Given the known effects of metal ions on the activities of various DNA and RNA polymerases, we tested if metal ions could affect selleck chemical hepadnavirus RT priming. We report here that Mn(2+), in comparison with Mg(2+), showed dramatic effects on the priming activity of MiniRT2 as well as the full-length, RT. First and foremost, MiniRT2 exhibited full polymerization activity in the presence of Mn(2+), indicating that MiniRT2 contains all sequences essential for polymerization but is unable to transition from initiation to polymerization with Mg(2+). Second,

the initiation activities of MiniRT2 and the full-length RT were much stronger with Mn(2+). Third, the nucleotide and template specificities during protein priming were decreased in the presence of Mn(2+). Fourth, polymerization was sensitive to inhibition by a pyrophosphate analog in the presence of Mn(2+) but not in the presence of Mg(2+). Finally, limited proteolysis provided direct evidence that the priming active MiniRT2 adopted distinct conformations depending on the presence of Mn(2+) versus that of Mg(2+) and that the transition from initiation to polymerization was accompanied by RT conformational change.”
“In this study, we establish that cholesterol and sphingolipid associated with hepatitis C virus (HCV) particles

click here are important for virion maturation and infectivity. In a recently developed culture system WZB117 cost enabling study of the complete life cycle of HCV, mature virions were enriched with cholesterol as assessed by the molar ratio of cholesterol to phospholipid in virion and cell membranes. Depletion of cholesterol from the virus or hydrolysis of virion-associated sphingomyelin almost completely abolished HCV infectivity. Supplementation of cholesterol-depleted virus with exogenous cholesterol enhanced infectivity to a level equivalent to that of the untreated control.

Cholesterol-depleted or sphingomyelin-hydrolyzed virus had markedly defective internalization, but no influence on cell attachment was observed. Significant portions of HCV structural proteins partitioned into cellular detergent-resistant, lipid-raft-like membranes. Combined with the observation that inhibitors of the sphingolipid biosynthetic pathway block virion production, but not RNA accumulation, in a JFH-1 isolate, our findings suggest that alteration of the lipid composition of HCV particles might be a useful approach in the design of anti-HCV therapy.”
“Manganese (Mn) is a transition metal that is essential for normal cell growth and development, but is toxic at high concentrations. While Mn deficiency is uncommon in humans, Mn toxicity is known to be readily prevalent due to occupational overexposure in miners, smelters and possibly welders.

“
“The aim of this study was to explore the changes evoked by organ culture in the signalling pathways activated by noradrenaline in rat resistance mesenteric artery. Contractile responses and calcium signalling were significantly more sensitive to noradrenaline in arteries cultured for 48-72 h in the absence of growth factors compared to fresh arteries. Both calcium release activated see more by noradrenaline in

calcium-free solution and calcium entry measured after the addition of external calcium were higher in cultured arteries than in fresh tissue. Blockers of non-selective cation channels (SKF-96365, flufenamic acid, Gd(3+)) more potently inhibited noradrenaline contraction in cultured arteries than in fresh ones. The src kinase inhibitors genistein or PP2 normalised the increased contraction and the increased calcium release evoked by noradrenaline in cultured arteries. In cultured arteries, trpc1 (transient receptor potential canonical 1) mRNA expression

was decreased by 47 +/- 8% (n = 5, p < 0.05), while trpc6 mRNA expression www.selleckchem.com/products/nepicastat-hydrochloride.html was increased by 92 +/- 24% (n = 5, p < 0.05) in comparison with non-cultured arteries. Immunofluorescence analysis of protein expression confirmed the up-regulation of TRPC6 protein after culture. These results indicate that mesenteric artery culture results in src kinase-dependent increase in the responses to noradrenaline and in a change in cation channel selleckchem activity, which could contribute to the increased contraction. Copyright (C) 2009 S. Karger AG, Basel”
“Repeated, intermittent exposure to drugs of abuse results in response enhancements to subsequent drug treatments, a phenomenon referred to as sensitization. As persistent neuronal sensitization may contribute to the long-lasting consequences of drug abuse, characterizing the neuroanatomical substrates of sensitization is providing insights into addiction. It is known that the ventral tegmental area (VTA) is necessary for induction, and expression involves the nucleus accumbens (NAc). We reveal here that the ventral pallidum (VP), a brain region reciprocally

innervated by the VTA and the NAc, is a critical mediator of opiate-induced behavioral sensitization. Blockade of VP mu-opioid receptors (via intra-VP CTOP injections) negated the ability of systemic administration of the opiate, morphine to induce motor sensitization, and for sensitized rats to subsequently express enhanced responding to a morphine challenge. Intra-VP morphine was sufficient to induce motor sensitization, and this sensitization was expressed following 17 days of withdrawal. Rats with a treatment history of intra-VP morphine demonstrated cross-sensitization to a challenge injection of systemically administered morphine. Conversely, repeated systemic treatments of morphine cross-sensitized to an intra-VP morphine challenge.

All rights reserved.”
“Nicotinic acetylcholine receptors (nAChRs) containing either the alpha 4 and/or alpha 6 subunit are robustly expressed in dopaminergic nerve terminals in dorsal striatum where they are hypothesized to modulate dopamine (DA) release via acetylcholine (ACh) stimulation from cholinergic interneurons. However, pharmacological blockade of nAChRs or genetic deletion of individual nAChR subunits, including alpha 4 and alpha

6, in mice, yields little effect on motor behavior. Based on the putative role of nAChRs containing the alpha 4 subunit in modulation of DA in dorsal striatum, Elafibranor chemical structure we hypothesized that mice expressing a single point mutation in the alpha 4 nAChR subunit, Leu9′Ala, that renders nAChRs hypersensitive to agonist, would exhibit exaggerated differences in motor behavior compared to WT mice. To gain insight into these

differences, we challenged WT and Leu9′Ala mice with the alpha 4 beta 2 nAChR antagonist dihydro-beta-erythroidine (DH beta E). Interestingly, in Leu9′Ala mice, DH beta E elicited a robust, reversible motor impairment S3I-201 characterized by hypolocomotion, akinesia, catalepsy, clasping, and tremor; whereas the antagonist had little effect in WT mice at all doses tested. Pre-injection of nicotine (0.1 mg/kg) blocked DH beta E-induced motor impairment in Leu9′Ala mice confirming that the phenotype was mediated RSL3 ic50 by antagonism of nAChRs. In addition, SKF82958 (1 mg/kg)

and amphetamine (5 mg/kg) prevented the motor phenotype. DH beta E significantly activated more neurons within striatum and substantia nigra pars reticulata in Leu9′Ala mice compared to WT animals, suggesting activation of the indirect motor pathway as the circuit underlying motor dysfunction. ACh evoked DA release from Leu9′Ala striatal synaptosomes revealed agonist hypersensitivity only at alpha 4(non-alpha 6)* nAChRs. Similarly, alpha 6 nAChR subunit deletion in an alpha 4 hypersensitive nAChR (Leu9′Ala/alpha 6 KO) background had little effect on the DH beta E-induced phenotype, suggesting an alpha 4(non-alpha 6)* nAChR-dependent mechanism. Together, these data indicate that alpha 4(non-alpha 6)* nAChR have an impact on motor output and may be potential molecular targets for treatment of disorders as ociated with motor impairment. (C) 2013 Elsevier Ltd. All rights reserved.”
“Background. Medication use is a potentially reversible cause of urinary incontinence (UI). The objective of this longitudinal cohort study was to evaluate whether self-reported UI in community-dwelling older women is associated with the use of different classes of antihypertensive agents.

Methods. The sample consisted of 959 black and white women aged 7281 years without baseline (Year 1) UI from the Health, Aging, and Body Composition Study.

These results show that the core gene ac68 encodes a per os infectivity factor (pif6). The lef3KO virus was also analyzed, and virus replication was drastically reduced compared to WT virus, but very low LGK-974 datasheet levels of lef3KO virus DNA replication and BV production could be detected. In addition, in transfected cells P143 was transported to the nucleus in the absence of LEF3. This study therefore shows for the first time that even though the loss of LEF3 severely impairs virus replication, it is not absolutely essential for P143 nuclear import or viral replication.”
“Background. Patients with obsessive-compulsive disorder (OCD) have to repeat their actions before feeling satisfied that the action

reached its intended goal. Learning theory predicts that this may be due to a failure in the processing of external feedback.

Method. We examined the performance of 29 OCD patients and 28 healthy volunteers on an associative learning task, in which initial learning is based solely on external feedback signals. Feedback valence was manipulated with monetary gains and losses.

Results. As predicted, OCD patients were impaired during initial, external feedback-driven learning but not during later learning stages. The emotional salience of the feedback modulated learning during the initial

stage in patients and controls alike. During later learning stages, however, patients approached near-normal performance with rewarding feedback but continued to produce deficient learning with punishing feedback.

Conclusion. OCD patients have a fundamental impairment in updating behavior based on the external outcome of their actions, possibly Sotrastaurin mediated by faulty error signals in response selection processes.”
“Exposure to traumatic events can lead to posttraumatic stress disorder (PTSD). Current PTSD treatments typically only produce partial improvement. Hence, there is a need for preclinical research to identify new candidate drugs and to develop novel therapeutic approaches. Animal studies

have indicated that fear memories can be weakened by blocking restabilization after retrieval, a process known as reconsolidation. Furthermore, evidence suggests that there are important alterations of the noradrenergic system in PTSD, and hence it may be of interest to study drugs that target this C188-9 molecular weight pathway. Here, we investigated the efficacy of clonidine, an alpha 2-adrenoreceptor agonist, to block reconsolidation in an animal model of persistent traumatic memories. Using an auditory fear conditioning paradigm in rats, we tested the efficacy of clonidine to weaken fear memory retention when administered systemically after retrieval. We evaluated dosage, number of treatments, and specificity in reconsolidation blockade. We found that postretrieval administration of clonidine disrupts fear-related memories in a dose-dependent manner and that two treatments are sufficient for maximal memory impairment.

Glucose-regulated protein 78 (GRP78) is a molecular chaperone that acts within the ER. During ER stress, GRP78 expression is induced as part of the unfolded protein response (UPR). We found that nerve growth factor (NGF) prevented 2DG-triggered ER stress-mediated apoptosis, but

not the induction of GRP78 expression, in PC12 cells. Surprisingly, GRP78 expression was further up-regulated when NGF was added to 2DG-treated PC12 cells. When a specific inhibitor of phosphatidylinositol 3-kinase (PI3-K), LY294002, was added to 2DG plus NGF-treated cells, both the effects of NGF on 2DG-induced apoptosis and GRP78 expression Torin 1 were significantly diminished. In addition, versipelostatin (VST), a specific inhibitor of GRP78 expression, and small interfering RNA (siRNA) against GRP78 mRNA also decreased both the effects of NGF on 2DG-induced apoptosis and GRP78 expression. RT-PCR and Western blot analyses revealed that enhanced production of nuclear p50 ATF6, but not spliced XBP1, mainly contributed to the NGF-induced enhancement of GRP78 expression in 2DG-treated

cells. These results suggest that the NGF-activated PI3-K/Akt signaling pathway plays a protective role against ER stress-mediated apoptosis via enhanced expression of GRP78 in PC12 cells. (C) 2009 Elsevier Ireland see more Ltd and the Japan Neuroscience Society. All rights reserved.”
“Purpose: Voiding cystourethrography is a routine component in evaluating children awaiting renal transplantation. We examined whether this assessment is necessary in children with renal failure due to dysplasia/aplasia/hypoplasia syndrome and unknown etiology, which account for up to 25% of those with renal failure requiring renal replacement therapies.

Materials and Methods: We performed an institutional review board approved, retrospective review of 191 children undergoing transplantation between 2002 and 2007. We reviewed clinical factors associated with positive findings on

voiding cysto-urethrogram. We also reviewed cystography results in children with chronic kidney disease due to renal dysplasia and unknown selleck chemicals etiology.

Results: We identified 113 boys and 78 girls who underwent renal transplantation during the study period. Pre-transplant voiding cystourethrography was documented in 108 children (57%). Predictors of positive pre-transplant results included history of hydronephrosis, urinary tract infections and renal failure due to urological causes. No pre-transplant cystogram was positive in children with renal failure due to dysplasia or unknown etiology.

Conclusions: We recommend selective use of voiding cystourethrography to evaluate children awaiting renal transplantation. We continue to support performing this test in children with renal failure due to urological causes and those with a history of urinary tract infection, hydronephrosis or voiding dysfunction.

Infection with HSV-1 reporter viruses expressing enhanced Selleckchem Trichostatin A green fluorescent protein (EGFP) from immediate early (IE), early, and late gene

promoters indicated that the block to productive infection occurred before IE gene expression. Trichostatin A treatment of quiescently infected neurons induced productive infection preferentially from non-A5(+) neurons, demonstrating that the nonpermissive neuronal subtype is also nonpermissive for reactivation. Thus, HSV-1 is capable of entering the majority of sensory neurons in vitro; productive infection occurs within a subset of these neurons; and this differential distribution of productive infection is determined at or before the expression of the viral Liproxstatin-1 IE genes.”
“A significant body of data suggests that GABA(A) receptors are altered in the CNS of subjects with schizophrenia. However, subjects with schizophrenia are treated with antipsychotic drugs and, in some cases,

antipsychotic drugs and benzodiazepines. It has therefore been suggested that the changes in GABA(A) receptors in the CNS of subjects with schizophrenia are due to such drug treatments. Surprisingly, there appear to be no studies to determine the effect of a combined antipsychotic-benzodiazepine treatment on GABA(A) receptors. We therefore measured both the GABA binding site ([H-3]muscimol) and the benzodiazepine binding site ([H-3]flumazenil) in the CNS of rats treated Selleck PKC412 with either haloperidol, diazepam or a combination of the two drugs. The main findings of our study are that treatment with diazepam or the combination of diazepam and haloperidol results in regionally selective increases GABA binding sites but treatment with haloperidol alone decreases the GABA binding site in the thalamus but increases these sites in the hypothalamus. By contrast, treatment with diazepam, haloperidol and a combination of the two drugs resulted in widespread decreases

in the number of benzodiazepine binding sites in the rat CNS. The notable exception to this outcome was increased numbers of benzodiazepine binding sites in the frontal cortex of rats that had received diazepam. Our data suggests that there are complex changes in the GABA(A) receptor following treatment with haloperidol, diazepam or a combination of these drugs. This outcome may be relevant to the therapeutic benefits of using both drugs in conjunction early in the treatment of a psychotic episode. (c) 2007 Elsevier Inc. All rights reserved.”
“Most bacteria have much more complex chemosensory systems than those of the extensively studied Escherichia coli. Rhodobacter sphaeroides, for example, has multiple homologues of the E. coli chemosensory proteins. The roles of these homologues have been extensively investigated using a combination of deletion, subcellular localization and phosphorylation assays.

rHuEPO- and darbepoetin alfa-treated animals exhibited a restricted brain injury with nearly normal parenchymal architecture. In contrast, the saline-treated group exhibited extensive cerebral cytoarchitectural disruption and edema. The number of surviving NeuN-positive neurons was significantly higher in the rats treated with rHuEPO and darbepoetin alfa compared with those that received saline (P < 0.05).

CONCLUSION: These results demonstrate that weekly administered darbepoetin alfa confers behavioral and histological neuroprotection after ICH in rats similar to that of daily EPO administration. Administration of EPO and its long-lasting recombinant forms affords

Copanlisib significant neuroprotection in an ICH model and may hold promise for future clinical applications.”
“Neurofibromatosis type 2 is an autosomal-dominant multiple neoplasia syndrome that results from mutations in the NF2 tumour suppressor gene located on chromosome 22q. It has a frequency of one in 25 000 livebirths and nearly 100% penetrance by 60 years of age. Half of patients inherit a germline mutation from an affected

parent and the remainder acquire a de novo mutation for neurofibromatosis type 2. Patients develop nervous system tumours (schwannomas, meningiomas, ependymomas, astrocytomas, and neurofibromas), peripheral neuropathy, ophthalmological lesions (cataracts, epiretinal membranes, and retinal hamartomas), and cutaneous lesions (skin tumours). Optimum treatment is multidisciplinary because of the complexities associated with management of the multiple, progressive, and protean lesions associated with https://www.selleckchem.com/products/mek162.html the disorder. We review the molecular pathogenesis, genetics, clinical findings, and management strategies for neurofibromatosis MycoClean Mycoplasma Removal Kit type 2.”
“OBJECTIVE:

Vascular endothelial growth factor (VEGF) enhances neurogenesis in ischemic brains. However, in most circumstances, endogenous VEGF expression is limited and insufficient to prevent brain damage. We transferred the VEGF gene into brain tissue with recombinant adeno-associated virus serotype 1 (rAAV1) vectors and determined the effect of VEGF expression on neurogenesis and recovery of neurological function after brain ischemia.

METHODS: Two groups (n = 32) of Sprague Dawley rats received intraventricular injection of AAV1-VEGF or AAV1-lacZ. Twenty-one days after gene transfer, rats underwent transient middle cerebral artery occlusion, and neurological severity score was measured 1, 2, 3, 7, 14, and 21 days later. Immunostaining was used to identify the quantity and distribution of VEGF expression. Double-immunofluorescence for doublecortin and bromodeoxyuridine or neuronal nuclei was performed to detect neurogenesis and the migration of neural progenitor cells.

RESULTS: VEGF expression reduced the size of cerebral infarction and improved neurological function. It also enhanced the proliferation of neural progenitor cells in the subventricular zone and promoted their migration to the ischemic lesion.

A glutamine substitution at this position stabilizes the native GPC complex and thereby prevents the induction of pH-dependent membrane fusion. In efforts to identify the intersubunit interactions of K33, we performed alanine-scanning mutagenesis at charged residues in the membrane-proximal ectodomain of G2 and determined the ability of these mutations to rescue the fusion GSK621 molecular weight deficiency in K33Q GPC. Four second-site mutations that specifically complement K33Q were identified (D400A, E410A, R414A, and K417A). Moreover, complementation was also observed at three hydrophobic positions in the membrane-spanning domain of G2 (F427, W428, and F438). Interestingly, all of the complementing mutations restored wild-type

pH sensitivity to the K33Q mutant, while none themselves affected the pH of membrane fusion. Our studies demonstrate a specific interaction between SSP and G2 that is involved in priming the native GPC complex for pH-induced membrane fusion. Importantly, this pH-dependent interaction has been shown to be vulnerable

to small-molecule compounds that stabilize the native complex and prevent the activation of membrane fusion. A detailed mechanistic understanding of the control of GPC-mediated membrane fusion will be important in guiding the development of effective therapeutics against arenaviral hemorrhagic fever.”
“The E2 protein of human papillomavirus (HPV) binds to specific sites in the viral genome to regulate its transcription, replication, and maintenance in infected cells. Like most regulatory proteins, E2 is rapidly Selleck Blasticidin S turned over. A high-throughput assay was developed

to quantify the EPZ015666 manufacturer expression and stability of E2 in vivo, based on its fusion to Renilla luciferase (RLuc). The steady-state levels of Rluc-E2 were quantified by measuring the amounts of associated luciferase activity, and its degradation was measured by monitoring the decrease in enzymatic activity occurring after a block of translation with cycloheximide. Using this assay, the E2 proteins from a low-risk (HPV11) and a high-risk (HPV31) human papillomavirus (HPV) type were found to have short half-lives of 60 min in C33A cervical carcinoma cells and to be ubiquitinated and degraded by the proteasome. Analysis of mutant proteins showed that the instability of E2 is independent of its DNA-binding and transcriptional activities but is encoded within its transactivation domain, the region that binds to the cellular chromatin factor bromodomain-containing protein 4 (Brd4) to regulate viral gene transcription. Overexpression of Brd4, or of its C-terminal E2-interaction domain, was found to increase the steady-state levels and stability of wild-type E2 but not of E2 mutants defective for binding Brd4. These results indicate that the stability of E2 is increased upon complex formation with Brd4 and highlight the value of the luciferase assay for the study of E2 degradation.

0 ng/ml (OR 2.4, 95% CI 1.4-4.0) independent of other clinicopathological variables. In men with nondistant disease at diagnosis ductal histology was associated with 2.2-fold (CI 1.4-3.5) increased disease specific mortality.

Conclusions: In what is to our knowledge the largest series of this histological subtype ductal cancer cases were more likely to present with advanced stage cancer and lower prostate specific antigen, suggesting that timely disease Cisplatin solubility dmso detection is a significant challenge. Also, men with locoregional disease were more likely to

die of the disease.”
“Intraindividual trial-to-trial reaction time (RT) variability is commonly found to be higher in clinical populations or life periods that are associated with impaired cognition. In the present study,

higher within-person trial-to-trial RT variability in a perceptual speed task is related to more forgetting and dedifferentiation of memory functions in older adults (aged 60-71 years). More specifically, our study showed that individuals in a high-variability group (n = 175) forgot more JSH-23 in vitro memory scenes over a 1-week retention interval than individuals in the low-variability group (n = 174). In contrast, slower RT speed was associated with poorer episodic memory in general, but unrelated to the amount of forgetting. Moreover, results from multiple group latent factor analyses showed that episodic memory and working memory functions were more highly correlated in the high-variability (r=.63) than in the low-variability (r=.25) group. Given that deficits in dopamine (DA) modulation may underlie increases in RT variability, the present findings are in line with (i) recent animal studies implicating DA in long-term episodic memory

consolidation and (ii) neurocomputational work linking DA modulation of performance variability to dedifferentiation of cognitive functions whatever in old age. (C) 2011 Elsevier Ltd. All rights reserved.”
“Purpose: Skeletal muscle involvement by prostate cancer is considered to be ambiguous for extraprostatic extension when it is found at the apex, where benign prostatic glands naturally blend with the skeletal muscle of the rhabdosphincter. We investigated the significance of skeletal muscle involvement by cancer in needle biopsies in predicting adverse outcomes at radical prostatectomy.

Materials and Methods: From 2000 to 2009, we retrospectively identified 40 cases with Gleason score 6 adenocarcinoma involving up to 20% of 1 core, with skeletal muscle involvement. Outcomes of radical prostatectomy were compared with a control group of 82 cases with the same parameters without skeletal muscle involvement from the same period.

Results: In radical prostatectomy specimens Gleason score greater than 6, extraprostatic extension and positive margins were found in 15.0%, 7.5% and 12.5% of patients in the study group, compared to 20.7%, 11.0% and 4.9% of patients in the control group, respectively.

In BDL rats and isolated HSCs, the treatment with sorafenib reduced hepatic alpha SMA and procollagen-1 alpha mRNA expression. As shown by immunohistochemical staining, perisinusoidal alpha SMA expression was reduced by sorafenib in BDL rats. This was associated

with reduced perisinusoidal deposition of extracellular matrix, as revealed by Sirius red staining. Although no change in PARP cleavage and only a minor increase in hepatic caspase-3 activity were detected in BDL rats in response to sorafenib, livers of sorafenib-treated BDL rats contained small DNA fragments, which were not observed in untreated BDL rats. In conclusion, sorafenib treatment reduces the number of activated HSCs BMS-754807 supplier in cirrhotic livers. This leads to the decrease in intrahepatic vascular resistance, but also to liver damage in the dosage we used. Therefore, any translation to portal hypertensive patients who may profit from sorafenib should be done with particular care. Laboratory Investigation (2011) 91, 241-251; doi:10.1038/labinvest.2010.148; published online 4 October 2010″
“Primary sclerosing cholangitis (PSC) is a cholestatic liver disease with high propensity to develop into LY294002 in vitro cholangiocarcinoma. The hepatobiliary disorder of PSC is due to progressive fibrosis surrounding the intra-and extrahepatic bile ducts. Until now, no effective medical therapy exists.

To study the progression of sclerosing cholangitis after inhibition of the sympathetic nervous system by blockade of the beta-adrenoceptors, we used the Mdr2(-/-) mouse model, which develops periportal fibrosis similar to human PSC. Liver tissues of Mdr2(-/-) mice untreated or treated with the beta-adrenoceptor antagonist propranolol were analyzed for inflammation and fibrosis progression at different time points by histological scoring and immunostaining for alpha-smooth muscle actin (alpha-SMA), CD45 and S100A4. Transaminases and hydroxyproline contents were buy WZB117 determined. Expression of angiotensinogen, endothelin-1, TGF-beta,

TNF-alpha, CTGF and procollagen 1A1 was studied by real-time PCR on laser-microdissected areas of acinar zones I and II-III. After 3 months, periportal fibrosis had developed in Mdr2(-/-) mice, but immunostaining revealed no sinusoidal and only minor periportal contribution of myofibroblasts with prominent fibroblasts. Propranolol treatment of Mdr2(-/-) mice improved liver architecture. Additionally, inflammation and fibrosis were significantly reduced. After 3 months of treatment, the antifibrotic effect of the beta-blockade was most obvious. The transcript levels of procollagen 1A1, TNF-alpha, TGF-beta, CTGF and endothelin-1 were markedly repressed in the portal areas of treated mice. Taken together, these data show that propranolol efficiently delays progression of sclerosing cholangitis.