Recent studies indicate differential involvement of the centromedial amygdala (CM) and the bed nucleus of the stria terminalis (BNST) during processing (anticipation and confrontation) of threat ...stimuli. Here, temporal predictability was shown to be a relevant factor. In this study, we want to investigate the relevance of these effects, which were found in healthy subjects, for anxiety disorders. Therefore, we investigated the differential involvement of CM and BNST in the anticipation and confrontation of phobic stimuli under variation of temporal predictability in spider phobia. 21 patients with spider phobia and 21 healthy controls underwent a temporally predictable/unpredictable phobic and neutral anticipation and confrontation paradigm using functional magnetic resonance imaging (fMRI) and ROI analyses. During the anticipation phase, healthy controls showed higher CM and BNST activity during the predictable compared with the unpredictable condition compared with the anxiety patients. During a confrontation phase that followed the anticipation phase, CM was more activated than BNST during the phobic compared with the neutral confrontation. While this effect was independent of threat predictability in patients, healthy controls showed higher activation in the CM compared with the BNST only during the predictable spider confrontation compared with the predictable bird confrontation. The results contribute to a better understanding of the separate roles of the CM and BNST during phobic processes. The CM was found to be more relevant to phobic confrontation in patients with spider phobia compared with the BNST.
Machine-learning prediction studies have shown potential to inform treatment stratification, but recent efforts to predict psychotherapy outcomes with clinical routine data have only resulted in ...moderate prediction accuracies. Neuroimaging data showed promise to predict treatment outcome, but previous prediction attempts have been exploratory and reported small clinical sample sizes. Herein, we aimed to examine the incremental predictive value of neuroimaging data in contrast to clinical and demographic data alone (for which results were previously published), using a two-level multimodal ensemble machine-learning strategy. We used pretreatment structural and task-based fMRI data to predict virtual reality exposure therapy outcome in a bicentric sample of N=190 patients with spider phobia. First, eight 1st-level random forest classifications were conducted using separate data modalities (clinical questionnaire scores and sociodemographic data, cortical thickness and gray matter volumes, functional activation, connectivity, connectivity-derived graph metrics, and BOLD signal variance). Then, the resulting predictions were used to train a 2nd-level classifier that produced a final prediction. No 1st-level or 2nd-level classifier performed above chance level except BOLD signal variance, which showed potential as a contributor to higher-level prediction from multiple regions across the brain (1st-level balanced accuracy=0.63). Overall, neuroimaging data did not provide any incremental accuracy for treatment outcome prediction in patients with spider phobia with respect to clinical and sociodemographic data alone. Thus, we advise caution in the interpretation of prediction performances from small-scale, single-site patient samples. Larger multimodal datasets are needed to further investigate individual-level neuroimaging predictors of therapy response in anxiety disorders.
Alcohol-related pancreatitis is associated with a disproportionately large number of hospitalisations among GI disorders. Despite its clinical importance, genetic susceptibility to alcoholic chronic ...pancreatitis (CP) is poorly characterised. To identify risk genes for alcoholic CP and to evaluate their relevance in non-alcoholic CP, we performed a genome-wide association study and functional characterisation of a new pancreatitis locus.
1959 European alcoholic CP patients and population-based controls from the KORA, LIFE and INCIPE studies (n=4708) as well as chronic alcoholics from the GESGA consortium (n=1332) were screened with Illumina technology. For replication, three European cohorts comprising 1650 patients with non-alcoholic CP and 6695 controls originating from the same countries were used.
We replicated previously reported risk loci
,
,
and
in alcoholic CP patients. We identified
(chymotrypsin B1 and B2) as a new risk locus with lead single-nucleotide polymorphism (SNP)
(OR 1.35, 95% CI 1.23 to 1.6). We found that a 16.6 kb inversion in the
locus was in linkage disequilibrium with the CP-associated SNPs and was best tagged by
. The association was replicated in three independent European non-alcoholic CP cohorts of 1650 patients and 6695 controls (OR 1.62, 95% CI 1.42 to 1.86). The inversion changes the expression ratio of the CTRB1 and CTRB2 isoforms and thereby affects protective trypsinogen degradation and ultimately pancreatitis risk.
An inversion in the
locus modifies risk for alcoholic and non-alcoholic CP indicating that common pathomechanisms are involved in these inflammatory disorders.
Shedding of proteins localized at the cell surface is an important regulatory step in the function of many of these proteins. Human meprin (N-benzoyl-l-tyrosyl-p-aminobenzoic acid hydrolase, PPH, EC ...3.4.24.18) a zinc-metalloendopeptidase of the astacin family is an oligomeric protein complex of α- and β-subunits and is expressed abundantly in the intestine and kidney as well as in leukocytes of the lamina propria and in cancer cells. In transfected cells intracellular proteolytic removal of the membrane anchor results in the secretion of the meprin α-subunit. In rats and mice, the β-subunit exists in a membrane-anchored form. In contrast, human meprinβ is constitutively converted into a secretable form. We now show that phorbol 12-myristate 13-acetate (PMA) stimulates an increased release of hmeprinβ from transfected COS-1 cells, whereas hmeprinα secretion is not influenced. This stimulatory effect is inhibited by the protein kinase C (PKC) inhibitor staurosporine, suggesting that activation of PKC mediates PMA-induced hmeprinβ shedding. The use of different protease inhibitors shows that two different metalloprotease activities are responsible for the constitutive and the PMA-stimulated hmeprinβ shedding. We identified tumor necrosis factor α-converting enzyme (TACE or ADAM17) as the protease that mediates the PMA-induced release. We also demonstrate that hmeprinβ is phosphorylated by PMA treatment on Ser687 within a PKC consensus sequence in the cytosolic domain of the protein. This phosphorylation of hmeprinβ is not, however, implicated in the enhanced secretion by PMA treatment.
Shedding of proteins localized at the cell surface is an important regulatory step in the function of many of these proteins. Human meprin (N-benzoyl-l-tyrosyl-p-aminobenzoic acid hydrolase, PPH, EC ...3.4.24.18) a zinc-metalloendopeptidase of the astacin family is an oligomeric protein complex of alpha- and beta-subunits and is expressed abundantly in the intestine and kidney as well as in leukocytes of the lamina propria and in cancer cells. In transfected cells intracellular proteolytic removal of the membrane anchor results in the secretion of the meprin alpha-subunit. In rats and mice, the beta-subunit exists in a membrane-anchored form. In contrast, human meprinbeta is constitutively converted into a secretable form. We now show that phorbol 12-myristate 13-acetate (PMA) stimulates an increased release of hmeprinbeta from transfected COS-1 cells, whereas hmeprinalpha secretion is not influenced. This stimulatory effect is inhibited by the protein kinase C (PKC) inhibitor staurosporine, suggesting that activation of PKC mediates PMA-induced hmeprinbeta shedding. The use of different protease inhibitors shows that two different metalloprotease activities are responsible for the constitutive and the PMA-stimulated hmeprinbeta shedding. We identified tumor necrosis factor alpha-converting enzyme (TACE or ADAM17) as the protease that mediates the PMA-induced release. We also demonstrate that hmeprinbeta is phosphorylated by PMA treatment on Ser687 within a PKC consensus sequence in the cytosolic domain of the protein. This phosphorylation of hmeprinbeta is not, however, implicated in the enhanced secretion by PMA treatment.
Shedding of proteins localized at the cell surface is an important regulatory step in the function of many of these proteins.
Human meprin ( N -benzoyl- l -tyrosyl- p -aminobenzoic acid hydrolase, ...PPH, EC 3.4.24.18) a zinc-metalloendopeptidase of the astacin family is an oligomeric protein
complex of α- and β-subunits and is expressed abundantly in the intestine and kidney as well as in leukocytes of the lamina
propria and in cancer cells. In transfected cells intracellular proteolytic removal of the membrane anchor results in the
secretion of the meprin α-subunit. In rats and mice, the β-subunit exists in a membrane-anchored form. In contrast, human
meprinβ is constitutively converted into a secretable form. We now show that phorbol 12-myristate 13-acetate (PMA) stimulates
an increased release of hmeprinβ from transfected COS-1 cells, whereas hmeprinα secretion is not influenced. This stimulatory
effect is inhibited by the protein kinase C (PKC) inhibitor staurosporine, suggesting that activation of PKC mediates PMA-induced
hmeprinβ shedding. The use of different protease inhibitors shows that two different metalloprotease activities are responsible
for the constitutive and the PMA-stimulated hmeprinβ shedding. We identified tumor necrosis factor α-converting enzyme (TACE
or ADAM17) as the protease that mediates the PMA-induced release. We also demonstrate that hmeprinβ is phosphorylated by PMA
treatment on Ser 687 within a PKC consensus sequence in the cytosolic domain of the protein. This phosphorylation of hmeprinβ is not, however,
implicated in the enhanced secretion by PMA treatment.
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