Targeted interplay between bacterial pathogens and host autophagy

Due to the critical role played by autophagy in pathogen clearance, pathogens have developed diverse strategies to subvert autophagy. Despite previous key findings of bacteria-autophagy interplay, a systems level insight into selective targeting by the host and autophagy modulation by the pathogens is lacking. We predicted potential interactions between human autophagy proteins and effector proteins from 56 pathogenic bacterial species by identifying bacterial proteins predicted to have recognition motifs for selective autophagy receptors p62/NDP52 and LC3. Conversely, using structure-based interaction prediction methods, we identified bacterial effector proteins that could putatively modify core autophagy components. Our analysis revealed that autophagy receptors in general potentially target mostly genus specific proteins, and not those present in multiple genera. We also show that the complementarity between the predicted p62 and NDP52 targets, which has been shown for Salmonella, Listeria and Shigella, could be observed across other pathogens. Using literature evidence, we hypothesize that this complementarity potentially leave the host more susceptible to chronic infections upon the mutation of one of the autophagy receptors. To check any bias caused by our pathogenic protein selection criteria, control analysis using proteins derived from entero-toxigenic and non-toxigenic Bacillus outer membrane vesicles indicated that autophagy targets pathogenic proteins rather than non-pathogenic ones. We also observed a pathogen specific pattern as to which autophagy phase could be modulated by specific genera. We found intriguing examples of bacterial proteins which could modulate autophagy, and in turn capable of being targeted by the autophagy receptors and LC3 as a host defence mechanism. To demonstrate the validity of our predictions, we confirmed experimentally with in vitro Salmonella invasion assays the bi-directional interactions underlying the interplay between a Salmonella protease, YhjJ and autophagy. Our comparative meta-analysis points out key commonalities and differences in how pathogens could affect autophagy and how autophagy potentially recognises these pathogenic effectors

SignaFish: A Zebrafish-Specific Signaling Pathway Resource

Understanding living systems requires an in-depth knowledge of the signaling networks that drive cellular homeostasis, regulate intercellular communication, and contribute to cell fates during development. Several resources exist to provide high-throughput data sets or manually curated interaction information from human or invertebrate model organisms. We previously developed SignaLink, a uniformly curated, multi-layered signaling resource containing information for human and for the model organisms nematode Caenorhabditis elegans and fruit fly Drosophila melanogaster. Until now, the use of the SignaLink database for zebrafish pathway analysis was limited. To overcome this limitation, we created SignaFish ( http://signafish.org ), a fish-specific signaling resource, built using the concept of SignaLink. SignaFish contains more than 200 curation-based signaling interactions, 132 further interactions listed in other resources, and it also lists potential miRNA-based regulatory connections for seven major signaling pathways. From the SignaFish website, users can reach other web resources, such as ZFIN. SignaFish provides signaling or signaling-related interactions that can be examined for each gene or downloaded for each signaling pathway. We believe that the SignaFish resource will serve as a novel navigating point for experimental design and evaluation for the zebrafish community and for researchers focusing on nonmodel fish species, such as cyclids

Can Emotional and Behavioral Dysregulation in Youth Be Decoded from Functional Neuroimaging?

High comorbidity among pediatric disorders characterized by behavioral and emotional dysregulation poses problems for diagnosis and treatment, and suggests that these disorders may be better conceptualized as dimensions of abnormal behaviors. Furthermore, identifying neuroimaging biomarkers related to dimensional measures of behavior may provide targets to guide individualized treatment. We aimed to use functional neuroimaging and pattern regression techniques to determine whether patterns of brain activity could accurately decode individual-level severity on a dimensional scale measuring behavioural and emotional dysregulation at two different time points

Integrated Systems Biology Approach Identifies Novel Maternal and Placental Pathways of Preeclampsia

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Decreased amygdala–insula resting state connectivity in behaviorally and emotionally dysregulated youth

The Research Domain Criteria (RDoC) adopts a dimensional approach for examining pathophysiological processes underlying categorically defined psychiatric diagnoses. We used this framework to examine relationships among symptom dimensions, diagnostic categories, and resting state connectivity in behaviorally and emotionally dysregulated youth selected from the Longitudinal Assessment of Manic Symptoms study (n=42) and healthy control youth (n=18). Region of interest analyses examined relationships among resting state connectivity, symptom dimensions (behavioral and emotional dysregulation measured with the Parent General Behavior Inventory-10 Item Mania Scale [PGBI-10M]; dimensional severity measures of mania, depression, anxiety), and diagnostic categories (Bipolar Spectrum Disorders, Attention Deficit Hyperactivity Disorder, Anxiety Disorders, Disruptive Behavior Disorders). After adjusting for demographic variables, two dimensional measures showed significant inverse relationships with resting state connectivity, regardless of diagnosis: 1) PGBI-10M with amygdala-left posterior insula/bilateral putamen; and 2) depressive symptoms with amygdala-right posterior insula connectivity. Diagnostic categories showed no significant relationships with resting state connectivity. Resting state connectivity between amygdala and posterior insula decreased with increasing severity of behavioral and emotional dysregulation and depression; this suggests an intrinsic functional uncoupling of key neural regions supporting emotion processing and regulation. These findings support the RDoC dimensional approach for characterizing pathophysiologic processes that cut across different psychiatric disorders

Emotional Face Processing in Pediatric Bipolar Disorder: Evidence for Functional Impairments in the Fusiform Gyrus

Pediatric bipolar disorder involves poor social functioning, but the neural mechanisms underlying these deficits are not well understood. Previous neuroimaging studies have found deficits in emotional face processing localized to emotional brain regions. However, few studies have examined dysfunction in other regions of the face processing circuit. This study assessed hypoactivation in key face processing regions of the brain in pediatric bipolar disorder

White Matter Structure in Youth With Behavioral and Emotional Dysregulation Disorders: A Probabilistic Tractographic Study

Psychiatric disorders in youth characterized by behavioral and emotional dysregulation are often comorbid and difficult to distinguish. An alternative approach to conceptualizing these disorders is to move toward a diagnostic system based on underlying pathophysiologic processes that may cut across conventionally defined diagnoses. Neuroimaging techniques have potentials for the identification of these processes