Selective Interaction of Syntaxin 1A with KCNQ2: Possible Implications for Specific Modulation of Presynaptic Activity

KCNQ2/KCNQ3 channels are the molecular correlates of the neuronal M-channels, which play a major role in the control of neuronal excitability. Notably, they differ from homomeric KCNQ2 channels in their distribution pattern within neurons, with unique expression of KCNQ2 in axons and nerve terminals. Here, combined reciprocal coimmunoprecipitation and two-electrode voltage clamp analyses in Xenopus oocytes revealed a strong association of syntaxin 1A, a major component of the exocytotic SNARE complex, with KCNQ2 homomeric channels resulting in a ∼2-fold reduction in macroscopic conductance and ∼2-fold slower activation kinetics. Remarkably, the interaction of KCNQ2/Q3 heteromeric channels with syntaxin 1A was significantly weaker and KCNQ3 homomeric channels were practically resistant to syntaxin 1A. Analysis of different KCNQ2 and KCNQ3 chimeras and deletion mutants combined with in-vitro binding analysis pinpointed a crucial C-terminal syntaxin 1A-association domain in KCNQ2. Pull-down and coimmunoprecipitation analyses in hippocampal and cortical synaptosomes demonstrated a physical interaction of brain KCNQ2 with syntaxin 1A, and confocal immunofluorescence microscopy showed high colocalization of KCNQ2 and syntaxin 1A at presynaptic varicosities. The selective interaction of syntaxin 1A with KCNQ2, combined with a numerical simulation of syntaxin 1A's impact in a firing-neuron model, suggest that syntaxin 1A's interaction is targeted at regulating KCNQ2 channels to fine-tune presynaptic transmitter release, without interfering with the function of KCNQ2/3 channels in neuronal firing frequency adaptation

Responsible research in health disparities using the Adolescent Brain Cognitive DevelopmentSM (ABCD) study

PurposeThe Adolescent Brain Cognitive DevelopmentSM (ABCD) Study is the largest longitudinal study on brain development and adolescent health in the United States. The study includes a sociodemographically diverse cohort of nearly 12,000 youth born 2005-2009, with an open science model of making data rapidly available to the scientific community. The ABCD Study® data has been used in over 1100 peer-reviewed publications since its first data release in 2018. The dataset contains a broad scope and comprehensive set of measures of youths' behavioral, health, and brain outcomes, as well as extensive contextual and environmental measures that map onto the social determinants of health (SDOH). Understanding the impact of SDOH on the developmental trajectories of youth will help to address early lifecourse health inequities that lead to disparities later in life. However, the open science model and extensive use of ABCD data highlight the need for guidance on appropriate, responsible, and equitable use of the data.Design methodsOur conceptual framework integrates the National Institute on Minority Health and Health Disparities (NIMHD) Research Framework with strength-based and data equity perspectives. We use this framework to articulate best practices and methods for investigations that aim to identify the multilevel pathways by which structural and systemic inequities impact adolescent health trajectories.ResultsUsing our conceptual model, we provide recommendations for equitable health disparities research using ABCD Study data. We identify over fifty ABCD measures that can encompass SDOH across five levels of influence: individual, interpersonal, school, community, and societal. We expand the societal level to acknowledge structural discrimination as the root cause of systemic and structural inequities resulting in health disparities among marginalized youth. We apply the methodological recommendations in an example data analysis using a multi-level approach that integrates strength-based and data equity perspectives to elucidate pathways by which social and structural inequities may influence cognitive decision making in youth. We conclude with recommendations for strengthening the utility of ABCD data for health disparities research now and in the future.ConclusionAdolescence is a critical period of development with subsequent ramifications for health outcomes across the lifespan. Thus, understanding SDOH among diverse youth can inform prevention interventions before the emergence of health disparities in adulthood

In-Orbit Performance of the GRACE Follow-on Laser Ranging Interferometer

The Laser Ranging Interferometer (LRI) instrument on the Gravity Recovery and Climate Experiment (GRACE) Follow-On mission has provided the first laser interferometric range measurements between remote spacecraft, separated by approximately 220 km. Autonomous controls that lock the laser frequency to a cavity reference and establish the 5 degree of freedom two-way laser link between remote spacecraft succeeded on the first attempt. Active beam pointing based on differential wavefront sensing compensates spacecraft attitude fluctuations. The LRI has operated continuously without breaks in phase tracking for more than 50 days, and has shown biased range measurements similar to the primary ranging instrument based on microwaves, but with much less noise at a level of $1\,{\rm nm}/\sqrt{\rm Hz}$ at Fourier frequencies above 100 mHz