Identifying the Neural Correlates of Resting State Affect Processing Dynamics.

There exists growing interest in understanding the dynamics of resting state functional magnetic resonance imaging (rs-fMRI) to establish mechanistic links between individual patterns of spontaneous neural activation and corresponding behavioral measures in both normative and clinical populations. Here we propose and validate a novel approach in which whole-brain rs-fMRI data are mapped to a specific low-dimensional representation-affective valence and arousal processing-prior to dynamic analysis. This mapping process constrains the state space such that both independent validation and visualization of the system's dynamics become tractable. To test this approach, we constructed neural decoding models of affective valence and arousal processing from brain states induced by International Affective Picture Set image stimuli during task-related fMRI in (n = 97) healthy control subjects. We applied these models to decode moment-to-moment affect processing in out-of-sample subjects' rs-fMRI data and computed first and second temporal derivatives of the resultant valence and arousal time-series. Finally, we fit a second set of neural decoding models to these derivatives, which function as neurally constrained ordinary differential equations (ODE) underlying affect processing dynamics. To validate these decodings, we simulated affect processing by numerical integration of the true temporal sequence of neurally decoded derivatives for each subject and demonstrated that these decodings generate significantly less (p < 0.05) group-level simulation error than integration based upon decoded derivatives sampled uniformly randomly from the true temporal sequence. Indeed, simulations of valence and arousal processing were significant for up to four steps of closed-loop simulation (Δt = 2.0 s) for both valence and arousal, respectively. Moreover, neural encoding representations of the ODE decodings include significant clusters of activation within brain regions associated with affective reactivity and regulation. Our work has methodological implications for efforts to identify unique and actionable biomarkers of possible future or current psychopathology, particularly those related to mood and emotional instability.

Action-value processing underlies the role of the dorsal anterior cingulate cortex in performance monitoring during self-regulation of affect.

In this study, we merged methods from engineering control theory, machine learning, and human neuroimaging to critically test the putative role of the dorsal anterior cingulate cortex (dACC) in goal-directed performance monitoring during an emotion regulation task. Healthy adult participants (n = 94) underwent cued-recall and re-experiencing of their responses to affective image stimuli with concurrent functional magnetic resonance imaging and psychophysiological response recording. During cued-recall/re-experiencing trials, participants engaged in explicit self-regulation of their momentary affective state to match a pre-defined affective goal state. Within these trials, neural decoding methods measured affect processing from fMRI BOLD signals across the orthogonal affective dimensions of valence and arousal. Participants' affective brain states were independently validated via facial electromyography (valence) and electrodermal activity (arousal) responses. The decoded affective states were then used to contrast four computational models of performance monitoring (i.e., error, predicted response outcome, action-value, and conflict) by their relative abilities to explain emotion regulation task-related dACC activation. We found that the dACC most plausibly encodes action-value for both valence and arousal processing. We also confirmed that dACC activation directly encodes affective arousal and also likely encodes recruitment of attention and regulation resources. Beyond its contribution to improving our understanding of the roles that the dACC plays in emotion regulation, this study introduced a novel analytical framework through which affect processing and regulation may be functionally dissociated, thereby permitting mechanistic analysis of real-world emotion regulation strategies, e.g., distraction and reappraisal, which are widely employed in cognitive behavioral therapy to address clinical deficits in emotion regulation.

Origins of glycan selectivity in streptococcal Siglec-like adhesins suggest mechanisms of receptor adaptation.

Bacterial binding to host receptors underlies both commensalism and pathogenesis. Many streptococci adhere to protein-attached carbohydrates expressed on cell surfaces using Siglec-like binding regions (SLBRs). The precise glycan repertoire recognized may dictate whether the organism is a strict commensal versus a pathogen. However, it is currently not clear what drives receptor selectivity. Here, we use five representative SLBRs and identify regions of the receptor binding site that are hypervariable in sequence and structure. We show that these regions control the identity of the preferred carbohydrate ligand using chimeragenesis and single amino acid substitutions. We further evaluate how the identity of the preferred ligand affects the interaction with glycoprotein receptors in human saliva and plasma samples. As point mutations can change the preferred human receptor, these studies suggest how streptococci may adapt to changes in the environmental glycan repertoire.

Arrestin-3 interaction with maternal embryonic leucine-zipper kinase.

Maternal embryonic leucine-zipper kinase (MELK) overexpression impacts survival and proliferation of multiple cancer types, most notably glioblastomas and breast cancer. This makes MELK an attractive molecular target for cancer therapy. Yet the molecular mechanisms underlying the involvement of MELK in tumorigenic processes are unknown. MELK participates in numerous protein-protein interactions that affect cell cycle, proliferation, apoptosis, and embryonic development. Here we used both in vitro and in-cell assays to identify a direct interaction between MELK and arrestin-3. A part of this interaction involves the MELK kinase domain, and we further show that the interaction between the MELK kinase domain and arrestin-3 decreases the number of cells in S-phase, as compared to cells expressing the MELK kinase domain alone. Thus, we describe a new mechanism of regulation of MELK function, which may contribute to the control of cell fate.