NASH was diagnosed in 59% and 74% of the patients with normal and

NASH was diagnosed in 59% and 74% of the patients with normal and increased ALT, respectively (P = 0.01). In the JIB-04 in vitro overall series of patients, NASH was independently predicted by ALT (odds ratio [OR], 1.11; 95% confidence interval [CI], 1.04-1.19 per 10-IU/mL increase) and diabetes (OR, 1.5; 95% CI, 1.1-2.0). The same variables were selected in patients with increased ALT, whereas in those with normal ALT, HOMA-IR and ALT were independent predictors. Severe fibrosis was independently

predicted by serum ferritin (OR, 1.04; 95% CI, 1.001-1.08 per 50-ng/mL increase), ALT (OR, 1.07; 95% CI, 1.02-1.14), and diabetes (OR, 1.8; 95% CI, 1.4-2-3) in the overall series, serum ferritin and diabetes in those with increased ALT, and only HOMA-IR (OR, 1.97; 95% CI, 1.2-3.7) in patients with normal ALT. Conclusion: Normal ALT is not a valuable criterion to exclude patients from liver biopsy. Alterations in glucose metabolism and insulin resistance SIS3 in subjects with normal ALT should also be considered in the selection of NAFLD cases for histological assessment

of disease severity and progression.”
“Macrophages and neutrophils are essential elements of host cellular defense systems that function, at least in part, by generating respiration-driven oxidative toxins in response to external stimuli. In both cells, encapsulation by phagocytosis provides a mechanism to direct the toxins against the microbes. The toxic chemicals formed by these two phagocytic cells differ markedly, as do the enzymatic catalysts that generate them. Nitrite ion is microbicidal under certain conditions, is generated by activated macrophages, and is present

at elevated concentration levels at infection sites. In this review, we consider potential roles that nitrite might play in cellular disinfection by these phagocytes within the context of available experimental information. Although the suggested roles are plausible, based upon the chemical and biochemical reactivity PP2 of NO(2)(-), studies to date provide little support for their implementation within phagosomes. (C) 2009 Elsevier Inc. All rights reserved.”
“The genes involved in DNA repair system play a crucial role in the protection against mutations. It has been hypothesized that functional deficiencies in highly conserved DNA repair processes resulting from polymorphic variation may increase genetic susceptibility to breast cancer (BC). The aim of the present study was to evaluate the association of genetic polymorphisms in 2 DNA repair genes, XPD (Asp312Asn) and XRCC1 (A399G), with BC susceptibility. We further investigated the potential combined effect of these DNA repair variants on BC risk.

“Background: Adherence to tuberculosis (TB) treatment is t

“Background: Adherence to tuberculosis (TB) treatment is troublesome, due to long therapy duration, quick therapeutic response which allows the patient to disregard about the rest of their treatment and the lack of motivation on behalf of the patient for improved. The objective of this study was to develop and validate a scoring system to predict the probability of lost Trichostatin A to follow-up outcome in TB patients as a way to identify patients suitable for directly observed treatments (DOT) and other interventions to improve adherence.\n\nMethods: Two prospective cohorts, were used to develop

and validate a logistic regression model. A scoring system was constructed, based on the coefficients of factors associated with a lost to follow-up outcome.

The probability of lost to follow-up outcome associated with each score was calculated. Predictions in both cohorts were tested using receiver operating characteristic curves (ROC).\n\nResults: The best model to predict lost to follow-up outcome included the following characteristics: immigration BI 2536 (1 point value), living alone (1 point) or in an institution (2 points), previous anti-TB treatment (2 points), poor patient understanding (2 points), intravenous drugs use (IDU) (4 points) or unknown IDU status (1 point). Scores of 0, 1, 2, 3, 4 and 5 points were associated with a lost to follow-up probability of 2,2% 5,4% 9,9%, 16,4%, 15%, and 28%, respectively. The ROC curve for the validation group demonstrated a good fit (AUC: 0,67 [95% CI; 0,65-0,70]).\n\nConclusion: This model has a good capacity to predict a lost to follow-up outcome. Its use could help TB Programs to determine which patients are good candidates for DOT and other strategies to improve TB treatment adherence.”
“Motivation: Metabolite identification from tandem mass spectra is an important problem in metabolomics, underpinning subsequent metabolic modelling and network analysis. Yet, currently this task requires matching the observed spectrum against a database of reference spectra originating from similar equipment and closely matching operating parameters, a condition that is rarely satisfied in public repositories.

PR-171 Furthermore, the computational support for identification of molecules not present in reference databases is lacking. Recent efforts in assembling large public mass spectral databases such as MassBank have opened the door for the development of a new genre of metabolite identification methods.\n\nResults: We introduce a novel framework for prediction of molecular characteristics and identification of metabolites from tandem mass spectra using machine learning with the support vector machine. Our approach is to first predict a large set of molecular properties of the unknown metabolite from salient tandem mass spectral signals, and in the second step to use the predicted properties for matching against large molecule databases, such as PubChem.

(C) 2010 AEU Published by Elsevier Espana, S L All rights reser

(C) 2010 AEU. Published by Elsevier Espana, S.L. All rights reserved.”
“A breed known for its versatility, the American Quarter Horse (QH), is increasingly bred for performance in specific disciplines. The impact of selective breeding on the diversity and structure of the QH breed was evaluated using pedigree analysis and genome-wide SNP data from horses representing 6 performance groups (halter, western pleasure, reining, working cow, cutting, and racing). Genotype data (36 037 single nucleotide polymorphisms [SNPs]) from 36 Thoroughbreds were also evaluated with those from the 132 performing QHs to evaluate the Thoroughbreds

influence on QH diversity. Results showed significant population structure among all QH performance groups excepting the comparison between the cutting and working cow horses; divergence was greatest between the cutting and racing QHs, the latter of which had a large contribution of Thoroughbred selleck products ancestry. Significant coancestry and the potential for inbreeding exist within performance groups, especially when considering the elite performers. GSK923295 inhibitor Relatedness within performance groups is increasing with popular sires contributing disproportionate levels

of variation to each discipline. Expected heterozygosity, inbreeding, F-ST, cluster, and haplotype analyses suggest these QHs can be broadly classified into 3 categories: stock, racing, and pleasure/halter. Although the QH breed as a whole contains substantial genetic diversity, current breeding practices have resulted in this variation being sequestered into subpopulations.”
“The propagation of phosphorylation downstream of receptor tyrosine

kinases is a key dynamic cellular event involved in signal transduction, which is often deregulated in disease states such as cancer. Probing phosphorylation dynamics is therefore crucial for understanding receptor tyrosine kinases’ function and finding ways to inhibit their effects. MS methods combined with metabolic labeling such as stable isotope labeling with amino acids in cell culture (SILAC) have already proven successful in deciphering temporal phosphotyrosine perturbations. However, they are limited in terms of multiplexing, and they also are time consuming, because several experiments need to be performed separately. Here, we introduce an innovative approach based on 5-plex SILAC that allows monitoring of phosphotyrosine signaling perturbations induced by a drug treatment in one single experiment. Using this new labeling strategy specifically tailored for phosphotyrosines, it was possible to generate the time profiles for 318 unique phosphopeptides belonging to 215 proteins from an erlotinib-treated breast cancer cell line model. Hierarchical clustering of the time profiles followed by pathway enrichment analysis highlighted epidermal growth factor receptor (EGFR or ErbB1) and ErbB2 signaling as the major pathways affected by erlotinib, thereby validating the method.

The ideal and accurate preoperative planning of plating and screw

The ideal and accurate preoperative planning of plating and screwing can be achieved in the real surgery assisted by the 3D models library of implants and the patient-specific navigational

template. This technology improves the accuracy and efficiency of personalized internal fixation surgery and we have proved this in our clinical applications.”
“Background and PurposeMost Silmitasertib forms of human obesity are characterized by impaired leptin sensitivity and, therefore, the effectiveness of anti-obesity leptin therapy in these leptin-resistant obese patients is marginal. Hence, the development of strategies to increase leptin sensitivity is of high priority in the field of obesity research. Experimental ApproachWe first examined the effects of co-administration of leptin and meta-chlorophenylpiperazine (mCPP), an agonist of 5-HT2C and 5-HT1B receptors, on energy balance in leptin-resistant diet-induced obese (DIO) mice. We further assessed leptin-induced phosphorylation of the STAT-3 (pSTAT3) in various brain regions of DIO mice pretreated with mCPP or in mice genetically Selleck Natural Product Library lacking 5-HT2C receptors. ResultsCo-administration of mCPP with leptin had an additive effect on reducing body weight in DIO mice.

Furthermore, mCPP pretreatment in DIO mice enhanced leptin-induced pSTAT3 in the arcuate nucleus, the ventromedial hypothalamic nucleus, and the ventral premammillary nucleus. Finally, deletion of 5-HT2C KYT-0353 receptors significantly blunted leptin-induced pSTAT3 in these same hypothalamic regions. Conclusions and ImplicationsOur study provides evidence that drugs, which activate 5-HT2C receptors, could function as leptin sensitizers and be used in combination with leptin to provide additional weight loss in DIO.”
“The action of VEGF (vascular endothelial growth factor)

is essential to maintain proper endothelial and vascular function. VEGF stimulates virtually all aspects of endothelial function, namely proliferation, migration, permeability and nitric oxide production and release. in addition, the action of VEGF makes the endothelium anti-apoptotic. in turn, the inhibition of VEGF action is associated with endothelial dysfunction. Likewise, endothelial dysfunction can be found in the presence of several cardiovascular risk factors, including diabetes mellitus, hypercholesterolaemia and smoking. As circulating monocytes express functionally active VEGFR-1 (VEGF receptor 1) on their surface, monocytes and the related VEGFR-1-mediated signal transduction cascades have come into focus. The function of monocytes is negatively affected by diabetes mellitus, resulting in monocyte dysfunction. More specifically, a VEGF-related signal transduction defect can be detected in monocytes isolated from diabetic individuals. This reduced monocyte response to VEGF, demonstrated by a reduced chemotactic response, can be regarded as VEGF resistance.

Analysis of human fetal livers suggests that similar progenitors

Analysis of human fetal livers suggests that similar progenitors are present in human livers. Lineage tracing in mice provides in vivo evidence of a KDR+ hepatic progenitor for fetal hepatoblasts, adult hepatocytes, and adult cholangiocytes. Altogether, our buy GDC-0941 findings reveal that

KDR is a conserved marker for endoderm- derived hepatic progenitors and a functional receptor instructing early liver development.”
“Objectives: Uncomplicated acute type B aortic dissection (AD) treated conservatively has a 10% 30-day mortality and up to 25% need intervention within 4 years. In complicated AD, stent grafts have been encouraging. The aim of the present prospective randomised trial was to compare best medical treatment (BMT) with BMT and Gore TAG stent graft in patients with uncomplicated AD. The primary endpoint was a combination of incomplete/no false lumen thrombosis, aortic dilatation, or aortic rupture AMN-107 at 1 year. Methods: The AD history had to be less than 14

days, and exclusion criteria were rupture, impending rupture, malperfusion. Of the 61 patients randomised, 80% were DeBakey type IIIB. Results: Thirty-one patients were randomised to the BMT group and 30 to the BMT+TAG group. Mean age was 63 years for both groups. The left subclavian artery was completely covered in 47% and in part in 17% of the cases. During the first 30 days, CBL0137 mouse no deaths occurred in either group, but there were three crossovers from the BMT to the BMT TAG group, all due to progression of disease within 1 week. There were two withdrawals from

the BMT+TAG group. At the 1-year follow up there had been another two failures in the BMT group: one malperfusion and one aneurysm formation (p = .056 for all). One death occurred in the BMT TAG group. For the overall endpoint BMT+TAG was significantly different from BMT only (p smaller than .001). Incomplete false lumen thrombosis, was found in 13 (43%) of the TAG+BMT group and 30 (97%) of the BMT group (p smaller than .001). The false lumen reduced in size in the BMT+TAG group (p smaller than .001) whereas in the BMT group it increased. The true lumen increased in the BMT TAG (p smaller than .001) whereas in the BMT group it remained unchanged. The overall transverse diameter was the same at the beginning and after 1 year in the BMT group (42.1 mm), but in the BMT+TAG it decreased (38.8 mm; p = .062). Conclusions: Uncomplicated AD can be safely treated with the Gore TAG device. Remodelling with thrombosis of the false lumen and reduction of its diameter is induced by the stent graft, but long term results are needed. (C) 2014 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

Within switchers, median time to switch was 53 days Switching

Within switchers, median time to switch was 53 days. Switching

patients had generally a more severe PSI-7977 psychiatric profile, including more previous episodes of depression or other psychiatric disorders. They also had a higher proportion of concurrent psychiatric disorders (especially anxiety) and concomitant prescription of anxiolytics or hypnotics. Patients initially prescribed amitriptyline were almost twice as likely to switch (27%) as patients prescribed venlafaxine (17%) or an SSRI (15%). Conclusions: This population-based study confirmed that antidepressant switch is more likely to occur within the first 3 months of treatment and in patients with a more severe psychiatric profile. A particular attention paid to these patients within the early phase of treatment may therefore help to improve their management.”
“A number

of single CH5183284 nmr gene mutations in laboratory mice produce hair follicle defects resulting in deformed hair shafts. The radiation-induced (SB/LeJ-Foxq1(sa)) satin mutant mice have a satin-like sheen to their hair and dilute colouration. This sheen is due to failure of the hair shafts to develop normal medullas, while the pigment dilution is due to the unrelated beige (lysosomal trafficking regulator, Lyst(bg)) mutation. A new allelic mutation, Foxq1(sa-J), arose spontaneously on the albino (tyrosinase, Tyr(c)) MRL/MpJ-Fas(lpr) background. The Foxq1(sa-J) allele has a C to T transition at position 490. By contrast, the Foxq1(sa) mutant allele was confirmed to be a 67 base pair deletion followed by two base changes (GA to AT). Morphologic changes were similar to those seen in Hoxc13 transgenic and targeted mutant mice. This new allelic mutation provides yet another tool to investigate formation of the interior structures of hair shafts.”
“People vary in their proneness to dominate as a function of their motivation to fulfill their need for reward and social status. Recent research suggests that in humans dominant individuals respond vigilantly to angry faces, whereas non-dominant individuals

rapidly signal submission. Dominance motivation CHIR-99021 datasheet has been suggested to reside in asymmetrical patterns of cortical and subcortical processing. The ratio between delta and beta band oscillations has been proposed as a proxy for this asymmetry, which we here aimed to map onto individual patterns of the event-related potentials (N170) as well as behavioral responses to facial anger in the context of dominance motivation. Results show that dominance motivation indeed predicts increased delta in the delta/beta asymmetry; a pattern that further translates into behavioral vigilance as well as attenuation of the event-related response to angry faces. The present data are interpreted to suggest that dominance motivation is related to increased subcortical and decreased cortical processing, and that this translates into increased vigilance in dominance challenges.

The water binding capacity

The water binding capacity (WBC) (P smaller than 0.01), swelling capacity (P smaller than 0.01) of gestation diets, the concentration of total short chain fatty acids (P smaller than 0.05) after in vitro fermentation of gestation diets increased linearly with increasing inclusion amounts of KF. During the second reproductive cycle, increasing dietary KF linearly increased plasma concentrations of short chain fatty acids (SCFA) 4h postprandial (P smaller than 0.05) and glucagon-like peptide (GLP-1) 2h post-prandial (P smaller than 0.05), but decreased the plasma concentration of cortisol (linearly, P smaller than 0.05) 1 h postprandial. In addition, there was

a linear decrease of the non-feeding oral behavior of gestating sows (P smaller than 0.01) when dietary KF increased. There were linear increases in lactation feed intake of sows during entire lactation period (P smaller than 0.01) with increasing amounts of KF in the gestation selleck chemicals diet. In addition, the number of piglets weaned (linearly, P smaller than 0.01; quadratic, P = 0.01), average piglet weights and litter weights on day 21 of lactation (linearly, P smaller than 0.01) increased with increasing inclusion amounts of KF. In conclusion, inclusion of dietary fiber with great WBC, swelling

capacity and fermentation capacity in the gestation diet was beneficial for enhancing postprandial satiety in pregnant sows, increasing lactation feed intake and improved number of piglets weaned per litter through greater pre-weaning survival. (C) 2014 Published by Elsevier B.V.”
“Natural graphite flakes were intercalated with strong oxidizing agents and were converted into thermally expanded graphite (TEG) through thermal exfoliation. Thermally expanded graphite was delaminated and transformed into graphene nanoplatelets (GNP) by using ultrasonic irradiation. GNP integrated polyaniline (PANi) nanocomposites were synthesized via in-situ polymerization of aniline monomers in the presence of GNP. The structure and morphology of composite was evidenced by scanning electron microscopy, Transmission electron microscopy (TEM), X-ray diffraction and Raman spectroscopy. TEM micrographs revealed that GNP consists of 20-25 graphene layers and PANi was uniformly coated on GNP. From Raman analysis it was showed significant interactions between GNP and polyaniline. Electrical conductivity was measured by using 4-point probe device, enhanced conductivity was obtained for composite. (C) 2015 Elsevier Ltd. All rights reserved.”
“Objective. To investigate the expression of vascular endothelial growth factor (VEGF) in muscle biopsy specimens and serum from patients with polymyositis and patients with dermatomyositis compared with that in healthy control subjects.\n\nMethods. Muscle biopsy specimens from 33 patients with polymyositis or dermatomyositis and 15 healthy control subjects and serum samples from 56 patients and 56 healthy control subjects were analyzed.

Patients receiving immunosuppression had reduced odds of persiste

Patients receiving immunosuppression had reduced odds of persistent hemophilia, with combination chemotherapy being the most efficacious (OR 0.04, CI 0.01-0.23) and steroid therapy alone being the least (OR 0.38, CI 0.140.94). In acquired hemophilia, increased age, underlying malignancy, and lack of complete

remission are risk factors for death. Although the included studies were not randomized, patients treated with combination chemotherapy had the greatest odds of remission and the lowest odds of death. Blood Coagul Fibrinolysis 20:517-523 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.”
“The purpose of this study was to investigate the effect of Raf kinase inhibitor protein (RKIP) on the growth, proliferation, invasion and metastasis of triple-negative breast cancer (TNBC) cells to provide experimental evidence for selleck compound developing future therapies against human TNBC. The pcDNA3.1-RKIP eukaryotic expression vector was constructed and transfected into the TNBC cell line MDA-MB-231. The alterations of the biological characteristics of RKIP-transfected MDA-MB-231 cells were analyzed using the following

approaches: a growth curve, a 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide (MTT) assay, bromodeoxyuridine (BrdU) staining and a cell migration assay. The effects of the RKIP gene on MMP-1 and MMP-2 expression were also examined. The pcDNA3.1 empty vector-transfected and mock-transfected MDA-MB-231 cells were used as control groups. Compared with the empty vector-transfected and mock-transfected cells, the cell growth check details of RKIP-transfected MDA-MB-231 cells was significantly reduced. The empty vector-transfected group was not significantly different compared with the mock-transfected MDA-MB-231 cells. The results of the MTT and BrdU assays demonstrated that the proliferation of pcDNA3.1-RKIP-transfected cells was significantly reduced compared to the control cells (P < 0.05). The result of the cell migration assay suggested

that the cross-membrane migration rate of the pcDNA3.1-RKIP-transfected cells was significantly lower than that of the control MDA-MB-231 cells (P < 0.05). We also demonstrated that RKIP may inhibit MMP-1 and MMP-2 expression in P005091 MDA-MB-231 cells. The RKIP gene may play a role in inhibiting cellular proliferation. The RKIP gene may also have some inhibitory effects on the invasiveness and metastatic capability of human TNBC cells.”
“We studied expression of tight junction proteins and formation of the barrier properties in the culture of umbilical vein endothelial cells under conditions of co-culturing with allogenic GFAP-positive astrocytes. This culturing signifi cantly increases of expression of tight junction proteins (claudin-5, occludin, and ZO-1).

Thirty-one of 290 (10 7 %) patients had experienced 42 newly

\n\nThirty-one of 290 (10.7 %) patients had experienced 42 newly developed symptomatic secondary OVCFs. Among 169 operation (53.3 % vertebroplasty, 46.7 % kyphoplasty) and 121 comparison patients, there is no significant statistical difference of new OVCFs incidence between the two groups calculated

by patient proportion. However, in separate, the rate of secondary adjacent fractures calculated by vertebral refracture number is significantly higher than non-adjacent levels in PVP/PKP group but no significant statistical difference was observed in conservative group. The time interval of recompression after operative procedure was much shorter than that for comparison group (9.7 +/- A 17.8 versus 22.4 +/- A 7.99 months, p = 0.017). In addition, older age, gender, fracture times, location of original fracture segment, the amount of cement, cement leakage, operation modality (PVP or PKP),and initial see more number of OVCFs were documented, but these were not the influencing factors in this study (p > 0.05).\n\nPatients who had experienced PVP/PKP were not associated with an increased risk of recompression in new levels. However, recompression in new levels of PVP/PKP group occurred much sooner than that of conservative group in the follow-up period. The incidence of new vertebral fractures observed at adjacent levels was substantially

higher but no sooner than at distant levels in PVP/PKP group. No major risk factors involving new OVCFs have Cilengitide been found in this study and augmentation for sandwich situation is not necessary.”
“The reported data on the developmental expression of Hsd17b10 gene in Danio rerio is crucial to the utilization of the D. rerio embryo as an animal model for human developmental disorders caused either by mutations on HSD17B10 (formerly

HADH2) or by defective expression of the gene. Related diseases were summarized, and it was noticed that hyperinsulinaemic hypoglycaemia is not linked to HSD17B10. This inherited disease is actually caused by a deletion in the HADH gene on chromosome 4. Moreover, it was MAPK Inhibitor Library screening found by a revision of the reported phylogenetic tree that hydroxyacyl-CoA dehydrogenase II or rather hydroxysteroid (17beta) dehydrogenase 10 (HSD10) of amphioxus Branchiostoma belcheri-occupies a transition position from HSD10 orthologs of invertebrates to those of vertebrates.”
“For effective guideline implementation it is recommended to develop and apply carefully designed implementation strategies and instruments. Computerized decision support systems (CDSSs) are such instruments as they can improve guideline adherence by providing advice at the point of care. To improve the implementation of the Dutch cardiac rehabilitation guidelines a CDSS, named CARDSS, was developed. CARDSS actively provides care professionals with patient-specific, guideline-based treatment recommendations at the onset of a patient’s rehabilitation trajectory.

SCI rats did not exceed the Z-threshold during CMG ConclusionsWe

SCI rats did not exceed the Z-threshold during CMG. ConclusionsWe standardized a suitable urodynamic protocol to study supraspinal activation during reflexive micturition using simultaneous CMG/fMRI with high spatial resolution. Small contractions in SCI rats may be caused by increased excitability of afferent pathways without brain activation. Our results represent the first fMRI study in SCI rats. Neurourol. Urodynam. 34:469-474, 2015. (c) 2014 Wiley Periodicals, Inc.”
“Through alternative splicing, find more the human cannabinoid CB1 receptor gene encodes three variants of protein products (hCB(1), hCB(1a), and hCB(1b),) that differ in amino

acid sequence at the N terminus of the receptors. By semi-quantitative PCR from human adult and fetal brain mRNA, we demonstrated that the transcript encoding hCB(1) is the major transcript, and estimated that those of hCB(1a) and hCB(1b) represent fewer than 5% of the total human cannabinoid CB1 receptor transcripts. We characterized

the three variants stably expressed in CHO cells. In the contrary to the study by Ryberg et al. (FEBS Lett 579[1], 259-64), we did not find substantial difference among the three variants according to the binding affinity, functional potency, and efficacy of meth-anandamide, 2-arachiclonoyl glycerol, virodhamine, Noladin ether, docosatetraenylethanolamide,, CP55940, AM251, and compound 35e (an acyclic class human CB1 receptor inverse agonist similar to MK-0364). GW4869 chemical structure The functional significance of different hurnan cannabinoid CB1 receptor variants remains to be clarified. (C) 2008 Elsevier B.V. All rights reserved.”
“Cyclic adenosine 3′,5′-monophosphate (cAMP) and cyclic guanosine 3′,5′-monophosphate (cGMP) are second messengers for numerous mammalian cell functions. The natural occurrence and synthesis of a third cyclic nucleotide (cNMP), cyclic cytidine 3′,5′-monophosphate (cCMP), is a matter of controversy, and almost nothing is known about, cyclic uridine 3′,5′-monophosphate (cUMP). Bacillus anthracis and Bordetella pertussis secrete the adenylyl cyclase (AC) toxins edema factor (EF) and CyaA,

respectively, weakening immune responses and facilitating bacterial proliferation. A cell-permeable cCMP analogue inhibits human neutrophil superoxide production. Here, we report that EF and CyaA also possess cytidylyl cyclase (CC) and uridylyl cyclase (UC) activity. CC and UC activity was determined by a radiometric assay, using [alpha-(32)P]CTP and [alpha-(32)P]UTP as substrates, respectively, and by a high-performance liquid chromatography method. The identity of cNMPs was confirmed by mass spectrometry. On the basis of available crystal structures, we developed a model illustrating conversion of CTP to cCMP by bacterial toxins. In conclusion, we have shown both El: and CyaA have a rather broad substrate specificity and exhibit cytidylyl and uridylyl cyclase activity. Both cCMP and cUMP may contribute to toxin actions.