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The CO2 receptor in mosquitoes is broadly tuned to detect many diverse odorants. The receptor consists of three subunits (Gr1, Gr2, and Gr3) in mosquitoes but only two subunits in Drosophila: Gr21a (Gr1 ortholog) and Gr63a (Gr3 ortholog). We demonstrate that Gr21a is required for CO2 responses in Drosophila, as has been shown for Gr63a. Next, we generate a Drosophila double mutant for Gr21a and Gr63a, and in this background, we functionally express combinations of Aedes Gr1, Gr2, and Gr3 genes in the CO2 empty neuron. Only two subunits, Gr2 and Gr3, suffice for response to CO2. Addition of Gr1 increases sensitivity to CO2, whereas it decreases the response to pyridine. The inhibitory effect of the antagonist isobutyric acid is observed upon addition of Gr1. Gr1 therefore increases the diversity of ligands of the receptor and modulates the response of the receptor complex.

AbstractThe CO2 receptor in mosquitoes is broadly tuned to detect many diverse odorants. The receptor consists of three 7-TM subunits (Gr1, Gr2, and Gr3) in mosquitoes but only two subunits in Drosophila: Gr21a (Gr1 ortholog) and Gr63a (Gr3 ortholog). We demonstrate that Gr21a is required for CO2 responses in Drosophila as has been shown for Gr63a. Next, we generate a Drosophila double mutant for Gr21a and Gr63a, and in this background we functionally express combinations of Aedes Gr1, 2, and 3 genes in the “CO2 empty neuron.” Only two subunits, Gr2 and Gr3, suffice for response to CO2. Addition of Gr1 increases sensitivity to CO2 while it decreases the response to pyridine. The inhibitory effect of the antagonist isobutyric acid is observed upon addition of Gr1. Gr1 therefore increases the diversity of ligands of the receptor, and also modulates the response of the receptor complex.

While religion and spirituality (R/S) have been broadly studied for their positive mental health impacts, instances of abuse within religious or spiritual contexts remain under-researched. This scoping review aims to elucidate how individuals experiencing such abuse navigate their trauma, find meaning, and foster posttraumatic growth (PTG). The research was conducted using a scoping review methodology as a guide, and 10 articles were selected based on predefined inclusion and exclusion criteria. Synthesizing these articles revealed the following three central themes: recognizing abuse, relaying one's story, and redefining spirituality. Survivors often face disbelief and stigma, hindering their ability to process their experiences. However, narrative sharing enables many to reclaim agency and healing through validation and the integration of the narrative into one's life story. Additionally, survivors often transform spirituality, shifting from rigid frameworks to more nuanced and flexible understandings of the Divine and self. These findings underscore the importance of trauma-informed, spiritually sensitive clinical approaches that validate survivors' experiences, facilitate narrative sharing, and support spiritual redefining. Future research must address knowledge gaps, including the development of improved assessment tools, exploration of effective treatment strategies, and the unifying of terms to better support survivors' healing journeys and promote meaning-making and PTG in the aftermath of R/S abuse. [ABSTRACT FROM AUTHOR]

Patient-derived induced pluripotent stem cells (iPSCs) provide a powerful tool for identifying cellular and molecular mechanisms of disease. Macular telangiectasia type 2 (MacTel) is a rare, late-onset degenerative retinal disease with an extremely heterogeneous genetic architecture, lending itself to the use of iPSCs. Whole-exome sequencing screens and pedigree analyses have identified rare causative mutations that account for less than 5% of cases. Metabolomic surveys of patient populations and GWAS have linked MacTel to decreased circulating levels of serine and elevated levels of neurotoxic 1-deoxysphingolipids (1-dSLs). However, retina-specific, disease- contributing factors have yet to be identified. Here, we used iPSC-differentiated retinal pigmented epithelial (iRPE) cells derived from donors with or without MacTel to screen for novel cell-intrinsic pathological mechanisms. We show that MacTel iRPE cells mimicked the low serine levels observed in serum from patients with MacTel. Through RNA-Seq and gene set enrichment pathway analysis, we determined that MacTel iRPE cells are enriched in cellular stress pathways and dysregulation of central carbon metabolism. Using respirometry and mitochondrial stress testing, we functionally validated that MacTel iRPE cells had a reduction in mitochondrial function that was independent of defects in serine biosynthesis and 1-dSL accumulation. Thus, we identified phenotypes that may constitute alternative disease mechanisms beyond the known serine/sphingolipid pathway., Introduction Complex diseases of aging provide unique challenges for the identification of specific disease-causing genetic variants and associated cellular dysfunctions using traditional genetic approaches. Disease modeling using iPSCs is a [...]

Biomolecules exist and function in cellular microenvironments that control their spatial organization, local concentration, and biochemical reactivity. Due to the complexity of native cytoplasm, the development of artificial bioreactors and cellular mimics to compartmentalize, concentrate, and control the local physico-chemical properties is of great interest. Here, we employ self-assembling polypeptide coacervates to explore the partitioning of the ubiquitous cytoskeletal protein actin into liquid polymer-rich droplets. We find that actin spontaneously partitions into coacervate droplets and is enriched by up to ∼30-fold. Actin polymerizes into micrometer-long filaments and, in contrast to the globular protein BSA, these filaments localize predominately to the droplet periphery. We observe up to a 50-fold enhancement in the actin filament assembly rate inside coacervate droplets, consistent with the enrichment of actin within the coacervate phase. Together these results suggest that coacervates can serve as a versatile platform in which to localize and enrich biomolecules to study their reactivity in physiological environments.

Histone deacetylases (HDACs) have been extensively studied as drug targets in neurodegenerative diseases, but less is known about their role in healthy neurons. We tested zinc-dependent HDACs using RNAi in Drosophila melanogaster and found memory deficits with RPD3 and HDAC6. We demonstrate that HDAC6 is required in both the larval and adult stages for normal olfactory memory retention. Neuronal expression of HDAC6 rescued memory deficits, and we demonstrate that the N-terminal deacetylase (DAC) domain is required for this ability. This suggests that deacetylation of synaptic targets associated with the first DAC domain, such as the active-zone scaffold Bruchpilot, is required for memory retention. Finally, electrophysiological experiments at the neuromuscular junction reveal that HDAC6 mutants exhibit a partial block of homeostatic plasticity, suggesting that HDAC6 may be required for the stabilization of synaptic strength. The learning deficit we observe in HDAC6 mutants could be a behavioral consequence of these synaptic defects.

Neurons exhibit a striking degree of functional diversity, each one tuned to the needs of the circuitry in which it is embedded. A fundamental functional dichotomy occurs in activity patterns, with some neurons firing at a relatively constant “tonic” rate, while others fire in bursts, a “phasic” pattern. Synapses formed by tonic versus phasic neurons are also functionally differentiated, yet the bases of their distinctive properties remain enigmatic. A major challenge toward illuminating the synaptic differences between tonic and phasic neurons is the difficulty in isolating their physiological properties. At the Drosophila neuromuscular junction, most muscle fibers are coinnervated by two motor neurons: the tonic “MN-Ib” and phasic “MN-Is.” Here, we used selective expression of a newly developed botulinum neurotoxin transgene to silence tonic or phasic motor neurons in Drosophila larvae of either sex. This approach highlighted major differences in their neurotransmitter release properties, including probability, short-term plasticity, and vesicle pools. Furthermore, Ca21 imaging demonstrated ;2-fold greater Ca21 influx at phasic neuron release sites relative to tonic, along with an enhanced synaptic vesicle coupling. Finally, confocal and super-resolution imaging revealed that phasic neuron release sites are organized in a more compact arrangement, with enhanced stoichiometry of voltage-gated Ca21 channels relative to other active zone scaffolds. These data suggest that distinctions in active zone nano-architecture and Ca21 influx collaborate to differentially tune glutamate release at tonic versus phasic synaptic subtypes. [ABSTRACT FROM AUTHOR]