Now showing items 1-20 of 2965

    • CD20/MS4A1 is a mammalian olfactory receptor expressed in a subset of olfactory sensory neurons that mediates innate avoidance of predators

      Jiang, Hao-Ching; Park, Sung Jin; Wang, I-Hao; Bear, Daniel M; Nowlan, Alexandra; Greer, Paul L (2024-04-18)
      The mammalian olfactory system detects and discriminates between millions of odorants to elicit appropriate behavioral responses. While much has been learned about how olfactory sensory neurons detect odorants and signal their presence, how specific innate, unlearned behaviors are initiated in response to ethologically relevant odors remains poorly understood. Here, we show that the 4-transmembrane protein CD20, also known as MS4A1, is expressed in a previously uncharacterized subpopulation of olfactory sensory neurons in the main olfactory epithelium of the murine nasal cavity and functions as a mammalian olfactory receptor that recognizes compounds produced by mouse predators. While wildtype mice avoid these predator odorants, mice genetically deleted of CD20 do not appropriately respond. Together, this work reveals a CD20-mediated odor-sensing mechanism in the mammalian olfactory system that triggers innate behaviors critical for organismal survival.
    • Dopamine control of social novelty preference is constrained by an interpeduncular-tegmentum circuit

      Molas, Susanna; Freels, Timothy G; Zhao-Shea, Rubing; Lee, Timothy; Gimenez-Gomez, Pablo; Barbini, Melanie; Martin, Gilles E; Tapper, Andrew R (2024-04-03)
      Animals are inherently motivated to explore social novelty cues over familiar ones, resulting in a novelty preference (NP), although the behavioral and circuit bases underlying NP are unclear. Combining calcium and neurotransmitter sensors with fiber photometry and optogenetics in mice, we find that mesolimbic dopamine (DA) neurotransmission is strongly and predominantly activated by social novelty controlling bout length of interaction during NP, a response significantly reduced by familiarity. In contrast, interpeduncular nucleus (IPN) GABAergic neurons that project to the lateral dorsal tegmentum (LDTg) were inhibited by social novelty but activated during terminations with familiar social stimuli. Inhibition of this pathway during NP increased interaction and bout length with familiar social stimuli, while activation reduced interaction and bout length with novel social stimuli via decreasing DA neurotransmission. These data indicate interest towards novel social stimuli is encoded by mesolimbic DA which is dynamically regulated by an IPN→LDTg circuit to control NP.
    • Targeting the GPI transamidase subunit GPAA1 abrogates the CD24 immune checkpoint in ovarian cancer

      Mishra, Alok K; Ye, Tianyi; Banday, Shahid; Thakare, Ritesh P; Su, Chinh Tran-To; Pham, Ngoc N H; Ali, Amjad; Kulshreshtha, Ankur; Chowdhury, Shreya Roy; Simone, Tessa M; et al. (2024-04-03)
      CD24 is frequently overexpressed in ovarian cancer and promotes immune evasion by interacting with its receptor Siglec10, present on tumor-associated macrophages, providing a "don't eat me" signal that prevents targeting and phagocytosis by macrophages. Factors promoting CD24 expression could represent novel immunotherapeutic targets for ovarian cancer. Here, using a genome-wide CRISPR knockout screen, we identify GPAA1 (glycosylphosphatidylinositol anchor attachment 1), a factor that catalyzes the attachment of a glycosylphosphatidylinositol (GPI) lipid anchor to substrate proteins, as a positive regulator of CD24 cell surface expression. Genetic ablation of GPAA1 abolishes CD24 cell surface expression, enhances macrophage-mediated phagocytosis, and inhibits ovarian tumor growth in mice. GPAA1 shares structural similarities with aminopeptidases. Consequently, we show that bestatin, a clinically advanced aminopeptidase inhibitor, binds to GPAA1 and blocks GPI attachment, resulting in reduced CD24 cell surface expression, increased macrophage-mediated phagocytosis, and suppressed growth of ovarian tumors. Our study highlights the potential of targeting GPAA1 as an immunotherapeutic approach for CD24+ ovarian cancers.
    • Combinatorial expression of neurexin genes regulates glomerular targeting by olfactory sensory neurons [preprint]

      Park, Sung Jin; Wang, I-Hao; Lee, Namgyu; Jiang, Hao-Ching; Uemura, Takeshi; Futai, Kensuke; Kim, Dohoon; Macosko, Evan; Greer, Paul (2024-04-02)
      Precise connectivity between specific neurons is essential for the formation of the complex neural circuitry necessary for executing intricate motor behaviors and higher cognitive functions. While trans -interactions between synaptic membrane proteins have emerged as crucial elements in orchestrating the assembly of these neural circuits, the synaptic surface proteins involved in neuronal wiring remain largely unknown. Here, using unbiased single-cell transcriptomic and mouse genetic approaches, we uncover that the neurexin family of genes enables olfactory sensory neuron (OSNs) axons to form appropriate synaptic connections with their mitral and tufted (M/T) cell synaptic partners, within the mammalian olfactory system. Neurexin isoforms are differentially expressed within distinct populations of OSNs, resulting in unique pattern of neurexin expression that is specific to each OSN type, and synergistically cooperate to regulate axonal innervation, guiding OSN axons to their designated glomeruli. This process is facilitated through the interactions of neurexins with their postsynaptic partners, including neuroligins, which have distinct expression patterns in M/T cells. Our findings suggest a novel mechanism underpinning the precise assembly of olfactory neural circuits, driven by the trans -interaction between neurexins and their ligands.
    • Lactate transporter MCT1 in hepatic stellate cells promotes fibrotic collagen expression in nonalcoholic steatohepatitis

      Min, Kyounghee; Yenilmez, Batuhan; Kelly, Mark; Echeverria, Dimas; Elleby, Michael; Lifshitz, Lawrence M; Raymond, Naideline; Tsagkaraki, Emmanouela; Harney, Shauna M; DiMarzio, Chloe; et al. (2024-04-02)
      Circulating lactate is a fuel source for liver metabolism but may exacerbate metabolic diseases such as nonalcoholic steatohepatitis (NASH). Indeed, haploinsufficiency of lactate transporter monocarboxylate transporter 1 (MCT1) in mice reportedly promotes resistance to hepatic steatosis and inflammation. Here, we used adeno-associated virus (AAV) vectors to deliver thyroxin binding globulin (TBG)-Cre or lecithin-retinol acyltransferase (Lrat)-Cre to MCT1fl/fl mice on a choline-deficient, high-fat NASH diet to deplete hepatocyte or stellate cell MCT1, respectively. Stellate cell MCT1KO (AAV-Lrat-Cre) attenuated liver type 1 collagen protein expression and caused a downward trend in trichrome staining. MCT1 depletion in cultured human LX2 stellate cells also diminished collagen 1 protein expression. Tetra-ethylenglycol-cholesterol (Chol)-conjugated siRNAs, which enter all hepatic cell types, and hepatocyte-selective tri-N-acetyl galactosamine (GN)-conjugated siRNAs were then used to evaluate MCT1 function in a genetically obese NASH mouse model. MCT1 silencing by Chol-siRNA decreased liver collagen 1 levels, while hepatocyte-selective MCT1 depletion by AAV-TBG-Cre or by GN-siRNA unexpectedly increased collagen 1 and total fibrosis without effect on triglyceride accumulation. These findings demonstrate that stellate cell lactate transporter MCT1 significantly contributes to liver fibrosis through increased collagen 1 protein expression in vitro and in vivo, while hepatocyte MCT1 appears not to be an attractive therapeutic target for NASH.
    • Single-cell genomics and regulatory networks for 388 human brains [preprint]

      Emani, Prashant S; Liu, Jason J; Clarke, Declan; Jensen, Matthew; Warrell, Jonathan; Gupta, Chirag; Meng, Ran; Lee, Che Yu; Xu, Siwei; Dursun, Cagatay; et al. (2024-03-30)
      Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet, little is understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly processed single-nuclei, multi-omics datasets into a resource comprising >2.8M nuclei from the prefrontal cortex across 388 individuals. For 28 cell types, we assessed population-level variation in expression and chromatin across gene families and drug targets. We identified >550K cell-type-specific regulatory elements and >1.4M single-cell expression-quantitative-trait loci, which we used to build cell-type regulatory and cell-to-cell communication networks. These networks manifest cellular changes in aging and neuropsychiatric disorders. We further constructed an integrative model accurately imputing single-cell expression and simulating perturbations; the model prioritized ~250 disease-risk genes and drug targets with associated cell types.
    • Vocal learning-associated convergent evolution in mammalian proteins and regulatory elements

      Wirthlin, Morgan E; Schmid, Tobias A; Elie, Julie E; Zhang, Xiaomeng; Kowalczyk, Amanda; Redlich, Ruby; Shvareva, Varvara A; Rakuljic, Ashley; Ji, Maria B; Bhat, Ninad S; et al. (2024-03-29)
      Vocal production learning ("vocal learning") is a convergently evolved trait in vertebrates. To identify brain genomic elements associated with mammalian vocal learning, we integrated genomic, anatomical, and neurophysiological data from the Egyptian fruit bat (Rousettus aegyptiacus) with analyses of the genomes of 215 placental mammals. First, we identified a set of proteins evolving more slowly in vocal learners. Then, we discovered a vocal motor cortical region in the Egyptian fruit bat, an emergent vocal learner, and leveraged that knowledge to identify active cis-regulatory elements in the motor cortex of vocal learners. Machine learning methods applied to motor cortex open chromatin revealed 50 enhancers robustly associated with vocal learning whose activity tended to be lower in vocal learners. Our research implicates convergent losses of motor cortex regulatory elements in mammalian vocal learning evolution.
    • Sex differences in time to initiate NSAIDs or bDMARDs among patients with axial spondyloarthritis

      Shridharmurthy, Divya; Lapane, Kate L; Baek, Jonggyu; Nunes, Anthony P; Weisman, Michael H; Kay, Jonathan; Liu, Shao-Hsien (2024-03-27)
      Objective: We evaluated sex differences in time to initiation of nonsteroidal anti-inflammatory agents (NSAIDs) or biologic disease modifying antirheumatic drugs (bDMARDs) among patients with axial spondyloarthritis (axSpA). Methods: Using the 2013-2018 IBM® MarketScan® Database, we identified 174,632 axSpA patients aged ≥18 years. We evaluated the time between axSpA diagnosis and the first prescription NSAID dispensing (among those with no baseline NSAIDs use) or bDMARDs infusion/procedure claim (among those dispensed ≥ two different prescription NSAIDs in the baseline period). Adjusted hazard ratios (aHR) for time to initiation of NSAIDs or bDMARDs were computed using survival analyses. Cox proportional hazard models estimated associations between sex and predictors of treatment initiation. Results: Average age at diagnosis was 48.2 years, 65.7% were females, and 37.8% had ≥ one NSAIDs dispensing before axSpA diagnosis. Of those without dispensing for ≥ two different prescription NSAIDs before diagnosis, NSAIDs were initiated earlier in females than males (NSAID initiators: Females (32.9%), Males (29.3%); aHR: 1.14, 95% CI: 1.11-1.16). Among those with ≥ two different prescription NSAIDs dispensations in the baseline period, 4.2% initiated a bDMARD while 77.9% continued NSAIDs use after diagnosis. Time to bDMARDs initiation was longer for females than males (aHR:0.61, 95% CI:0.52-0.72), but bDMARDs were initiated sooner among those with NSAIDs use in the baseline period. Conclusion: Prescription NSAID use was more common than initiation of bDMARDs among patients newly diagnosed with axSpA. Females appeared more likely to continue NSAIDs after diagnosis, and the time to initiation of bDMARDs was longer for females than males.
    • Expression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microglia

      Funes, Salome; Jung, Jonathan; Gadd, Del Hayden; Mosqueda, Michelle; Zhong, Jianjun; Shankaracharya; Unger, Matthew; Stallworth, Karly; Cameron, Debra; Rotunno, Melissa S; et al. (2024-03-20)
      Microglia play a pivotal role in neurodegenerative disease pathogenesis, but the mechanisms underlying microglia dysfunction and toxicity remain to be elucidated. To investigate the effect of neurodegenerative disease-linked genes on the intrinsic properties of microglia, we studied microglia-like cells derived from human induced pluripotent stem cells (iPSCs), termed iMGs, harboring mutations in profilin-1 (PFN1) that are causative for amyotrophic lateral sclerosis (ALS). ALS-PFN1 iMGs exhibited evidence of lipid dysmetabolism, autophagy dysregulation and deficient phagocytosis, a canonical microglia function. Mutant PFN1 also displayed enhanced binding affinity for PI3P, a critical signaling molecule involved in autophagic and endocytic processing. Our cumulative data implicate a gain-of-toxic function for mutant PFN1 within the autophagic and endo-lysosomal pathways, as administration of rapamycin rescued phagocytic dysfunction in ALS-PFN1 iMGs. These outcomes demonstrate the utility of iMGs for neurodegenerative disease research and implicate microglial vesicular degradation pathways in the pathogenesis of these disorders.
    • Calcineurin promotes adaptation to chronic stress through two distinct mechanisms [preprint]

      Flynn, Mackenzie J; Harper, Nicholas W; Li, Rui; Zhu, Lihua Julie; Lee, Michael J; Benanti, Jennifer A (2024-03-20)
      Adaptation to environmental stress requires coordination between stress-defense programs and cell cycle progression. The immediate response to many stressors has been well characterized, but how cells survive in challenging environments long-term is unknown. Here, we investigate the role of the stress-activated phosphatase calcineurin (CN) in adaptation to chronic CaCl2 stress in Saccharomyces cerevisiae. We find that prolonged exposure to CaCl2 impairs mitochondrial function and demonstrate that cells respond to this stressor using two CN-dependent mechanisms - one that requires the downstream transcription factor Crz1 and another that is Crz1-independent. Our data indicate that CN maintains cellular fitness by promoting cell cycle progression and preventing CaCl2-induced cell death. When Crz1 is present, transient CN activation suppresses cell death and promotes adaptation despite high levels of mitochondrial loss. However, in the absence of Crz1, prolonged activation of CN prevents mitochondrial loss and further cell death by upregulating glutathione (GSH) biosynthesis genes thereby mitigating damage from reactive oxygen species. These findings illustrate how cells maintain long-term fitness during chronic stress and suggest that CN promotes adaptation in challenging environments by multiple mechanisms.
    • Modular vector assembly enables rapid assessment of emerging CRISPR technologies

      McGee, Abby V; Liu, Yanjing V; Griffith, Audrey L; Szegletes, Zsofia M; Wen, Bronte; Kraus, Carolyn; Miller, Nathan W; Steger, Ryan J; Escude Velasco, Berta; Bosch, Justin A; et al. (2024-03-13)
      The diversity of CRISPR systems, coupled with scientific ingenuity, has led to an explosion of applications; however, to test newly described innovations in their model systems, researchers typically embark on cumbersome, one-off cloning projects to generate custom reagents that are optimized for their biological questions. Here, we leverage Golden Gate cloning to create the Fragmid toolkit, a modular set of CRISPR cassettes and delivery technologies, along with a web portal, resulting in a combinatorial platform that enables scalable vector assembly within days. We further demonstrate that multiple CRISPR technologies can be assessed in parallel in a pooled screening format using this resource, enabling the rapid optimization of both novel technologies and cellular models. These results establish Fragmid as a robust system for the rapid design of CRISPR vectors, and we anticipate that this assembly approach will be broadly useful for systematic development, comparison, and dissemination of CRISPR technologies.
    • Social engagement and cognitive impairment among nursing home residents: The role of sensory impairment

      Xu, Shu; Jesdale, William M; Dubé, Catherine E; Nielsen, Natalia N; McPhillips, Emily A; Lapane, Kate L (2024-03-05)
      Background and objectives: Using US national nursing home data, this cross-sectional study sought to evaluate 1) the association between lack of social engagement and level of cognitive impairment; and 2) the extent to which this association differs by hearing and visual impairment. Research design and methods: Our sample included 793,846 nursing home residents aged ≥ 50 years. The Index of Social Engagement was categorized as none/lower (0, 1, 2) or higher levels (3 through 6). Cognitive Performance Scale was grouped as intact/mild (0, 1, 2), moderate (3, 4), or severe (5, 6). Multinomial models provided adjusted odds ratio (aOR) and 95 % confidence intervals (CI) between none/lower social engagement and cognitive impairment. We estimated relative excess risk due to interaction (RERI) to quantify the joint effects of social engagement and sensory impairment types. Results: Overall, 12.6 % had lower social engagement, 30.3 % had hearing impairment, and 40.3 % had visual impairment. Compared to residents with high social engagement, those with lower social engagement were more likely to have moderate/severe cognitive impairment (aORmoderate = 2.21, 95 % CI 2.17-2.26; aORsevere = 6.49, 95 % CI 6.24-6.74). The impact of low social engagement on cognitive impairment was more profound among residents with hearing impairment and/or visual impairment (RERIhearing = 3.89, 95 % CI 3.62-4.17; RERIvisual = 25.2, 95 % CI 23.9-26.6)). Discussion and implications: Residents with lower social engagement had higher levels of cognitive impairment. Residents with sensory impairments are potentially more susceptible to the negative impact of lower levels of social engagement on level of cognitive impairment.
    • Silencing Parkinson's risk allele Rit2 sex-specifically compromises motor function and dopamine neuron viability

      Kearney, Patrick J; Zhang, Yuanxi; Liang, Marianna; Tan, Yanglan; Kahuno, Elizabeth; Conklin, Tucker L; Fagan, Rita R; Pavchinskiy, Rebecca G; Shaffer, Scott A; Yue, Zhenyu; et al. (2024-02-23)
      Parkinson's disease (PD) is the second most prevalent neurodegenerative disease and arises from dopamine (DA) neuron death selectively in the substantia nigra pars compacta (SNc). Rit2 is a reported PD risk allele, and recent single cell transcriptomic studies identified a major RIT2 cluster in PD DA neurons, potentially linking Rit2 expression loss to a PD patient cohort. However, it is still unknown whether Rit2 loss itself impacts DA neuron function and/or viability. Here we report that conditional Rit2 silencing in mouse DA neurons drove motor dysfunction that occurred earlier in males than females and was rescued at early stages by either inhibiting the DA transporter (DAT) or with L-DOPA treatment. Motor dysfunction was accompanied by decreased DA release, striatal DA content, phenotypic DAergic markers, DA neurons, and DAergic terminals, with increased pSer129-alpha synuclein and pSer935-LRRK2 expression. These results provide clear evidence that Rit2 loss is causal for SNc cell death and motor dysfunction, and reveal key sex-specific differences in the response to Rit2 loss.
    • Racial and Ethnic Disparities in Use of Colorectal Cancer Screening Among Adults With Chronic Medical Conditions: BRFSS 2012-2020

      Castañeda-Avila, Maira A; Tisminetzky, Mayra; Oyinbo, Atinuke G; Lapane, Kate L (2024-02-22)
      Introduction: People with chronic conditions and people with colorectal cancer (CRC) may share common risk factors; thus, CRC screening is important for people with chronic conditions. We examined racial and ethnic differences in the use of CRC screening among people with various numbers of chronic conditions. Methods: We included data on adult respondents aged 50 to 75 years from the Behavioral Risk Factor Surveillance System in 2012 through 2020. We categorized counts of 9 conditions as 0, 1, 2, 3, and ≥4. We classified self-reported CRC screening status as up to date or not. We used Poisson models to estimate adjusted prevalence ratios (APRs) among the different counts of chronic conditions in 4 racial and ethnic groups: Hispanic adults with limited English proficiency (LEP), Hispanic adults without LEP, non-Hispanic Black adults, and non-Hispanic White adults. Results: Overall, 66.5% of respondents were up to date with CRC screening. The prevalence of being up to date increased with the number of chronic conditions. We found disparities among racial and ethnic groups. Hispanic respondents with LEP had lower rates than non-Hispanic White adults of being up to date with CRC screening across all counts of chronic conditions (APR for 0 conditions = 0.67; 95% CI, 0.64-0.71; APR for ≥4 conditions = 0.85; 95% CI, 0.79-0.91). Hispanic respondents without LEP with 0, 1, or 2 conditions were less likely than non-Hispanic White respondents to be up to date with CRC screening. We found no significant differences between non-Hispanic Black and non-Hispanic White respondents. Conclusion: We found disparities among Hispanic BRFSS respondents with LEP, who had lower rates than non-Hispanic White respondents of being up to date with CRC screening, regardless of the number of chronic conditions. Tailored interventions are needed to address these disparities and improve screening rates, particularly among Hispanic people.
    • Persistent False Positive Covid-19 Rapid Antigen Tests

      Herbert, Carly; McManus, David D; Soni, Apurv (2024-02-22)
      Rapid antigen tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are effective tools for the diagnosis of acute infection, particularly when used serially. The percentage of rapid antigen tests with false positive results is reported to be less than 1%. However, we have observed persons who repeatedly test positive with rapid antigen tests despite concurrent negative molecular tests; this infrequent phenomenon occurs predominantly among women and persons with autoimmune disorders.
    • Domain-inlaid Nme2Cas9 adenine base editors with improved activity and targeting scope

      Bamidele, Nathan; Zhang, Han; Dong, Xiaolong; Cheng, Haoyang; Gaston, Nicholas; Feinzig, Hailey; Cao, Hanbing; Kelly, Karen; Watts, Jonathan K; Xie, Jun; et al. (2024-02-17)
      Nme2Cas9 has been established as a genome editing platform with compact size, high accuracy, and broad targeting range, including single-AAV-deliverable adenine base editors. Here, we engineer Nme2Cas9 to further increase the activity and targeting scope of compact Nme2Cas9 base editors. We first use domain insertion to position the deaminase domain nearer the displaced DNA strand in the target-bound complex. These domain-inlaid Nme2Cas9 variants exhibit shifted editing windows and increased activity in comparison to the N-terminally fused Nme2-ABE. We next expand the editing scope by swapping the Nme2Cas9 PAM-interacting domain with that of SmuCas9, which we had previously defined as recognizing a single-cytidine PAM. We then use these enhancements to introduce therapeutically relevant edits in a variety of cell types. Finally, we validate domain-inlaid Nme2-ABEs for single-AAV delivery in vivo.
    • Genome-wide kinetic profiling of pre-mRNA 3' end cleavage

      Torres Ulloa, Leslie; Calvo-Roitberg, Ezequiel; Pai, Athma A (2024-02-16)
      Cleavage and polyadenylation is necessary for the formation of mature mRNA molecules. The rate at which this process occurs can determine the temporal availability of mRNA for subsequent function throughout the cell and is likely tightly regulated. Despite advances in high-throughput approaches for global kinetic profiling of RNA maturation, genome-wide 3' end cleavage rates have never been measured. Here, we describe a novel approach to estimate the rates of cleavage, using metabolic labeling of nascent RNA, high-throughput sequencing, and mathematical modeling. Using in silico simulations of nascent RNA-seq data, we show that our approach can accurately and precisely estimate cleavage half-lives for both constitutive and alternative sites. We find that 3' end cleavage is fast on average, with half-lives under a minute, but highly variable across individual sites. Rapid cleavage is promoted by the presence of canonical sequence elements and an increased density of polyadenylation signals near a cleavage site. Finally, we find that cleavage rates are associated with the localization of RNA polymerase II at the end of a gene, and faster cleavage leads to quicker degradation of downstream readthrough RNA. Our findings shed light on the features important for efficient 3' end cleavage and the regulation of transcription termination.
    • Examining racial/ethnic inequities in treatment participation among perinatal individuals with depression

      Boama-Nyarko, Esther; Flahive, Julie; Zimmermann, Martha; Allison, Jeroan J.; Person, Sharina D.; Moore Simas, Tiffany A; Byatt, Nancy (2024-02-15)
      Objective: A cluster randomized controlled trial (RCT) of two interventions for addressing perinatal depression treatment in obstetric settings was conducted. This secondary analysis compared treatment referral and participation among Minoritized perinatal individuals compared to their non-Hispanic white counterparts. Methods: Among perinatal individuals with depression symptoms, we examined rates of treatment 1) referral (i.e., offered medications or referred to mental health clinician), 2) initiation (i.e., attended ≥1 mental health visit or reported prescribed antidepressant medication), and 3) sustainment (i.e., attended >1 mental health visit per study month or prescribed antidepressant medication at time of study interviews). We compared non-Hispanic white (NHW) (n = 149) vs. Minoritized perinatal individuals (Black, Asian, Hispanic/Latina, Pacific Islander, Native American, Multiracial, and white Hispanic/Latina n = 157). We calculated adjusted odds ratios (aOR) for each outcome. Results: Minoritized perinatal individuals across both interventions had significantly lower odds of treatment referral (aOR = 0.48;95% CI = 0.27-0.88) than their NHW counterparts. There were no statistically significant differences in the odds of treatment initiation (aOR = 0.64 95% CI:0.36-1.2) or sustainment (aOR = 0.54;95% CI = 0.28-1.1) by race/ethnicity. Conclusions: Perinatal mental healthcare inequities are associated with disparities in treatment referrals. Interventions focusing on referral disparities across race and ethnicity are needed.
    • Microglia-astrocyte crosstalk regulates synapse remodeling via Wnt signaling [preprint]

      Faust, Travis E; Lee, Yi-Han; O'Connor, Ciara; Boyle, Margaret A; Gunner, Georgia; Badimon, Ana; Ayata, Pinar; Schaefer, Anne; Schafer, Dorothy P (2024-02-09)
      Astrocytes and microglia are emerging key regulators of activity-dependent synapse remodeling that engulf and remove synapses in response to changes in neural activity. Yet, the degree to which these cells communicate to coordinate this process remains an open question. Here, we use whisker removal in postnatal mice to induce activity-dependent synapse removal in the barrel cortex. We show that astrocytes do not engulf synapses in this paradigm. Instead, astrocytes reduce their contact with synapses prior to microglia-mediated synapse engulfment. We further show that reduced astrocyte-contact with synapses is dependent on microglial CX3CL1-CX3CR1 signaling and release of Wnts from microglia following whisker removal. These results demonstrate an activity-dependent mechanism by which microglia instruct astrocyte-synapse interactions, which then provides a permissive environment for microglia to remove synapses. We further show that this mechanism is critical to remodel synapses in a changing sensory environment and this signaling is upregulated in several disease contexts.
    • Clocks at sea: the genome-editing tide is rising

      Kwiatkowski, Erica R; Rosenthal, Joshua J C; Emery, Patrick (2024-02-08)
      The coastline is a particularly challenging environment for its inhabitants. Not only do they have to cope with the solar day and the passing of seasons, but they must also deal with tides. In addition, many marine species track the phase of the moon, especially to coordinate reproduction. Marine animals show remarkable behavioral and physiological adaptability, using biological clocks to anticipate specific environmental cycles. Presently, we lack a basic understanding of the molecular mechanisms underlying circatidal and circalunar clocks. Recent advances in genome engineering and the development of genetically tractable marine model organisms are transforming how we study these timekeeping mechanisms and opening a novel era in marine chronobiology.