Conclusion: Ulcerative colitis associated with neoplastic polyps patients characteristics of histopathological types, risk factors were more similar to polyps canceration, clinical diagnosis and treatment should be given high priority. Key Word(s): 1. Ulcerative Colitis; 2. Neoplastic Polyps; Presenting Author: JIA SONG Additional Authors: XIAOLAN ZHANG Corresponding Author: XIAOLAN ZHANG Affiliations: The Second Hospital of Hebei Medical

University Objective: Intestinal fibrosis is a serious complication of inflammatory bowel disease (IBD), especially Crohn’s disease (CD). Transforming growth factor-β1 (TGF-β1) is one of the most important fibrogenic cytokines secreted by intestinal myofibroblasts which are the key cells PD98059 in intestinal fibrogenesis. TGF-β1/Smad3 signaling pathway plays a critical role in the process of intestinal fibrosis. Tumor necrosis factor ligand-related molecule-1A (TL1A) combines with its receptor death receptor 3, mainly expressed in activated T cells, providing a costimulatory signal for the activation of T lymphocytes and affecting immune regulation in IBD. TL1A may promote the collagen metabolism of intestinal fibroblasts that are activated by TGF-β1 in vitro. Methods: CCD-18Co is intervened with 10 ng/ml TGF-β1

and the supernatant of peripheral check details blood mononuclear cells (PBMCs) that are intervened by 10 ng/ml TL1A. Cells were grouped as follows: Control group (cultured without TGF-β1 and the supernatant of PBMCs intervened by TL1A), TL1A group (cultured in without TGF-β1), TGF-β1 group (cultured without the HAS1 supernatant of PBMCs intervened by TL1A), TL1A+TGF-β1 group (cultured with TGF-β1 and the supernatant of PBMCs intervened by

TL1A). CCD-18Co proliferation is tested by BrdU assay. The cell cycle is analyzed by Flow cytometric analysis. The activation of CCD-18Co is analyzed by immunocytochemical staining of α-SMA. The hydroxyproline content of CCD-18Co culture medium was measured by hydroxyproline kit (digestion). The expressions of Col1α2, Col3α1, MMP-3, TIMP-1, TGF-β1, Smad3 protein and mRNA in CCD-18Co were detected by western blot and real-time Q-PCR, respectively. Results: Arrested in S phase, the CCD-18Co in TL1A+TGF-β1 group significantly increased the DNA synthesis relative to Control group. Incubation of the CCD-18Co with TL1A and TGF-β1 remarkably changed α-SMA levels. The CCD-18Co in TL1A+TGF-β1 group exhibited enhanced hydroxyproline contents and cell proliferation. The expressions of Col1α2, Col3α1, MMP3, TIMP-1, TGF-β1 and Smad3 protein and mRNA were significantly increased in TL1A+TGF-β1 group compared with that in other groups, while MMP3 /TIMP-1 were declined. Conclusion: Cooperated with TGF-β1, TL1A mediates intestinal fibroblasts activation, proliferation and collagens deposition; its mechanism may be related to TGF-β1/Smad3 signaling pathway. Key Word(s): 1. TL1A; 2. intestinal fibrosis; 3.

There could also be an increase in the number of elements in complex vocalizations, in H1–H2 (‘hoarseness’ or ‘breathiness’ in human voice), in jitter, in the time of peak frequency and possibly of noise (harmonic-to-noise ratio and spectral noise, but see entropy). Therefore, with an increase in arousal, vocalizations 3-deazaneplanocin A chemical structure typically become longer, louder and harsher, with

higher and more variable frequencies, and they are produced at faster rates. These changes correspond closely to those described for humans (Scherer, 1986; Murray & Arnott, 1993; Bachorowski & Owren, 1995; Banse & Scherer, 1996; Zei Pollermann & Archinard, 2002; Juslin & Scherer, 2005; Li et al., 2007). Furthermore, they correspond closely to the effects of the physiological changes linked to an increase in arousal on the acoustic structure of vocalizations, which have been described in humans (Scherer, 1986); increase in the action and/or tension of the respiratory muscles (longer duration, higher amplitude and higher F0), decrease in salivation (higher formant frequencies), increase in the action and/or tension of the cricothyroid www.selleckchem.com/products/Belinostat.html muscles that stretch the vocal folds (higher F0), and increase in pharyngeal constriction and tension of the vocal tract walls (increase of the proportion of energy in

the upper part of the frequency spectrum). The other parameter changes listed in Table 4 are supported by only one study or are not clear (i.e. both increases and decreases have been reported). There is strong evidence for the increase in arousal level associated with the increase in vocalization/element rate, F0 contour, F0 range, amplitude contour, energy distribution (towards higher frequencies), frequency peak and formant contour and the decrease in inter-vocalization interval (5–21 studies, maximum two studies with opposite shift). These parameters appear therefore as ideal indicators of arousal. By contrast, the increase in vocalization/element duration is challenged by eight studies. For example, the increase in duration was not found for some alarm calls (Manser, 2001; Blumstein & Chi, 2011). In meerkats Suricata suricatta, for a given class of predator, high-urgency

situations seem to elicit longer calls than low-urgency situations. However, shorter alarm calls are given in response to more dangerous predators compared with distant predators or non-dangerous animals (Manser, 2001). PD184352 (CI-1040) Similarly, Blumstein & Arnold (1995) found that Alpine marmots Marmota marmo produce alarm calls with fewer elements in higher-urgency situations. Shorter alarm calls may reduce conspicuousness to predators and allow a faster response. Duration also decreased in guinea pigs Cavia porcellus with presumed higher arousal levels during periods of isolation (Monticelli, Tokumaru & Ades, 2004). In the same way, in piglets, the initial increase in duration and in most of the vocal parameters during the first 2 min of isolation was followed by a decrease (Weary & Fraser, 1995a).

Our data show that chronic hepatocellular NF-κB activation is sufficient for liver fibrosis development by way of

recruitment and activation of macrophages. α-SMA, alpha-smooth muscle actin; ALT, alanine amino transferase; AST, aspartate amino transferase; CA, constitutively active; CT, control; DOX, doxycycline; ECM, extracellular matrix; ELISA, enzyme-linked immunosorbent assay; EMSA, electrophoretic mobility shift assay; HPF, high-power field; HPRT, hypoxanthine-guanine phosphoribosyltransferase gene; HSC, hepatic stellate cell; IKK, IκB kinase; LAP, liver activator protein; LPS, lipopolysaccharide; NASH, nonalcoholic steatohepatitis; Torin 1 in vivo NF-κB, nuclear factor-κB; selleck kinase inhibitor PDGF, platelet-derived growth factor; RLU, relative light unit; SAA, serum amyloid A; TGF, transforming growth factor; tTA, tetracycline transactivator. We crossed mice carrying

a constitutively active human IKK2 (CAIKK2) allele17 under the control of a tissue-specific tetracycline-inducible system with animals expressing tetracycline-responsive transactivator (tTA) under the control of the rat liver activator protein (LAP) promotor.14 The generated mice were on a C57BL/6 and NMRI mixed background and were backcrossed at least four times to a C57BL/6 background. Studies were performed on male mice kept under specific pathogen-free conditions. The experiments were approved by the State of Baden-Württemberg in Germany and the University of Ulm Animal Care Committee. To avoid the embryonic activation of the IKK2/NF-κB system, all mice received 0.1 g/L doxycycline in drinking water until birth. In some cases, 4-week-old animals were readministered 0.1 g/L doxycycline (DOX) in drinking water for

3 days, or 12-week-old animals were readministered DOX for 3 weeks, to study whether a continuous CAIKK2 expression is required for the observed liver phenotype. Of note, CAIKK2 mice contain a bidirectional promoter, whose activation leads to simultaneous production of both IKK2 and Photinus pyralis luciferase.17 Mice were sacrificed by way of CO2 inhalation and blood was collected from vena cava inferior. After brief centrifugation, serum was collected and used for measurement of alanine and aspartate aminotransferase levels (ALT and AST; Reflotron Histamine H2 receptor system, Roche). Livers were removed, weighed, and divided into pieces that were fixed in 10% formaldehyde for histological/immunohistochemical analysis, snap-frozen in liquid nitrogen for molecular or biochemical analysis, or rapidly frozen for immunofluorescence staining. For preparing whole liver extract, frozen livers were lysed in Dignam C buffer18 or in RIPA buffer.19 The lysate was centrifuged at 20,000g for 30 minutes at 4°C and the supernatant was recovered. Protein extracts were electrophoresed and subsequently blotted.

Interestingly, knockdown of MAT2β inhibited both collagen and α-SMA expression in these cells. Similar to the results with MAT2A, MAT2β silencing also decreased growth and increased apoptosis after extended periods of knockdown.

Our previous work showed that MAT2β influenced leptin signaling in liver cancer cells and this involved regulation of ERK and PI-3K pathways.21 In this work, we examined the effect of MAT2β silencing on these two pathways because they are well-known survival mechanisms in HSCs and are essential components of profibrogenic response.30 Consistent with our previous findings on the effect of this gene on ERK and PI-3K,21 here we show that MAT2β knockdown ABT-888 in vivo also inhibited activation of these signaling components in LX-2 cells. This function was specific to MAT2β because MAT2A did not influence these signaling pathways. Selleck BMN673 Apart from its role in regulating MATII activity and SAMe homeostasis, MAT2β also plays an important part in regulating signaling in activated HSCs. In summary, we have demonstrated that MAT2A and MAT2β genes, the sole regulators of SAMe homeostasis in HSCs, are induced during in vitro and in vivo activation.

A drop in MATII enzyme activity and intracellular SAMe levels occur during HSC activation along with a fall in global DNA methylation. Silencing of MAT2A or MAT2β gene inhibits collagen and α-SMA expression and cell growth, markers of HSC activation. MAT2β gene affects HSC activation by influencing ERK and PI-3K survival signal mechanisms in HSCs, whereas MAT2A affects growth by changes in intracellular SAMe levels. These findings have important Tacrolimus (FK506) implications regarding

epigenetic changes during HSC activation as well as provide novel therapeutic targets against fibrosis. “
“In order to evaluate and judge a fibrotic stage of patients with chronic hepatitis B, multivariate regression analysis was performed using multiple fibrosis markers. A total of 227 patients from seven hepatology units and institutes were diagnosed by needle biopsy as having chronic liver disease caused by hepatitis B virus. Twenty-three variables and their natural logarithmic transformation were employed in the multivariate analysis. Multiple regression function was generated from data of 158 patients in one hospital, and validation was performed using the other data of 69 patients from six other hospitals. After stepwise variable selection, multivariate regression analysis finally obtained the following function: z = 1.40 × ln (type IV collagen 7S) (ng/mL) − 0.017 × (platelet count) (×10003/mm3) + 1.24 × ln (tissue inhibitor of matrix metalloproteinase-2) (ng/mL) + 1.19 × ln (α-2-macroglobulin) (mg/dL) − 9.15. Median values of fibrosis scores of F1 (n = 73), F2 (n = 42), F3 (n = 31) and F4 stages (n = 12) were calculated as 0.95, 2.07, 2.98 and 3.63, respectively.

6). A few factors may contribute to this phenomenon in fatty liver, as described below. Insulin insensitivity buy CH5424802 in the fatty liver is detrimental to the hormone’s

inhibitory role in gluconeogenesis, primarily through the inactivation of the phosphatidylinositol 3-kinase/serine/threonine kinase–signaling pathway,15 thereby enfeebling the suppression of key gluconeogenic enzymes PEPCK and glucose-6-phosphatase (G-6-Pase) expression.14 In addition, previous studies utilizing radioisotopic analysis also showed that carboxylation of pyruvate into OAA is up-regulated in the diabetic rat liver, concomitant with dramatic increases in PC,16 PEPCK, and G-6-Pase15 expression. These studies corroborate our finding that both PC and PEPCK enzyme activities

are increased Doxorubicin mouse in the fatty liver, leading to larger 13C-malate, -aspartate, and -OAA signals as well as higher rates of chemical exchange with pyruvate. Indeed, higher hepatic PC activity correlated with increased PEPCK activity (r2 = 0.82; P < 0.0001) (Supporting Fig. 4), further supporting the hypothesis that both PC and PEPCK are important regulators in gluconeogenesis.7 In diabetes, pathological alteration of the precise balance between insulin and glucagon action results in excessive hepatic gluconeogenesis and glycogenolysis, both of which induce hyperglycemia. Moreover, inadequate suppression of postprandial glucagon secretion by insulin in the diabetic state causes hyperglucagonemia and evokes elevated HGP, as observed in HFD mice. We previously reported that combined defects in insulin secretion and signaling were not sufficient to cause hyperglycemia in the absence of dysregulated glucagon secretion in a mouse model with deletion of calcium-sensing protein synaptotagmin-7.17 Indeed, glucagon plays a major role in promoting gluconeogenesis in enhancing G-6-Pase activity and PEPCK transcription in the liver, likely through the protein kinase A–signaling cascade mechanism.18 Thereafter, up-regulated gluconeogenesis increases the demand for OAA. In this work, we demonstrated up-regulated

PC activity in glucagon-stimulated HGP in Chow-fed animals, as detected next in vivo with hyperpolarized 13C MRS, through the biomarker kpyr->asp. Concomitantly, glucagon increases PDH activity.19 This technology appears to possess sufficient sensitivity to detect this phenomenon as well, as evident from the higher kpyr->bic exchange rate. Treatment with a glucagon-receptor antagonist appears to alleviate HGP in the diabetic liver,20 and reducing glucagon signaling is being explored as a potential therapy for diabetes.21 It will be interesting to measure corresponding changes in hepatic metabolism upon therapeutic intervention with a glucagon-receptor antagonist in diabetic animals, and that forms the next phase of our research.

3 [4]. It spans approximately 178 kb and contains 52 exons that range in size from 1.3 kb (exon 28) to 40 bp (exon 50) [5]. Analysis of the VWF gene is complicated by at least two other factors in addition to size: (1) there is a partial pseudogene on chromosome 22 with 97% sequence homology to exons 23–34 that necessitates the use of carefully selected gene-specific PCR amplification primers for this region [6] and (2) the VWF locus is highly polymorphic (to date >150 polymorphisms have been reported) (http://www.vwf.group.shef.ac.uk). This makes direct VWF sequencing the methodology of choice for genetic analysis, given that mutation screening selleckchem approaches such as conformation sensitive gel electrophoresis and denaturing

high performance liquid chromatography will be complicated Selleckchem SRT1720 by the frequent sequence variants. The role of genetic testing for each of the current VWD subtypes (Types 1, 2A, 2B, 2M, 2N and 3 VWD), established by the International Society on Thrombosis and Haemostasis, will be reviewed below [7]. (1) Type 1 VWD, a partial deficiency of qualitatively normal VWF, represents the most common form of the disease and is the most problematic in terms of its diagnosis. The genetic

basis of Type 1 VWD has been the focus of much recent investigation and three large multicentre trials have reported consistent results on ∼300 families [11–13]. Mutations (predominantly missense) were identified in ∼65% of index cases and were found more frequently, and with higher penetrance, in cases with Amobarbital lower VWF levels. The most frequently reported genetic variation (10–20% of index cases) identified in all studies was a missense mutation resulting in an amino acid substitution of tyrosine to cysteine at codon 1584 (Y1584C) [14]. Importantly however, some Type 1 VWD patients had no obvious VWF mutation identified and in these (often milder)

cases, the genetic determinants are likely to be more complex and could involve other genetic loci. These studies have therefore confirmed prior suspicions that the genetic basis of this condition is highly variable. This genetic complexity precludes the use of molecular genetic testing as a complementary diagnostic aid in the majority of Type 1 VWD cases at the present time. Type 2A VWD accounts for ∼10% of all VWD cases and is characterized by the loss of high and intermediate molecular weight multimers. Type 2A VWD has been associated with more than 50 different missense mutations that result in two types of pathogenetic mechanisms: either aberrant VWF dimer or multimer biosynthesis (group I mutations) or the synthesis of a protein with enhanced susceptibility to A disintegrin-like and metalloprotease with thrombospondin type 1 results (ADAMTS13)-mediated proteolysis (group II mutations) [15,16]. In addition to providing further insights into VWF structure/function, genetic testing for Type 2A VWD can be employed when phenotypic uncertainty exists.

53 We were not able to assess population substructure in our analysis, because ancestry-informative markers are not yet available for NHANES III. There is little clinical or epidemiological evidence that some individuals or populations may be biologically more resistant or susceptible to HAV infections. It is possible that the three SNPs

identified in our study may simply be markers of population subgroups who have higher exposure to HAV or who migrated to the United States from a region where HAV is highly endemic. Additionally, the statistical power to detect significant associations with uncommon genetic variants was limited. Y27632 This study had 80% power to detect associations in odds ratio ≥1.3 among variants with a minor allele frequency ≥12% in non-Hispanic whites, ≥16% in non-Hispanic blacks, TGF-beta inhibitor and ≥24% in Mexican Americans (Supporting Table 5). It did appear that this study was adequately powered to detect in each racial/ethnic group the three associations that were significant in the Mexican American population (Supporting Table 6). The implicated markers are suggested to be functional by epidemiological, in vitro, or in

vivo studies,35, 36, 42, 45-47 but it is possible that they may be proxies for the true causal variants. If this is the case, then differences in linkage disequilibrium (Supporting Fig. 1) may hamper our ability to detect associations across all three racial/ethnic groups, if they exist.54 The relatively small number

of variants that we examined for each gene also served as a limitation. Further fine mapping in all three racial/ethnic subpopulations may be warranted. Finally, this http://www.selleck.co.jp/products/Romidepsin-FK228.html study is cross-sectional, allowing us to test for disease susceptibility but not incidence or severity. Therefore, it will be important to examine these findings in additional populations and to assess whether these variants are also associated with other factors or characteristics associated with increased risk of hepatitis A infection, some of which may be unrelated to biological susceptibility. For example, some variants may simply be of higher prevalence among Mexican Americans who are of lower socioeconomic status (a risk factor for hepatitis A infection itself) or those who have a higher proportion of Native American ancestry. In conclusion, this study is the first to examine genetic associations with risk of HAV infection using a population-based and nationally representative sample of the United States population. We found significant associations between susceptibility to HAV infection and variants in TGFB1, XRCC1, and ABCB1 among Mexican Americans. It would be prudent to examine these findings in diverse populations. Furthermore, NHANES can be used to facilitate the population-level assessment of new and validated genetic variants for viral hepatitis susceptibility.

, MD (Abstract Reviewer) Speaking and Teaching: Salix, Merck, Vertex; Advisory Committee or Review Panel: Kadmon Gordon, Stuart C., MD (Clinical Research Committee, Abstract Reviewer) Advisory Committee or Review Panel: Gilead, Merck;

Consulting: Achillion, CVS Caremark, Speaking and Teaching: Merck, Gilead, Vertex Gorham, James D., MD U0126 cell line (Abstract Reviewer) Nothing to disclose Green, Richard M., MD (Federal Agencies Liaison Committee) Nothing to disclose Greenbaum, Linda, MD (Abstract Reviewer) Employment: Janssen (spouse) Guevara, Monica, MD (Program Evaluation Committee) Nothing to disclose Hagedorn, Curt H., MD (Abstract Reviewer) Nothing to disclose Hamilton, James P., MD (Program Evaluation Committee) Lectures: Advanced Studies in Medicine Hepatitis B CME Royalties: UpToDate Hardikar, Winita, MD, PhD (Surgery and Liver Transplantation Committee) Nothing to disclose Haynes-Williams, Vanessa E., MSN (Hepatology Associates Committee) Nothing to AP24534 mouse disclose Heimbach, Julie, MD (Abstract Reviewer) Nothing to disclose Heller, Theo, MD (Abstract Reviewer) Nothing to disclose Heuman, Douglas, MD (Abstract Reviewer) Consulting: Bayer AG; Speaking and Teaching: Otsuka America Pharmaceutical, Astellas;

Grants/Research Support: Novartis, SciClone, Scynexis, Bristol-Myers Squibb, MannKind, Wyeth, Ocera Therapeutics, Salix, Globelmmune, InterMune, Hoffman-LaRoche, UCB, Celgene, Centocor, Millennium Research Group, Osiris Pharmaceuticals, Otsuka America Pharmaceutical, Exelixis, Bayer AG Horne, Patrick M., MSN ARNP

(Annual Meeting Education Committee) Scientific Consultant: all Vertex Horslen, Simon P., MD (Surgery and Liver Transplantation Committee) Nothing to disclose Howell, Charles D., MD (Annual Meeting Education Committee) Advisory Board: Genetech; Grants/ Research Support: Boehringer Ingelheim Pharmaceuticals, Esal, Ikaria, Bristol-Myers Squibb; Leadership in Related Society: World Journal of Gastroenterology Hu, Ke-Qin, MD (Program Evaluation Committee) Speaking and Teaching: Bristol-Myers Squibb, Gilead, Genetech, Vertex, Bayer/Onyx Grants/Research Support: Bristol-Myers Squibb, Gilead, Genetech, Vertex, Bayer/Onyx, Merck Hubbard, Sarah B., PA-C (Abstract Reviewer) Advisory Committees or Review Panels: Vertex Pharmaceuticals Ioannou, George, MD (Clinical Research Committee) Nothing to disclose Iwakiri, Yasuko, MD (Abstract Reviewer) Nothing to disclose Janssen, Harry LA., MD (Abstract Reviewer) Consulting: DebioPharm, Abbot, Kirin, Medtronic, Santaris, Roche, Novartis, Bristol-Myers Squibb; Grants/Research Support: Gilead, Bristol-Myers Squibb; Consulting: Gilead, Novartis, Roche, Santaris, Medtronic, Anadys, Innogenetics Jensen, Donald M.

45; P < 0.001) and not serum storage duration Navitoclax (beta = 0.03; P = 0.786) was significantly associated with MDA levels. We also recognize that this cross-sectional study cannot imply causation, and that additional mechanistic studies will be required to definitively establish the role of RES cell iron in the induction of various apoptotic pathways. In conclusion, we found that both HC and RES iron deposition are associated with increased OS, compared to patients without stainable iron. However, RES, but not HC iron deposition, in this disease is characterized by increased apoptosis in the liver, as shown by both in situ

TUNEL staining in the liver and circulating CK18 levels and suggests a mechanism for increased disease severity.

By contrast, our data suggest that selective HC iron deposition in NAFLD may preferentially promote cell necrosis versus apoptosis. Longitudinal studies will also help delineate the dynamic relationship of iron and OS and the role of these in NAFLD progression. The authors thank Andrew Rhieu and Jilene Chua for their work in TUNEL assay development and imaging and Priya Handa for her helpful discussions. “
“The role vitamin D playing in patients with chronic hepatitis C has been intensively studied. However, studies on the potential interaction between vitamin D level and chronic hepatitis B are still limited. This study aimed to explore whether any association existed between serum vitamin D level buy MI-503 and liver histology or virological parameters in patients with chronic hepatitis B infection in Southern China. 25-hydroxyvitamin D serum levels

were determined in a cohort of 242 treatment-naïve chronic hepatitis B patients. Histologic assessment was based on Knodell histologic activity index and Ishak fibrosis staging. Predictors of vitamin D insufficiency were identified using multivariate analysis. Mean 25-hydroxyvitamin D value was 33.90ng/ml. The percentage of patients with different concentration of 25-hydroxyvitamin D (≥30ng/ml, 20-30ng/ml, <20ng/ml) were 59.9%, 31.4% and 8.7%, respectively. Gender, ZD1839 molecular weight season, age and viral genotype were independent predictors of vitamin D insufficiency (<30ng/ml). Patients with genotype B virus infection had a lower mean 25-hydroxyvitamin D level (p=0.023) and higher prevalence of vitamin D insufficiency than those with genotype C (p=0.021) , while no association was found between vitamin D status and viral load. In addition, 25-hydroxyvitamin D level did not significantly vary according to activity grade or fibrosis stage. The prevalence of vitamin D insufficiency is relatively low in our cohort. Patients infected with genotype B had a higher prevalence of vitamin D insufficiency than genotype C. 25-hydroxyvitamin D serum level is not associated with viral load or fibrosis stage in chronic hepatitis B patients.

Material from this area has, however, been documented extensively (MacKenzie et al. 1996, 2004) and the respective analyses indicate high morphological similarity with groups 5 and 6 isolates and the A. ostenfeldii morphotype. Genetic distinctions among the different groups and larger clusters BVD-523 order were further reflected by differences in toxin composition, particularly spirolide profiles. PSP toxins were mainly and most consistently encountered in group 1 of which all strains produced saxitoxin analogs. The composition of STX analogs was not related to specific genotypes, but varied according to geographic distribution, as Baltic strains consistently produced

a different suite of PSTs as compared to genetically similar East U.S. coast strains and the this website Chinese isolate. PSP toxins were less common in the other groups, where only one of the examined strains, IMPLBA033 from Peru, contained PSTs. Hence, presence of PSTs might be considered as a characteristic trait of group 1. However, the present analysis cannot be regarded as fully representative of the PST distribution within the A. ostenfeldii complex.

PST production is, for example, common in group 4 constituting A. ostenfeldii from New Zealand (MacKenzie et al. 1996), a group closely related to groups 5 and 6. Furthermore, low cellular concentrations of PSTs have been reported previously from several group 6 strains – Danish K-0287 (Hansen et al. 1992) and Scottish S06/013/01 (Brown et al. 2010) – found negative in our analysis. It has been discussed MRIP that the ability to produce PSTs may be lost in culture (Martins et al. 2004, Orr et al. 2011). Suikkanen et al. (2013) reported the presence of one of the two sxtA gene motives (sxtA1) involved in saxitoxin production (Stüken et al. 2011) from non-PST producing strains NCH 85 and S6/013/01, indicating that a genetic basis for PST production in group 6 strains exists, but is not operational (Stüken et al. 2011, Hackett et al. 2013). In contrast to PST distribution, spirolides were detected in strains from all investigated phylogenetic

groups, and their composition was clearly in accordance with the group structure. All spirolide producing strains of groups 1 and 2 contained almost exclusively 13dmC whereas groups 5 and 6 strains had diverse toxin profiles and other dominant spirolide analogs. Interestingly, spirolide composition differed quite considerably between groups 5 and 6 despite their close genetic relationship and the geographic proximity of their representative isolates. Spirolide profiles have been considered to be relatively conserved when measured at comparable growth state and thought to be insensitive to environmental change (MacLean et al. 2003, Suikkanen et al. 2013). The analyses presented here confirm the results of earlier spirolide profile characterizations and put them into a phylogenetic context. For example, 13dmC was found in locations and in strains representative of groups 1 (Van Wagoner et al.