The 8th International RASopathies Symposium: Expanding research and care practice through global collaboration and advocacy.

Germline pathogenic variants in the RAS/mitogen-activated protein kinase (MAPK) signaling pathway are the molecular cause of RASopathies, a group of clinically overlapping genetic syndromes. RASopathies constitute a wide clinical spectrum characterized by distinct facial features, short stature, predisposition to cancer, and variable anomalies in nearly all the major body systems. With increasing global recognition of these conditions, the 8th International RASopathies Symposium spotlighted global perspectives on clinical care and research, including strategies for building international collaborations and developing diverse patient cohorts in anticipation of interventional trials. This biannual meeting, organized by RASopathies Network, was held in a hybrid virtual/in-person format. The agenda featured emerging discoveries and case findings as well as progress in preclinical and therapeutic pipelines. Stakeholders including basic scientists, clinician-scientists, practitioners, industry representatives, patients, and family advocates gathered to discuss cutting edge science, recognize current gaps in knowledge, and hear from people with RASopathies about the experience of daily living. Presentations by RASopathy self-advocates and early-stage investigators were featured throughout the program to encourage a sustainable, diverse, long-term research and advocacy partnership focused on improving health and bringing treatments to people with RASopathies.

Persecution and migration experiences of lesbian, gay, bisexual, transgender, queer/questioning, and other sexual and gender minority asylum seekers.

Lesbian, gay, bisexual, transgender, queer/questioning, and other sexual and gender minority (LGBTQ+) asylum seekers are exposed to high rates of persecution. This study aimed to identify the forms of ill treatment and the impact of these experiences on the mental health of 66 self-identified LGBTQ+ asylum seekers from 24 nations through the analysis of human rights program intakes, sworn declarations, and pro bono forensic psychological evaluation affidavits. The results indicate that participants experienced physical assault (92.4%), harassment and intimidation (84.8%), and sexual assault (56.1%). Psychological sequelae included symptoms of posttraumatic stress disorder (PTSD; 83.3%), depression (72.7%), and anxiety (57.6%). LGBTQ+ asylum seekers faced additional hazards upon arrival in the United States. Still, these asylum seekers experienced resilience as they leveraged internal and external support. The results can serve to inform clinical professionals about the range and impact of exposures to harm experienced by LGBTQ+ asylum seekers as well as possible strategies for support and advocacy for this diverse community.

Unbalanced Regulation of α7 nAChRs by Ly6h and NACHO Contributes to Neurotoxicity in Alzheimer's Disease.

α7 nicotinic acetylcholine receptors (nAChRs) are widely expressed in the brain where they promote fast cholinergic synaptic transmission and serve important neuromodulatory functions. However, their high permeability to Ca2+ also predisposes them to contribute to disease states. Here, using transfected HEK-tsa cells and primary cultured hippocampal neurons from male and female rats, we demonstrate that two proteins called Ly6h and NACHO compete for access to α7 subunits, operating together but in opposition to maintain α7 assembly and activity within a narrow range that is optimal for neuronal function and viability. Using mixed gender human temporal cortex and cultured hippocampal neurons from rats we further show that this balance is perturbed during Alzheimer's disease (AD) because of amyloid ß (Aß)-driven reduction in Ly6h, with severe reduction leading to increased phosphorylated tau and α7-mediated neurotoxicity. Ly6h release into human CSF is also correlated with AD severity. Thus, Ly6h links cholinergic signaling, Aß and phosphorylated tau and may serve as a novel marker for AD progression.SIGNIFICANCE STATEMENT One of the earliest and most persistent hypotheses regarding Alzheimer's disease (AD) attributes cognitive impairment to loss of cholinergic signaling. More recently, interest has focused on crucial roles for amyloid ß (Aß) and phosphorylated tau in Alzheimer's pathogenesis. Here, we demonstrate that these elements are linked by Ly6h and its counterpart, NACHO, functioning in opposition to maintain assembly of nicotinic acetylcholine receptors (nAChRs) within the physiological range. Our data suggests that Aß shifts the balance away from Ly6h and toward NACHO, resulting in increased assembly of Ca2+-permeable nAChRs and thus a conversion of basal cholinergic to neurotoxic signaling.

Feeder-free generation and characterization of endocardial and cardiac valve cells from human pluripotent stem cells.

Valvular heart disease presents a significant health burden, yet advancements in valve biology and therapeutics have been hindered by the lack of accessibility to human valve cells. In this study, we have developed a scalable and feeder-free method to differentiate human induced pluripotent stem cells (iPSCs) into endocardial cells, which are transcriptionally and phenotypically distinct from vascular endothelial cells. These endocardial cells can be challenged to undergo endothelial-to-mesenchymal transition (EndMT), after which two distinct populations emerge-one population undergoes EndMT to become valvular interstitial cells (VICs), while the other population reinforces their endothelial identity to become valvular endothelial cells (VECs). We then characterized these populations through bulk RNA-seq transcriptome analyses and compared our VIC and VEC populations to pseudobulk data generated from normal valve tissue of a 15-week-old human fetus. By increasing the accessibility to these cell populations, we aim to accelerate discoveries for cardiac valve biology and disease.

The Model Minority Myth, Data Aggregation, and the Role of Medical Schools in Combating Anti-Asian Sentiment.

The COVID-19 pandemic has resulted in an alarming increase in hate incidents directed toward Asian Americans and Pacific Islanders (AAPIs), including verbal harassment and physical assault, spurring the nationwide #StopAsianHate movement. This rise in anti-Asian sentiment is occurring at a critical time of racial reckoning across the United States, galvanized by the Black Lives Matter movement, and of medical student calls for the implementation of antiracist medical curricula. AAPIs are stereotyped by the model minority myth, which posits that AAPIs are educated, hardworking, and therefore able to achieve high levels of success. This myth acts as a racial wedge between minorities and perpetuates harm that is pervasive throughout the field of medicine. Critically, the frequent aggregation of all AAPI subgroups as one monolithic community obfuscates socioeconomic and cultural differences across the AAPI diaspora while reinforcing the model minority myth. Here, the authors illustrate how the model minority myth and data aggregation have negatively affected the recruitment and advancement of diverse AAPI medical students, physicians, and faculty. Additionally, the authors discuss how data aggregation obscures health disparities across the AAPI diaspora and how the model minority myth influences the illness experiences of AAPI patients. Importantly, the authors outline specific actionable policies and reforms that medical schools can implement to combat anti-Asian sentiment and support the AAPI community.

Structural Analysis and Deletion Mutagenesis Define Regions of QUIVER/SLEEPLESS that Are Responsible for Interactions with Shaker-Type Potassium Channels and Nicotinic Acetylcholine Receptors.

Ly6 proteins are endogenous prototoxins found in most animals. They show striking structural and functional parallels to snake α-neurotoxins, including regulation of ion channels and cholinergic signaling. However, the structural contributions of Ly6 proteins to regulation of effector molecules is poorly understood. This question is particularly relevant to the Ly6 protein QUIVER/SLEEPLESS (QVR/SSS), which has previously been shown to suppress excitability and synaptic transmission by upregulating potassium (K) channels and downregulating nicotinic acetylcholine receptors (nAChRs) in wake-promoting neurons to facilitate sleep in Drosophila. Using deletion mutagenesis, co-immunoprecipitations, ion flux assays, surface labeling and confocal microscopy, we demonstrate that only loop 2 is required for many of the previously described properties of SSS in transfected cells, including interactions with K channels and nAChRs. Collectively our data suggest that QVR/SSS, and by extension perhaps other Ly6 proteins, target effector molecules using limited protein motifs. Mapping these motifs may be useful in rational design of drugs that mimic or suppress Ly6-effector interactions to modulate nervous system function.