Cognitive control is a critical executive function. Many studies have combined general linear modeling and the stop signal task (SST) to delineate the component processes of cognitive control. For instance, by contrasting stop success (SS) and stop error (SE) trials in the SST, investigators examined regional responses to stop signal inhibition. In contrast to this parameterized approach, independent component analysis (ICA) elucidates brain networks subserving cognitive control. In our earlier work of 59 adults performing the SST during fMRI, we characterized six independent components (ICs). However, none of these ICs correlated with stop signal performance, raising questions about their behavioral validity. Here, in a larger sample (n=100), we identified and explored 23 ICs for correlation with the stop signal reaction time (SSRT), a measure of the efficiency of response inhibition. At a corrected threshold (P < 0.0005), a paracentral lobule-midcingulate network and a left inferior parietal-supplementary motor-somatomotor network showed a positive correlation between SE beta weight and SSRT. In contrast, a midline cerebellum–thalamus–pallidum network showed a negative correlation between SE beta weight and SSRT. These findings suggest that motor preparation and execution prolongs the SSRT, likely via an interaction between the go and stop processes as suggested by the race model. Behaviorally, consistent with this hypothesis, the difference in G and SE reaction times is positively correlated with SSRT across subjects. These new results highlight the importance of cognitive motor regions in response inhibition and support the utility of ICA in uncovering functional networks for cognitive control in the SST.

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Anatomically interconnected, the ventromedial prefrontal cortex (vmPFC) and amygdala interact in emotion processing. However, no meta-analyses have focused on studies that reported concurrent vmPFC and amygdala activities. With activation likelihood estimation (ALE) we examined 100 experiments that reported concurrent vmPFC and amygdala activities, and distinguished responses to positive vs. negative emotions and to passive exposure to vs. active regulation of emotions. We also investigated whole-brain experiments for other regional activities. ALE and contrast analyses identified convergent anterior and posterior vmPFC response to passive positive and negative emotions, respectively, and a subregion in between to mixed emotions. A smaller area in the posterior ventral vmPFC is specifically involved in regulation of negative emotion. Whereas bilateral amygdala was involved during emotional exposure, only the left amygdala showed convergent activities during active regulation of negative emotions. Whole brain analysis showed convergent activity in left ventral striatum for passive exposure to positive Terms of use and reuse: academic research for non-commercial purposes, see here for full terms. https://www.springer.com/aamterms-v1

Background: In less than a year from its zoonotic entry into the human population, SARS-CoV-2 has infected more than 45 million people, caused 1.2 million deaths, and induced widespread societal disruption. Leading SARS-CoV-2 vaccine candidates immunize with the viral spike protein delivered on viral vectors, encoded by injected mRNAs, or as purified protein. Here we describe a different approach to SARS-CoV-2 vaccine development that uses exosomes to deliver mRNAs that encode antigens from multiple SARS-CoV-2 structural proteins. Approach: Exosomes were purified and loaded with mRNAs designed to express (i) an artificial fusion protein, LSNME, that contains portions of the viral spike, nucleocapsid, membrane, and envelope proteins, and (ii) a functional form of spike. The resulting combinatorial vaccine, LSNME/SW1, was injected into thirteen weeks-old, male C57BL/6J mice, followed by interrogation of humoral and cellular immune responses to the SARS-CoV-2 nucleocapsid and spike proteins, as well as hematological and histological analysis to interrogate animals for possible adverse effects. Results: Immunized mice developed CD4+, and CD8+ T-cell reactivities that respond to both the SARS-CoV-2 nucelocapsid protein and the SARS-CoV-2 spike protein. These responses were apparent nearly two months after the conclusion of vaccination, as expected for a durable response to vaccination. In addition, the spike-reactive CD4+ T-cells response was associated with elevated expression of interferon gamma, indicative of a Th1 response, and a lesser induction of interleukin 4, a Th2-associated cytokine. Vaccinated mice showed no sign of altered growth, injection-site hypersensitivity, change in white blood cell profiles, or alterations in organ morphology. Consistent with these results, we also detected moderate but sustained anti-nucleocapsid and anti-spike antibodies in the plasma of vaccinated animals. Conclusion: Taken together, these results validate the use of exosomes for delivering functional mRNAs into target cells in vitro and in vivo, and more specifically, establish that the LSNME/SW1 vaccine induced broad immunity to multiple SARS-CoV-2 proteins.

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The spike D614G mutation increases SARS-CoV-2 infectivity, viral load, and transmission but the molecular mechanism underlying these effects remains unclear. We report here that spike is trafficked to lysosomes and that the D614G mutation enhances the lysosomal sorting of spike and the lysosomal accumulation of spike-positive punctae in SARS-CoV-2-infected cells. Spike trafficking to lysosomes is an endocytosis-independent, V-ATPase-dependent process, and spike-containing lysosomes drive lysosome clustering but display poor lysotracker labeling and reduced uptake of endocytosed materials. These results are consistent with a lysosomal pathway of coronavirus biogenesis and raise the possibility that a common mechanism may underly the D614G mutation’s effects on spike protein trafficking in infected cells and the accelerated entry of SARS-CoV-2 into uninfected cells.

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) egress occurs by lysosomal exocytosis. We show that the Spike D614G mutation enhances Spike trafficking to lysosomes, drives Spike-mediated reprogramming of lysosomes, and reduces cell surface Spike expression by ~3-fold. D614G is not a human-specific adaptation. Rather, it is an adaptation to the earlier furin cleavage site insertion (FCSI) mutation that occurred at the genesis of SARS-CoV-2. While advantageous to the virus, furin cleavage of spike has deleterious effects on spike structure and function, inhibiting its trafficking to lysosomes and impairing its infectivity by the transmembrane serine protease 2(TMPRSS2)-independent, endolysosomal pathway. D614G restores spike trafficking to lysosomes and enhances the earliest events in SARS-CoV-2 infectivity, while spike mutations that restore SARS-CoV-2’s TMPRSS2-independent infectivity restore spike’s trafficking to lysosomes. Together, these and other results show that D614G is an intragenic suppressor of deleterious traits linked to the FCSI and lend additional support to the endolysosomal model of SARS-CoV-2 egress and entry.