Helicobacter pylori binds human Annexins via Lipopolysaccharide to interfere with Toll-like Receptor 4 signaling.

Helicobacter pylori colonizes half of the global population and causes gastritis, peptic ulcer disease or gastric cancer. In this study, we were interested in human annexin (ANX), which comprises a protein family with diverse and partly unknown physiological functions, but with a potential role in microbial infections and possible involvement in gastric cancer. We demonstrate here for the first time that H. pylori is able to specifically bind ANXs. Binding studies with purified H. pylori LPS and specific H. pylori LPS mutant strains indicated binding of ANXA5 to lipid A, which was dependent on the lipid A phosphorylation status. Remarkably, ANXA5 binding almost completely inhibited LPS-mediated Toll-like receptor 4- (TLR4) signaling in a TLR4-specific reporter cell line. Furthermore, the interaction is relevant for gastric colonization, as a mouse-adapted H. pylori increased its ANXA5 binding capacity after gastric passage and its ANXA5 incubation in vitro interfered with TLR4 signaling. Moreover, both ANXA2 and ANXA5 levels were upregulated in H. pylori-infected human gastric tissue, and H. pylori can be found in close association with ANXs in the human stomach. Furthermore, an inhibitory effect of ANXA5 binding for CagA translocation could be confirmed. Taken together, our results highlight an adaptive ability of H. pylori to interact with the host cell factor ANX potentially dampening innate immune recognition.

Pathologically reduced neural flexibility recovers during psychotherapy of OCD patients.

Flexibility is a key feature of psychological health, allowing the individual to dynamically adapt to changing environmental demands, which is impaired in many psychiatric disorders like obsessive-compulsive disorder (OCD). Adequately responding to varying demands requires the brain to switch between different patterns of neural activity, which are represented by different brain network configurations (functional connectivity patterns). Here, we operationalize neural flexibility as the dissimilarity between consecutive connectivity matrices of brain regions (jump length). In total, 132 fMRI scans were obtained from 17 patients that were scanned four to five times during inpatient psychotherapy, and from 17 controls that were scanned at comparable time intervals. Significant negative correlations were found between the jump lengths and the symptom severity scores of OCD, depression, anxiety, and stress, suggesting that high symptom severity corresponds to inflexible brain functioning. Further analyses revealed that impaired reconfiguration (pattern stability) of the brain seems to be more related to general psychiatric impairment rather than to specific symptoms, e.g., of OCD or depression. Importantly, the group × time interaction of a repeated measures ANOVA was significant, as well as the post-hoc paired t-tests of the patients (first vs. last scan). The results suggest that psychotherapy is able to significantly increase the neural flexibility of patients. We conclude that psychiatric symptoms like anxiety, stress, depression, and OCD are associated with an impaired adaptivity of the brain. In general, our results add to the growing evidence that dynamic functional connectivity captures meaningful properties of brain functioning.

Multi-level assessment of obsessive-compulsive disorder (OCD) reveals relations between neural and neurochemical levels.

BACKGROUND: While considerable progress has been made in exploring the psychological, the neural, and the neurochemical dimensions of OCD separately, their interplay is still an open question, especially their changes during psychotherapy. METHODS: Seventeen patients were assessed at these three levels by psychological questionnaires, fMRI, and venipuncture before and after inpatient psychotherapy. Seventeen controls were scanned at comparable time intervals. First, pre/post treatment changes were investigated for all three levels separately: symptom severity, whole-brain and regional activity, and the concentrations of cortisol, serotonin, dopamine, brain-derived neurotrophic factor (BDNF), and immunological parameters (IL-6, IL-10, TNFα). Second, stepwise linear modeling was used to find relations between the variables of the levels. RESULTS: The obsessive-compulsive, depressive, and overall symptom severity was significantly reduced after psychotherapy. At the neural level, the activity in the anterior cingulate cortex (ACC), in frontal regions, in the precuneus, and in the putamen had significantly decreased. No significant changes were found on the neurochemical level. When connecting the levels, a highly significant model was found that explains the decrease in neural activity of the putamen by increases of the concentrations of cortisol, IL-6, and dopamine. CONCLUSION: Multivariate approaches offer insight on the influences that the different levels of the psychiatric disorder OCD have on each other. More research and adapted models are needed.

The Therapy Process Questionnaire - Factor analysis and psychometric properties of a multidimensional self-rating scale for high-frequency monitoring of psychotherapeutic processes.

Many outcome measures and session-related questionnaires in psychotherapy are designed for weekly or biweekly administration. Yet, today, technical developments allow for higher frequency assessments to monitor human change dynamics more closely by daily assessments. For this purpose, the Therapy Process Questionnaire (TPQ) was developed, with a specific focus on inpatient psychotherapy. In this article, we present an explorative and confirmative factor analysis of the TPQ on the basis of the time series data of 150 patients collected during their hospital stay (mean time series length: 69.1 measurement points). A seven-factor solution was identified, which explains 68.7% of variance and associates 43 items onto the factors, which are "well-being and positive emotions," "relationship with fellow patients," "therapeutic relationship and clinical setting," "emotional and problem intensity," "insight/confidence/therapeutic progress," "motivation for change," and "mindfulness/self-care." The internal consistency (Cronbach's α), the inter-item correlations of the subscales, and the discriminative power of the items are excellent. The TPQ can be applied in practice and research for creating time series with equidistant measurement points and time series lengths, which are appropriate for the application of nonlinear analysis methods. Especially in clinical practice, it is important to identify precursors of phase transitions, changing synchronization patterns, and critical or instable periods of a process, which now is possible by internet- or app-based applications of this multidimensional questionnaire.

Erroneously Disgusted: fMRI Study Supports Disgust-Related Neural Reuse in Obsessive-Compulsive Disorder (OCD).

Objective: fMRI scans of patients with obsessive-compulsive disorder (OCD) consistently show a hyperactivity of the insular cortex, a region responsible for disgust-processing, when confronted with symptom-triggering stimuli. This asks for an investigation of the role of disgust and the insula in OCD patients. Methods: Seventeen inpatients with OCD and 17 healthy controls (HC) underwent fMRI scanning. Whole-brain contrasts were calculated for "Disgust vs. Neutral" for both groups, plus an analysis of variance (ANOVA) to assess the interaction between group and condition. Additionally, the emotional dimensions of valence and arousal, along with the ability to cope, were assessed by picture ratings. Results: The picture ratings confirmed the patients' heightened sensitivity to disgust with higher values for arousal and inability to cope, but not for valence. fMRI scans revealed no hyperactivity of the insula in patients compared to controls for the condition "Disgust vs. Neutral," indicating no basic hypersensitivity to disgusting stimuli. Increased activity in the precuneus in controls for this condition might correspond to the downregulation of arousal. Conclusions: The absent differences in neural activity of the insula in patients compared to controls for the disgust-condition, but heightened activity for symptom-provoking conditions, suggests that the illness is due to an erroneous recruitment of the insula cortex for OCD-stimuli. The finding is interpreted within the framework of the neural reuse hypothesis.

Individual OCD-provoking stimuli activate disorder-related and self-related neuronal networks in fMRI.

For patients with Obsessive-Compulsive Disorder (OCD), whose triggers are highly idiosyncratic, individual stimulus material has been used in several fMRI studies. This study aims at comparing individual to standardized picture sets and at investigating a possible overlap of the former with the self-referential neuronal network. During fMRI-scanning, 17 inpatients with OCD and 17 healthy controls were exposed to pictures of their personal triggers, photographed in their domestic environments, to standardized pictures designed to provoke OCD symptoms, and to neutral pictures. Whole-brain analyses were calculated and the pictures were rated by both patients and controls with respect to valence, arousal, and coping. Patients rated the individualized stimuli lower in valence and coping and higher in arousal compared to controls, and also compared to standardized OCD- and neutral stimuli. The individual stimuli elicited neuronal activity in the cingulate cortex, hippocampus, insula, middle frontal/precentral gyrus, superior/inferior parietal lobe, and precuneus, while no group difference was detected by the standardized OCD-stimuli. In conclusion, individual picture sets facilitate the detection of neuronal activity, but the results might be confounded due to the overlap with the network of self-referential processing and memory retrieval. The use of individual symptom-provoking and individual neutral stimuli would therefore be optimal.

The Helicobacter pylori adhesin protein HopQ exploits the dimer interface of human CEACAMs to facilitate translocation of the oncoprotein CagA.

Helicobacter pylori infects half of the world's population, and strains that encode the cag type IV secretion system for injection of the oncoprotein CagA into host gastric epithelial cells are associated with elevated levels of cancer. CagA translocation into host cells is dependent on interactions between the H. pylori adhesin protein HopQ and human CEACAMs. Here, we present high-resolution structures of several HopQ-CEACAM complexes and CEACAMs in their monomeric and dimeric forms establishing that HopQ uses a coupled folding and binding mechanism to engage the canonical CEACAM dimerization interface for CEACAM recognition. By combining mutagenesis with biophysical and functional analyses, we show that the modes of CEACAM recognition by HopQ and CEACAMs themselves are starkly different. Our data describe precise molecular mechanisms by which microbes exploit host CEACAMs for infection and enable future development of novel oncoprotein translocation inhibitors and H. pylori-specific antimicrobial agents.

Oleic acid induces the novel apolipoprotein O and reduces mitochondrial membrane potential in chicken and human hepatoma cells.

Non-alcoholic fatty liver disease (NAFLD) is marked by hepatic fat accumulation and reflects a spectrum of chronic liver diseases associated with obesity, impaired insulin sensitivity and dyslipidemia. Apolipoprotein O (ApoO) is a new member of the plasma apolipoprotein family that may play a role in lipid metabolism and electron transport activity of the mitochondrium. However, its physiological functions have not been elucidated yet. Based on our previous data in a non-mammalian experimental system [1], we hypothesized that hepatic expression of ApoO is tightly linked not only to diet-induced hepatosteatosis, but also to increased lipoprotein-production induced by, e.g., hormones and oxidative stress. To gain insight into a mammalian experimental system, we compared the effects of lipid loading on ApoO regulation in chicken hepatoma LMH cells with those in the human hepatoma cell line HepG2. Incubation of the cells with BSA-complexed oleic acid (OA-Alb) induced triglyceride accumulation, but did not affect cell viability. qPCR using specific primer pairs and Western blot analysis with in-house produced rabbit anti-ApoO antisera demonstrated significant increase in ApoO transcript and protein levels in both cell lines. ROS formation due to OA-Alb treatment was only slightly altered in LMH cells, indicating an intact antioxidant defense system of the cells. Oxidative stress applied by addition of H2O2 revealed induction of ApoO transcript and protein level in the same or even higher extent as monitored in the presence of OA-Alb. Upon treatment with estrogen for 24 h quantitative analysis of ApoO transcript and protein revealed increases of ApoO expression supporting the assumption that estrogen affects lipoprotein metabolism at various points. Furthermore, both cell lines showed a significant decrease of the mitochondrial membrane potential upon incubation with OA-Alb. Therefore, we assume that our findings support a role of ApoO as an effector of compromised mitochondrial function that likely accompanies the onset of non-alcoholic fatty liver disease.

Systemic Case Formulation, Individualized Process Monitoring, and State Dynamics in a Case of Dissociative Identity Disorder.

Objective: The aim of this case report is to demonstrate the feasibility of a systemic procedure (synergetic process management) including modeling of the idiographic psychological system and continuous high-frequency monitoring of change dynamics in a case of dissociative identity disorder. The psychotherapy was realized in a day treatment center with a female client diagnosed with borderline personality disorder (BPD) and dissociative identity disorder. Methods: A three hour long co-creative session at the beginning of the treatment period allowed for modeling the systemic network of the client's dynamics of cognitions, emotions, and behavior. The components (variables) of this idiographic system model (ISM) were used to create items for an individualized process questionnaire for the client. The questionnaire was administered daily through an internet-based monitoring tool (Synergetic Navigation System, SNS), to capture the client's individual change process continuously throughout the therapy and after-care period. The resulting time series were reflected by therapist and client in therapeutic feedback sessions. Results: For the client it was important to see how the personality states dominating her daily life were represented by her idiographic system model and how the transitions between each state could be explained and understood by the activating and inhibiting relations between the cognitive-emotional components of that system. Continuous monitoring of her cognitions, emotions, and behavior via SNS allowed for identification of important triggers, dynamic patterns, and psychological mechanisms behind seemingly erratic state fluctuations. These insights enabled a change in management of the dynamics and an intensified trauma-focused therapy. Conclusion: By making use of the systemic case formulation technique and subsequent daily online monitoring, client and therapist continuously refer to detailed visualizations of the mental and behavioral network and its dynamics (e.g., order transitions). Effects on self-related information processing, on identity development, and toward a more pronounced autonomy in life (instead of feeling helpless against the chaoticity of state dynamics) were evident in the presented case and documented by the monitoring system.

Hepatosteatosis and estrogen increase apolipoprotein O production in the chicken.

Apolipoprotein O (ApoO) is a recently discovered plasma apolipoprotein that may also play a role in the mitochondrial inner membrane. Possibly due to this complexity, its physiological functions have not been elucidated yet. To gain insight from a non-mammalian experimental system, we have investigated the regulation of ApoO levels in an alternative, well-suited model for studies on lipid metabolism, the chicken. qPCR using specific primer pairs and Western blot analysis with our rabbit anti-chicken ApoO antiserum demonstrated ApoO in the liver of chickens fed a control or a fat-enriched diet, as well as in 2 chicken hepatoma cell lines, LMH cells and the estrogen-responsive LMH-2A cells, under conditions of lipid loading by incubation with BSA-complexed oleic acid. Induced triglyceride accumulation in both the liver and the hepatic cells was associated with significantly increased levels of ApoO mRNA and protein. Furthermore, upon treatment for 24 h with estrogen of the estrogen receptor-expressing LMH-2A cells, quantitative analysis of ApoO transcripts and Western blotting revealed increases of ApoO expression. Finally, upon a single administration of estrogen to roosters that leads to hyperlipidemia, higher hepatic levels of both ApoO transcript and protein were observed within 24 h. Based on these data, we propose that hepatic expression of ApoO is tightly linked not only to diet-induced hepatosteatosis, but also to increased lipoprotein-production induced by, e.g., hormones. The findings support a role of ApoO as an effector of compromised mitochondrial function that likely accompanies the onset of non-alcoholic fatty liver disease.