8% of patients

treated with TVR twice daily and 72.8% of patients treated with TVR every 8 hours (see Supplementary Results). Relapse rates were similar between those treated with TVR twice daily (7.7%) and every 8 hours (6.5%). Virological response by IL28B genotype showed that the efficacy of TVR twice daily versus every 8 hours was similar regardless of IL28B genotype ( Figure 1B). SVR12 was higher in patients with CC versus non-CC R428 genotypes (90% vs 67%, respectively; P < .0001). In a post hoc analysis, IL28B genotype was strongly associated with SVR12 after adjustment for other baseline factors, including fibrosis stage (odds ratio, 5.00; 95% CI, 3.01–8.30; P < .0001). Virological response rates for TVR dosing twice daily and every 8 hours were also generally comparable across fibrosis stage subgroups ( Figure 1C). In patients without cirrhosis, SVR12 rates were 78% (245/315) and 77% (246/321) for TVR twice daily and every 8 hours, respectively; in patients with cirrhosis, SVR12 rates were 54% (29/54) and 49% (24/49), respectively. Overall, SVR12 was lower in patients with cirrhosis versus those without (51% vs 77%, respectively; P = .0001). When IL28B genotype and fibrosis stage were considered together, the highest SVR12 rate (90%; 95% CI, 84%–94%) was observed in patients with CC genotype with F0 to F2 fibrosis stage and the lowest SVR12 rate (47%; 95% CI, 39%–55%) was observed in patients with non-CC genotype with

advanced fibrosis or Selleck ATR inhibitor Morin Hydrate cirrhosis (F3–F4). Both IL28B genotype and fibrosis stage correlated strongly with SVR12 (P < .0001). Subgroup analyses for baseline characteristics, including sex, region, body mass index, insulin resistance (as measured by homeostasis model assessment of insulin resistance), HCV RNA level, and HCV genotype (1a and 1b), showed

similar SVR12 outcomes for TVR twice daily and every 8 hours (Figure 2). The low numbers of patients older than 65 years and who were Asian, black, or “other” race meant no reliable conclusions could be drawn on differences in SVR12 rate between the 2 TVR dosing regimens in these subgroups. The total treatment duration was determined by RVR rates, which were similar with TVR twice daily (69.4%) and every 8 hours (67.4%). For patients who achieved RVR and were eligible for 24 weeks of treatment (68.4%), SVR rates were 86.3% and 85.2% for TVR twice daily and every 8 hours, respectively. In patients with cirrhosis who achieved RVR, SVR rates after 24 weeks of treatment were 67.9% for TVR twice daily and 58.6% for TVR every 8 hours. The SVR12 rate for the minority of patients who did not achieve RVR was 47% for both dosing regimens. Overall, the extended RVR rates (<25 IU/mL, target not detectable at weeks 4 and 12) were 66.1% and 63.1% for TVR twice daily and every 8 hours, respectively. The proportion of patients with extended RVR rates who achieved SVR12 was 89.3% for both groups. On-treatment virological failure was observed in 38 (10.3%) and 36 (9.

In the early spermatids ( Fig. 7A) the cytoplasm symmetrically encircles the nucleus, which displays diffuse homogenous chromatin and has a circular outline. The centriolar complex lies laterally to the nucleus and is anchored to the plasma membrane. The proximal centriole is anterior and perpendicular to the distal centriole. The distal centriole differentiates into the basal body and forms the single flagellum. The nucleus rotates toward the centriolar complex ( Fig. 7B) with nuclear rotation of 90° considered complete. A depression is newly formed in the nuclear outline at the level of the centriolar complex that penetrates it ( Fig. 7C). Simultaneous to nuclear rotation, the cytoplasm projects in the direction

of the initial segment of the flagellum forming the cytoplasmic canal and midpiece

( Fig. 7A–C). The midpiece contains the mitochondria, forming vesicles and cytoplasmic canal housing the initial segment of the flagellum ( Fig. Etoposide 7B and C). In the spermatozoon of O. kneri the spherical nucleus (about 1.5 μm in diameter) contains highly condensed homogeneous chromatin interspersed by electron-lucent areas, and is surrounded by a narrow strip of cytoplasm with no organelles ( Fig. 7D selleck and E). In the nuclear outline that faces the midpiece there is a medial and moderately deep depression, the nuclear fossa ( Fig. 7D–F). The proximal centriole, initially anterior and perpendicular to distal one, attains an oblique acute angle to the distal centriole. The centrioles are covered by electron dense material and are fastened to one another, to the

nuclear envelope at the nuclear fossa, ID-8 and to the plasma membrane by stabilization fibrils. The proximal centriole and most of the distal centriole are inside the nuclear fossa ( Fig. 7F and G). The midpiece contains the mitochondria, abundant vesicles and the cytoplasmic canal in which lies the initial segment of the flagellum. The midpiece is slightly asymmetric due to the unequal distribution of mitochondria and vesicles. The mitochondria are elongated and mainly accumulated in the larger portion of the midpiece. Vesicles are elongated and mainly concentrated at the periphery and at the terminal regions of the midpiece ( Fig. 7H–K). The single flagellum contains a classic axoneme (9 + 2) ( Fig. 7L). Information on spermiogenesis in A. cataphractus is not available. In P. granulosus and R. dorbignyi, as in O. kneri, spermatogenesis is cystic and spermiogenesis is Type I. In the spermatozoa of A. cataphractus, P. granulosus and R. dorbignyi the nucleus contains highly condensed homogeneous chromatin and is surrounded by a narrow strip of cytoplasm with no organelles ( Fig. 8A, E, I). The nucleus is flattened at the tip and assumes an ovoid shape in P. granulosus (about 1.2 μm in height by 1.8 μm in width) vs. almost spherical in A. cataphractus (about 1.2 μm in height by 1.3 μm in width) and in R. dorbignyi (about 1.4 μm in height by 1.3 μm in width).

Setzt man eine Bioverfügbarkeit für Eisen aus der Nahrung von 18% bzw. 15% an, dann ergeben sich Empfehlungen für die Eisenaufnahme von 18 bzw. 20 mg Fe/Tag für die USA bzw. Europa. Die FAO/WHO nahm für junge Frauen unter Bedingungen einer niedrigen Bioverfügbarkeit einen Wert von 5% an, wodurch sich

die Empfehlung auf 58,8 mg Fe/Tag erhöht. Postmenopausale Frauen, AZD6244 die kein Blut mehr während der Menstruation verlieren, haben ein etwas geringeres Körpergewicht als Männer im gleichen Alter. Die entsprechende RDA für die USA liegt bei 8 mg Fe/Tag; die Werte der FAO/WHO sind ähnlich (Tabelle 1). Während der Schwangerschaft muss von einem basalen Verlust von 14 μg Fe/kg bei einem durchschnittlichen Körpergewicht von 64 kg über 280 Tage ausgegangen werden. Eine Reihe von Datensätzen erlaubt die Abschätzung des Eisentransfers zum Fetus und zur Plazenta: Die FAO/WHO schlägt 315 mg Fe [75] vor, andere Autoren 360 bzw. 450 mg [101] and [102]. Keiner dieser Datensätze bezieht die Veränderungen hinsichtlich des Eisentranfers von der Mutter zum Fetus im Verlauf der Schwangerschaft ein. Das US-FNB wählte für seine Extrapolation den Datensatz der FAO/WHO. Es wurde angenommen, dass der Zuwachs an Hämoglobinmasse während der Schwangerschaft MG-132 research buy 500 mg Fe erfordert. Dies summiert sich auf 1070 mg Fe während der Schwangerschaft. Der geschätzte Blutverlust während der Geburt entspricht jedoch nur 250 bis 350 mg Fe, was den Netto-Eisenverlust

auf 700

bis 800 mg beschränkt. Die prozentuale Eisenresorption steigt während der Schwangerschaft und liegt, nach Schätzung des US-FNB bei 25%. Alle diese Annahmen führen in Kombination zu einer RDA von 27 mg Fe/Tag in den USA und 30 mg Fe/Tag im deutschen Sprachraum [77]; andere Autoren [103] geben zu bedenken, dass dieser Wert zu niedrig sein könnte, da die Berechnung den im Verlauf der Schwangerschaft unterschiedlichen Eisenbedarf nicht berücksichtigt und so den täglichen Bedarf am Beginn der Schwangerschaft überschätzt und gegen Ende der Schwangerschaft unterschätzt. Die FAO/WHO [75] gibt keine RNIs für die Eisenaufnahme Carnitine dehydrogenase während der Schwangerschaft an. Sie argumentiert, dass die Eisenbilanz nicht nur von der Ernährung abhängt, sondern auch von der Größe der Eisenspeicher, die im Verlauf der Schwangerschaft stark variiert [104]. Infolge dieser Variationen steigt der tägliche Bedarf von 0,8 mg Fe/Tag während der frühen Phase der Schwangerschaft auf 10 mg Fe/Tag während der letzten sechs Wochen vor der Entbindung. Etwa 80% des fetalen Eisenbedarfs fallen während des letzten Trimesters an. Ein mütterlicher Eisenspeicher von 500 mg Fe im ersten und zweiten Trimester wären nötig, um ein adäquates Eisengleichgewicht bei der empfohlenen täglichen Aufnahme aufrecht zu erhalten. Da Eisenspeicher von solcher Größe bei Frauen in Entwicklungsländern selten sind, schließt die FAO/WHO, dass der Bedarf nicht allein über die Ernährung gedeckt werden kann [75].

A cloud albedo effect can be attributed Ku0059436 to changing emissions of sulphur dioxide and particulate matter. This effect is based on an analysis of a reprocessed set of satellite measurements from 1985 to 1999 (Krüger & Graßl 2002). Two episodes of cloud reflectance, in the late 1980s and the late 1990s, over the central European main emission area have been compared. The major result of the study was a pronounced

cloud albedo decrease of about 2% from the late 1980s to the late 1990s owing to the decrease in aerosol precursor gases. During winter in source regions of anthropogenic PM emissions, the cloud reflectance is smaller by more than 5%, which in addition points to an absorption effect caused by black carbon in clouds. Comparisons with emission data as well as model results of long range transport over Europe support the conclusion

that aerosol cloud-mediated processes are responsible for significantly changed cloud optical properties. The radiative forcing based on these data for the classical Twomey effect (Twomey 1974) amounts to about 1.5 W m−2 from the late 1980s to the late 1990s. Furthermore, during winter a radiative forcing of about 3 W m−2 due to the absorption effect, i.e. the albedo reduction of clouds (Graßl 1975), was estimated for both the late 1980s and the late 1990s. Further insights into cloud albedo changes can be obtained by considering different European atmospheric circulation patterns (Großwetterlagen). Therefore, the satellite data are evaluated separately for different circulation conditions. A promising way is to consider Großwetterlagen for analysis. Here, we use selleck compound the catalogue by Gerstengarbe & Werner (2005) containing the daily European atmospheric circulation patterns, provided by the Potsdam Institute for Climate Impact Research, together with the German

Weather Service. The atmospheric circulation patterns, which are defined as the mean air pressure distribution over an area at least as large as Europe, are eminently suitable for further subdividing the satellite data over central Europe. The original classification scheme considers three circulation groups comprising 10 major types and 29 sub-types plus undetermined cases. Here, the two major groups, zonal and meridional circulation, are taken into account to assess the influence Ribonucleotide reductase of aerosols on cloud albedo. The zonal circulation group definition in the catalogue is: ‘High sea level pressure covers subtropical and lower middle latitudes and low sea level pressure exists in the sub-arctic and higher middle latitudes. The upper airflow is west to east. Cyclone tracks run from the eastern North Atlantic into the European continent. The zonal circulations include all circulation types ‘West’. When using the data set by Krüger & Graßl (2002) the zonal circulation group during winter exists for 40% of the data for JFND8589 and 30% for JFND9699; but only 25% for MJJA8589 and 27% for MJJA9699.

The heat stimulus was applied with a constant water jet onto the centre of the receptive field. Data were captured and analysed by a CED 1401 interface coupled to a Pentium computer with Spike 2 software (Cambridge Electronic Design; PSTH and rate functions). Stable control responses to electrical and selected natural stimuli were established at 20 min intervals prior to drug administration; this was confirmed with at least 3 consistent responses (< 10%) to all measures. Means of these baseline responses were calculated and used as the ‘pre-drug’ controls from which drug effects on subsequent evoked responses were tested against. Ketanserin

(1, 10 and 100 μg/50 μl saline) was applied topically to the spinal cord in a cumulative manner or ritanserin (2 mg/kg) was administered subcutaneously

into EPZ015666 datasheet the scruff of the neck. DOI (3.6 and 17.8 μg/50 μl saline) was applied topically to the spinal cord in a cumulative manner; a low dose of ketanserin (1 μg/50 μl/saline), which does not produce any effect on neuronal activity on its own, was then administered to the spinal cord. The two routes were used because spinal application of a drug will localise its pharmacological target to pre-or postsynaptic elements in the dorsal horn. We used sub cutaneous administration to assess the effects of systemic Selleckchem NVP-BKM120 exposure. The effect of each drug was followed over an hour per dose, with tests carried out at 10, 30 and 50 min time points post drug application. The nature of the drug injection and recording protocol meant that just one experiment, on one neurone, was performed per animal used. Data are presented as mean ± standard error of mean (SEM) unless otherwise stated. For all studies the maximal effect, compared with pre-drug baseline control, for each dose was selected, this varied and was seen at any of the time points tested i.e. 10, 30 and 50 min post drug

administration. However, in most cases the maximal change in response was observed at 30 or 50 min post drug application. Drug effects were then expressed as the mean maximal effect of the pre-drug control for each dose. Analyses were performed using see more GraphPad Prism version 4 for Apple Macintosh OS 10.4, (GraphPad Software, USA), and for all data, a 95% confidence interval was used as a measure of statistical significance. All statistical analyses were performed on raw data using two-way analysis of variance with repeated measures (RM ANOVA) for responses to mechanical and thermal stimuli, and if significant, Bonferroni post hoc tests were performed. The effect of ketanserin and DOI effect on responses to electrical stimulation were assessed using a one-way RM ANOVA followed by Dunnett’s post hoc multiple comparisons test for significant values. The effect of ritanserin on electrical evoked responses was assessed using a paired Student’s t-test. This work was supported by the Wellcome Trust (R25878) and NIH (Y481862).

An important characteristic AZD2281 manufacturer of a learning organization is its adaptiveness to the surrounding, changing environment. For successful organizational change, crew member participation is vital as well as the will to make changes and improvements. Interestingly, the Reporting and Learning aspects were not closely related as they belonged to different clusters. In practical work settings, this is not uncommon. In Sweden, for example, shipping companies have made some progress along the path of setting up reporting systems and reporting incidents, although not to the extent expected or desired

to achieve good learning for safety. The succeeding steps in the learning cycle – those of analyzing and extracting safety knowledge from reports and of establishing feedback systems on the

improvements implemented – are not well developed in shipping companies or in the shipping industry. Results from other sectors, such as the process industry, show similar weaknesses. Jacobsson et al. [26], who studied learning from incidents in chemical process industries, found weaknesses in the organizational learning, both in horizontal learning (geographical spread of lessons learned) and vertical learning (double-loop learning). The results also showed that the effectiveness in the different steps of the learning cycle was low due to insufficient information in incident reports, superficial analyses of the reports,

decisions that focus on selleck inhibitor solving the problem locally where the incident took place, and late implementations of weak solutions [39]. Similar weaknesses are also believed to exist in the maritime sector and in many countries. The two aspects of Safety-related behavior and Risk perception were closely related, and to some extent there was a relationship to the Attitudes towards safety aspect. Studies have shown that risk perception may influence risk-taking behavior at an individual level e.g., [40], [41] and [42]. There is comprehensive empirical support these for the attitude-behavior relationship [42]. Concerning traffic safety, Iversen [43] summarizes findings on the relationships between attitudes towards safety and risk behavior. The Justness aspect was found to be a separate concept that did not belong to any cluster of aspects. Justness has to do with not blaming people for mistakes but learning from them. This, along with reporting, contributes to organizational learning. Lack of justness can permeate an organization and hinder employees from calling attention to deficiencies in work and safety. This can result in their hesitation to take initiative on the job because of anxiety of what could happen if something went wrong.

A more straightforward ELISA Bioactive Compound Library cell line based on mAbs to the LAP entity was therefore developed. When the LAP ELISA was used to measure Latent TGF-β1 in non-dissociated samples, the observed levels were comparable to total TGF-β1 levels determined by TGF-β1 ELISA. The correlation between the assays, together with the fact that total TGF-β1 levels to > 98.5% derived from Latent TGF-β1, demonstrated the ability of the LAP ELISA to measure Latent TGF-β1 in human samples. Compared to the conventional analysis by TGF-β1 ELISA,

the LAP ELISA provides several advantages. The LAP ELISA analysis can be made without preceding sample acidification and neutralization, procedures that are necessary for the total TGF-β1 ELISA but also involve an increased risk of errors due to incomplete dissociation after acidification or re-association after neutralization (Kropf et al., 1997). In the LAP ELISA, acid treatment did not affect the levels determined demonstrating an equal reactivity of Latent TGF-β1 and dissociated LAP. In addition

to simplifying the analytical C59 wnt mouse procedure, eliminating the use of acid facilitates inclusion of LAP-specific reagents in multiplex analyses including cytokines sensitive to low pH. Each TGF-β isoform is preserved through evolution with close to 100% homology across mammals. Human TGF-β1 is e.g. identical to bovine TGF-β1 and differs only by one amino acid from murine TGF-β1. TGF-β1 ELISAs therefore react with TGF-β1 from bovine Latent TGF-β1, if bovine serum has been added to human cell cultures. The LAP proteins are less conserved and human LAP1 displays 92% and 85% homology to bovine and murine LAP1, respectively. Accordingly, no reactivity with bovine Latent TGF-β1 was displayed by the LAP ELISA, making it possible to analyze human cell supernatants without interference by bovine Latent TGF-β1. The LAP ELISA did however react with Latent TGF-β1 from the evolutionary more closely related macaques. The similar levels detected by LAP and TGF-β1 ELISA in macaques samples

Anidulafungin (LY303366) indicate a high degree of cross-reactivity of the LAP ELISA which could be valuable considering the use of macaques as an animal model for various human diseases including AIDS. Compared to the high interspecies conservation of TGF-β1, the homology between human TGF-β isoforms is lower (≤ 77%) and even lower is the homology between LAP isoforms (≤ 41%). Consequently, the LAP ELISA did not recognize LAP from human Latent TGF-β2 and − 3. Also the individual reactivity of the mAbs used in LAP ELISA as well as MT324, the only mAb functional in Western blotting, was restricted to LAP1. A factor that could interfere with the detection of Latent TGF-β1 by LAP ELISA is the binding of LTBPs to LAP. The cysteine residue at position 33 in LAP can form a disulfide bond with LTBP and non-malignant cells generally secrete Latent TGF-β1 as a large latent complex associated with LTBPs (Mangasser-Stephan and Gressner, 1999).

, 1998). This effect co-exists with highly irregular firing on a single-cell level. Our findings allow for making testable predictions and can

be linked to cortical substrates of memory this website function. We examined oscillatory and spiking phenomena emerging during simulated memory retrieval in two different paradigms using a layer 2/3 attractor network. The network had a hypercolumnar structure (Fig. 1) spanning some 1.5×1.5 mm2 of a subsampled cortical sheet and comprising ~15,000 Hodgkin–Huxley-type multi-compartmental neurons and ~2,000,000 synapses. The model was constituted by 9 hypercolumns each containing 49 minicolumns. Pyramidal cells within the same functional minicolumn had dense recurrent connections and common inputs from layer 4 (Yoshimura et al., 2005). Each hypercolumn was defined by the minicolumns

sharing non-specific feedback inhibition (Yoshimura et al., 2005) from the same basket cell pool, and thus extending ~500 μm (Yuan et al., 2011). The model operated see more in a bistable regime (Amit and Brunel, 1997, Djurfeldt et al., 2008 and Lundqvist et al., 2010) with two distinct network states. During a so-called non-coding ground state all pyramidal cells exhibited low-level irregular activity (~0.2 s−1, Cv2=0.97±0.20), whereas in the coding attractor state each hypercolumn acted as a winner-take-all module with cells in only one minicolumn active at an elevated rate (~3–10 s−1, Cv2=0.98±0.25). There were 49 distinct, globally distributed patterns of network activity, or cell assemblies, acting as attractor memories. Although these patterns ( Fig. 1) were set up manually (see Experimental procedures), they could be assumed to have been formed by prior learning. They consisted of subsets of minicolumns, one from every hypercolumn, connected by structured horizontal

long-range axons ( Muir et al., 2010). The cell assemblies had finite life-time Protein kinase N1 due to the mechanism of cellular adaptation (see Experimental procedures), which forced them to terminate after ~300 ms and caused the network to return to the ground state, i.e. its default operational mode. In this work we considered two alternative approaches to disrupting this default state dynamics and forcing the network’s transition to the coding attractor state. They relate to two separate memory phenomena but result in similar retrieval dynamics once a cell assembly activation is initiated. The first approach, functionally corresponding to pattern completion from a fragmentary input, consisted in partial stimulation of one of the stored memory patterns (stimulation of 5 out of 9 minicolumns participating in a unique distributed pattern, see Experimental procedures) leading to a short-lasting activation of the cell assembly (Fig. 2A). In every 20-s simulation, 20 different patterns were stimulated (partially cued) at a rate of 1 s−1.

2011). River discharge is approximated in terms of monthly mean values for the period 1970–1990 (Bergström & Carlsson 1994). The salinity of river water is set to zero and its temperature equal to the ambient sea water temperature at the river mouth. This approximation (equivalent to ignoring EPZ015666 chemical structure the flux of heat and salt from the rivers) is reasonable for Baltic Sea conditions, where the salt content of river water is negligible and the difference between river and sea water temperatures

is moderate. As the winters during the period of interest were rather mild and the Gulf of Finland was mostly free of ice, we have neglected ice drift and used a simple parameterization for ice formation and melting. For water temperatures below freezing point, the wind stress is decreased by a factor of 10 in order to mimic the presence of ice and the resulting tilt of the ice-covered surface. At 0°C, the heat flux through the ice is stopped as long as cooling conditions prevail. The loss of heat during ice melting is approximated by decreasing the upward-directed heat flux in the early spring by a factor of four until the sea water temperature reaches the value of +1°C. The second key component of the method is a set of Lagrangian trajectories of water particles, which is equivalent INK-128 to a set of particular

solutions to the direct problem of propagation of an adverse impact. In order to create a large number of independent trajectories, the simulation interval is usually divided into shorter Methane monooxygenase (optionally partially overlapping) time windows (Soomere et al. 2010, Viikmäe et al. 2010). The necessary duration of these windows, the time lag between them and the number of trajectories considered (equivalent to the number of particles released into the water), depends essentially on the environment under scrutiny. In terms

of potential oil pollution, the transport of substances released from ships to the shoreline (referred to below as a ‘coastal hit’) is regarded as an undesirable event. For studies of ship-caused coastal pollution and for evaluating the potential risks of ship traffic in the Gulf of Finland, the optimum length of the time window is ca 10 days, during which an appreciable number of coastal hits occurs (Viikmäe et al. 2010). The results are almost insensitive to the time lag between windows, provided the number of windows is large enough. The resulting patterns of risk characteristics are also largely insensitive to the number of particles released into each grid cell (Soomere et al. 2010, Viikmäe et al. 2010). Based on the features discussed, we calculate the set of Lagrangian trajectories (Figure 3) as follows. The entire modelling period (1 May 1987–31 December 1991) is divided into 170 consecutive 10-day time windows.

Expression of the proneural bHLH transcription factor Ascl2

is associated with stemness and is absolutely required for intestinal stem cell maintenance. Active Notch is required for Ascl2 expression and its loss results in precocious crypt cell differentiation [8 and 10]. The proneural protein Atoh1 acts as a master regulator of fate specification learn more of the secretory lineage [2 and 11]. Ascl2 expression is maintained by active Notch signalling that also acts to suppress Atoh1. Expression of Atoh1 is cell-autonomously inhibited by Hes proteins and in the absence of Notch signalling, crypt stem cells precociously differentiate into secretory goblet cells [7 and 12]. The spatial organisation of cells expressing Notch ligand and receptor in the crypt evokes a classic lateral inhibition scenario for control of stem versus secretory fate (Figure 2). Stem cells towards the crypt base found preferentially adjacent to Delta-expressing Paneth cells, express Notch receptor [13• and 14], http://www.selleckchem.com/products/pexidartinib-plx3397.html and are maintained in an undifferentiated state by constant Notch signalling

and suppression of Atoh1 [7, 9, 15 and 16], As migrating cells lose contact with Paneth cells and the high Notch signalling they confer, they become poised between secretory and non-secretory fate. Lineage selection may then arise by stochastic variation in Delta expression leading some cells to express higher levels than others. This initial stochastic imbalance in Delta expression becomes reinforced allowing only a subset of cells (Delta high, Atoh high) rising up the crypt to become committed to a secretory fate while the rest become absorptive enterocytes. This regulation and functional organisation readily explains a binary fate in a supra-Paneth cell poised population but fits less well with a subsequent downstream cascade of secretory lineage choices specified after a series of cell divisions each progressing unidirectionally towards a more restricted fate. Moreover, recent evidence derived from regenerating systems casts doubt both on the existence of stable populations of

progenitors and the irreversibility of lineage specification. For many years it has also been known Janus kinase (JAK) that intestinal regeneration following damage is not solely a function of surviving stem cells expanding to restore homeostasis (Figure 3) [17]. Following radiation induced injury the clonogenic fraction of crypt cells is elevated suggesting that these might correspond to the abundant and immature absorptive cells present within the early transit-amplifying compartment of the lower crypt. In support, specific ablation of the key Lgr5+ population using targeted diptheria toxin is not catastrophic as non-Lgr5+ cells (Bmi1+) cells are able to act as a replacement stem cell pool at least for a limited time [18].