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  To treat or not to treat: a comparative effectiveness analysis of oral anticoagulant outcomes among U.S. nursing home residents with atrial fibrillation

  Chen, Qiaoxi; Baek, Jonggyu; Goldberg, Robert J.; Tjia, Jennifer; Lapane, Kate L; Alcusky, Matthew J (2024-07-19)

  Background: Nursing home residents with atrial fibrillation are at high risk for ischemic stroke, but most are not treated with anticoagulants. This study compared the effectiveness and safety between oral anticoagulant (OAC) users and non-users. Methods: We conducted a new-user retrospective cohort study by using Minimum Data Set 3.0 assessments linked with Medicare claims. The participants were Medicare fee-for-service beneficiaries with atrial fibrillation residing in US nursing homes between 2011 and 2016, aged ≥ 65 years. The primary outcomes were occurrence of an ischemic stroke or systemic embolism (effectiveness), occurrence of intracranial or extracranial bleeding (safety) and net clinical outcome (effectiveness or safety outcomes). Secondary outcomes included total mortality and a net clinical and mortality outcome. Cox proportional hazards and Fine and Grey models estimated multivariable adjusted hazard ratios (aHRs) and sub-distribution hazard ratios (sHRs). Results: Outcome rates were low (effectiveness: OAC: 0.86; non-users: 1.73; safety: OAC: 2.26; non-users: 1.75 (per 100 person-years)). OAC use was associated with a lower rate of the effectiveness outcome (sHR: 0.69; 95% Confidence Interval (CI): 0.61-0.77), higher rates of the safety (sHR: 1.70; 95% CI: 1.58-1.84) and net clinical outcomes (sHR: 1.20; 95% CI: 1.13-1.28) lower rate of all-cause mortality outcome (sHR: 0.60; 95% CI: 0.59-0.61), and lower rate of the net clinical and mortality outcome (sHR: 0.60; 95% CI: 0.59-0.61). Warfarin users, but not DOAC users, had a higher rate of the net clinical outcome versus OAC non-users. Conclusions: Our results support the benefits of treatment with OACs to prevent ischemic strokes and increase longevity, while highlighting the need to weigh apparent benefits against elevated risk for bleeding. Results were consistent with net favorability of DOACs versus warfarin.
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  Factors Influencing Margin Clearance and the Number of Stages of Mohs Micrographic Surgery in Basal Cell Carcinoma: A Retrospective Chart Review

  Daniel, Vijaya T; Azzolino, Vincent; Abraham, Maria; Leonard, Nicholas; Blankenship, Kaitlin; Lal, Karan; Flahive, Julie; Brown, Regina; Tkachenko, Elizabeth; Teymour, Shereen; et al. (2024-06-28)

  How patient and tumor factors influence clearance margins and the number of Mohs Micrographic Surgery (MMS) stages when treating basal cell carcinoma (BCC) remains widely uncharacterized. It is important to elucidate these relationships, as surgical outcomes may be compared nationally between colleagues. Our objective is to evaluate the relationships between defect size and patient demographics, as well as between BCC subtypes and the number of MMS stages. Our second objective is to compare practice patterns and characteristics of patients requiring MMS at academic centers and private practices. A retrospective chart review was performed using data collected at academic centers (2015-2018) and private practices (2011-2018) of BCC patients older than 18 years old who underwent MMS. In total, 7651 patients with BCC requiring MMS were identified. Academic center adjusted analyses demonstrated clearance margins 0.1 mm higher for every year's increase in age (p < 0.0001) and 0.25 increase in MMS stages for high-risk BCC (p < 0.0001). Private practice adjusted analyses demonstrated clearance margins 0.04 mm higher for every year's increase in age (p < 0.0001). Clearance margins correlate with older age, and additional MMS stages correlate with high-risk BCC, suggesting the role patient and tumor factors may play in predicting tumor clearance and MMS stages.
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  Preventing acute neurotoxicity of CNS therapeutic oligonucleotides with the addition of Ca and Mg in the formulation [preprint]

  Miller, Rachael; Paquette, Joseph; Barker, Alexandra; Sapp, Ellen; McHugh, Nicholas; Bramato, Brianna; Yamada, Nozomi; Alterman, Julia F; Echeverria, Dimas; Yamada, Ken; et al. (2024-06-08)

  Oligonucleotide therapeutics (ASOs and siRNAs) have been explored for modulation of gene expression in the central nervous system (CNS), with several drugs approved and many in clinical evaluation. Administration of highly concentrated oligonucleotides to the CNS can induce acute neurotoxicity. We demonstrate that delivery of concentrated oligonucleotides to the CSF in awake mice induces acute toxicity, observable within seconds of injection. Electroencephalography (EEG) and electromyography (EMG) in awake mice demonstrated seizures. Using ion chromatography, we show that siRNAs can tightly bind Ca2+ and Mg2+ up to molar equivalents of the phosphodiester (PO)/phosphorothioate (PS) bonds independently of the structure or phosphorothioate content. Optimization of the formulation by adding high concentrations (above biological levels) of divalent cations (Ca2+ alone, Mg2+ alone, or Ca2+ and Mg2+) prevents seizures with no impact on the distribution or efficacy of the oligonucleotide. The data here establishes the importance of adding Ca2+ and Mg2+ to the formulation for the safety of CNS administration of therapeutic oligonucleotides.
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  Bigtools: a high-performance BigWig and BigBed library in Rust

  Huey, Jack D; Abdennur, Nezar (2024-06-03)

  Motivation: The BigWig and BigBed file formats were originally designed for the visualization of next-generation sequencing data through a genome browser. Due to their versatility, these formats have long since become ubiquitous for the storage of processed sequencing data and regularly serve as the basis for downstream data analysis. As the number and size of sequencing experiments continues to accelerate, there is an increasing demand to efficiently generate and query BigWig and BigBed files in a scalable and robust manner, and to efficiently integrate these functionalities into data analysis environments and third-party applications. Results: Here, we present Bigtools, a feature-complete, high-performance, and integrable software library for generating and querying both BigWig and BigBed files. Bigtools is written in the Rust programming language and includes a flexible suite of command line tools as well as bindings to Python. Availability and implementation: Bigtools is cross-platform and released under the MIT license. It is distributed on Crates.io, Bioconda, and the Python Package Index, and the source code is available at https://github.com/jackh726/bigtools.
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  Dual engagement of the nucleosomal acidic patches is essential for deposition of histone H2A.Z by SWR1C

  Baier, Alexander S; Gioacchini, Nathan; Eek, Priit; Leith, Erik M; Tan, Song; Peterson, Craig L (2024-05-29)

  The yeast SWR1C chromatin remodeling enzyme catalyzes the ATP-dependent exchange of nucleosomal histone H2A for the histone variant H2A.Z, a key variant involved in a multitude of nuclear functions. How the 14-subunit SWR1C engages the nucleosomal substrate remains largely unknown. Studies on the ISWI, CHD1, and SWI/SNF families of chromatin remodeling enzymes have demonstrated key roles for the nucleosomal acidic patch for remodeling activity, however a role for this nucleosomal epitope in nucleosome editing by SWR1C has not been tested. Here, we employ a variety of biochemical assays to demonstrate an essential role for the acidic patch in the H2A.Z exchange reaction. Utilizing asymmetrically assembled nucleosomes, we demonstrate that the acidic patches on each face of the nucleosome are required for SWR1C-mediated dimer exchange, suggesting SWR1C engages the nucleosome in a 'pincer-like' conformation, engaging both patches simultaneously. Loss of a single acidic patch results in loss of high affinity nucleosome binding and nucleosomal stimulation of ATPase activity. We identify a conserved arginine-rich motif within the Swc5 subunit that binds the acidic patch and is key for dimer exchange activity. In addition, our cryoEM structure of a Swc5-nucleosome complex suggests that promoter proximal, histone H2B ubiquitylation may regulate H2A.Z deposition. Together these findings provide new insights into how SWR1C engages its nucleosomal substrate to promote efficient H2A.Z deposition.
• Single-cell genomics and regulatory networks for 388 human brains

  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. (2024-05-24)

  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, multiomics datasets into a resource comprising >2.8 million 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 >550,000 cell type-specific regulatory elements and >1.4 million 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.
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  Using a comprehensive atlas and predictive models to reveal the complexity and evolution of brain-active regulatory elements

  Pratt, Henry E; Andrews, Gregory; Shedd, Nicole; Phalke, Nishigandha; Li, Tongxin; Pampari, Anusri; Jensen, Matthew; Wen, Cindy; Gandal, Michael J; Geschwind, Daniel H; et al. (2024-05-23)

  Most genetic variants associated with psychiatric disorders are located in noncoding regions of the genome. To investigate their functional implications, we integrate epigenetic data from the PsychENCODE Consortium and other published sources to construct a comprehensive atlas of candidate brain cis-regulatory elements. Using deep learning, we model these elements' sequence syntax and predict how binding sites for lineage-specific transcription factors contribute to cell type-specific gene regulation in various types of glia and neurons. The elements' evolutionary history suggests that new regulatory information in the brain emerges primarily via smaller sequence mutations within conserved mammalian elements rather than entirely new human- or primate-specific sequences. However, primate-specific candidate elements, particularly those active during fetal brain development and in excitatory neurons and astrocytes, are implicated in the heritability of brain-related human traits. Additionally, we introduce PsychSCREEN, a web-based platform offering interactive visualization of PsychENCODE-generated genetic and epigenetic data from diverse brain cell types in individuals with psychiatric disorders and healthy controls.
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  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.
• Distinct members of the Caenorhabditis elegans CeMbio reference microbiota exert cryptic virulence that is masked by host defense

  Gonzalez, Xavier; Irazoqui, Javier E (2024-04-16)

  Microbiotas are complex microbial communities that colonize specific niches in the host and provide essential organismal functions that are important in health and disease. Understanding the ability of each distinct community member to promote or impair host health, alone or in the context of the community, is imperative for understanding how differences in community structure affect host health and vice versa. Recently, a reference 12-member microbiota for the model organism Caenorhabditis elegans, known as CeMbio, was defined. Here, we show the differential ability of each CeMbio bacterial species to activate innate immunity through the conserved PMK-1/p38 MAPK, ACh-WNT, and HLH-30/TFEB pathways. Although distinct CeMbio members differed in their ability to activate the PMK-1/p38 pathway, the ability to do so did not correlate with bacterial-induced lifespan reduction in wild-type or immunodeficient animals. In contrast, most species activated HLH-30/TFEB and showed virulence toward hlh-30-deficient animals. These results suggest that the microbiota of C. elegans is rife with bacteria that can shorten the host's lifespan if host defense is compromised and that HLH-30/TFEB is a fundamental and key host protective factor.
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  A single cell atlas of the mouse seminal vesicle [preprint]

  Sun, Fengyun; Desevin, Kathleen; Fu, Yu; Parameswaran, Shanmathi; Mayall, Jemma; Rinaldi, Vera; Krietenstein, Nils; Manukyan, Artur; Yin, Qiangzong; Galan, Carolina; et al. (2024-04-11)

  During mammalian reproduction, sperm are delivered to the female reproductive tract bathed in a complex medium known as seminal fluid, which plays key roles in signaling to the female reproductive tract and in nourishing sperm for their onwards journey. Along with minor contributions from the prostate and the epididymis, the majority of seminal fluid is produced by a somewhat understudied organ known as the seminal vesicle. Here, we report the first single-cell RNA-seq atlas of the mouse seminal vesicle, generated using tissues obtained from 23 mice of varying ages, exposed to a range of dietary challenges. We define the transcriptome of the secretory cells in this tissue, identifying a relatively homogeneous population of the epithelial cells which are responsible for producing the majority of seminal fluid. We also define the immune cell populations - including large populations of macrophages, dendritic cells, T cells, and NKT cells - which have the potential to play roles in producing various immune mediators present in seminal plasma. Together, our data provide a resource for understanding the composition of an understudied reproductive tissue with potential implications for paternal control of offspring development and metabolism.
• Association of perinatal depression and postpartum contraception intent, choice, and actual use

  Masters, Grace A; Julce, Clevanne; Carroll, Smita; Person, Sharina D.; Allison, Jeroan J.; Byatt, Nancy; Moore Simas, Tiffany A (2024-04-05)

  Objectives: Depression is common during pregnancy and the year following childbirth (the perinatal period). This study assessed the association of depressive symptoms and contraception decisions in perinatal individuals. Study design: We conducted a secondary analysis using data from the PRogram in Support of Moms (PRISM) study, a cluster randomized controlled trial of active interventions which aimed to address perinatal depression. This analysis included 191 individuals aged 18-45 who screened positive for depression on the Edinburgh Postnatal Depression Scale (EPDS, score ≥10) during pregnancy or up to 3 months postpartum. We assessed contraception intent and method choice at 1-3 months postpartum. At 5-7 months postpartum, we assessed contraceptive method used and EPDS depression scores. We used logistic regressions to examine the relationship between depression and contraceptive use/method. Results: At 1-3 months postpartum, the majority of participants (76.4%) expressed an intention to use contraception. Of those, over half (53.4%) indicated a preference for higher effectiveness contraception methods. Participants with persistent depression symptoms (positive EPDS) at 5-7 months were significantly less likely to report using higher effectiveness contraceptive methods (aOR = 0.28, 95% CI = 0.11-0.70) compared to those without. Among participants with persistent depressive symptoms, 21.1% reported using a contraception method of lower effectiveness than had originally intended. Conclusion: Perinatal individuals with persistent depressive symptoms at 5-7 months postpartum reported greater use of less-effective contraception methods than originally planned. Implications: We found associations between perinatal depression and use of less effective contraception use. Provider discussions regarding contraception planning is important, particularly in those with perinatal depression symptoms.
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  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.
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  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.
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  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.
• 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.
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  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.
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  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.
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  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.

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