (2011), SiO2-nanoparticles showed no significant toxicity in Chlorella up to the highest tested concentration of 1000 mg/L. A low level of toxicity was found in the alga Scenedesmus obliquus by Wei et al. (2010), using silica “nano”-particles (primary particle sizes of 10–20 nm, purity 99.

Evidence for the presence of stochastic fluctuations is provided by the small number of Bcd molecules in nuclei [ 21•, 22• and 77], which, in the absence of averaging mechanisms, cannot reliably specify the sharp borders observed in cycle 14. There are three main models for the reduction of initial variation. The first postulates an unknown posterior gradient, which is not (yet) supported by any experimental evidence (reviewed in [15••]). The second depends on pre-steady-state decoding of the Bcd gradient [31 and 34]. It is unlikely

to apply for reasons discussed above. The third model buy GDC-0941 predicts that reduction in variability occurs as a result of negative feedback loops within the gap gene network [49]. This mechanism was experimentally validated by measuring the variance of Hb boundary position in a mutant background lacking the relevant feedback regulation [49]. While this mechanism

Dabrafenib manufacturer can reduce the effect of variability in maternal gradients, it is doubtful that it can also provide robustness against internal molecular fluctuations. A number of recent modeling studies have provided new insights into the sources of fluctuations in Bcd levels and their effect on patterning precision. The first of these studies shows that positional precision provided by the Bcd gradient is largely limited by internal fluctuations, rather than embryo-to-embryo variability in the amplitude of the gradient [78•]. The signature of these fluctuations is passed on to target gene expression patterns indicating a significant and lasting

regulatory influence of Bcd on target gene expression during the blastoderm stage [79 and 80]. The effect Interleukin-2 receptor of these fluctuations on target gene expression can be reduced, however, by temporal and spatial integration of regulatory input [77] and hb auto-activation by maternal Hb in cycles 11–12 [ 21•]. Temporal and spatial averaging effects were confirmed and analyzed in detail by two studies based on stochastic models of hb regulation by Bcd [ 80 and 81]. Another modeling study reached similar conclusions [ 82]. However, it is based on immunostaining on fixed tissue rather than live imaging which tends to mask intrinsic noise [ 83]. Most models we have discussed so far coarse-grain the detailed structure of cis-regulatory elements, or the molecular mechanisms of transcriptional regulation. A number of models incorporating such details have been used to study the structure and function of regulatory sequences, and the mechanisms by which transcription factors act, or to predict expression patterns from sequence (Figure 2e; reviewed in [15••]). One recent study focused on the arrangement of activator versus repressor binding sites to investigate the mechanism of short-range repression, or quenching [84]. Another study also focused on the role of quenching, considering other transcriptional mechanisms such as co-operative and synergistic transcription factor binding as well [85].