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eScholarship@UMassChan

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eScholarship@UMassChan is a digital repository for UMass Chan Medical School's research and scholarship, including journal articles, theses, datasets and more. We welcome submissions from our faculty, staff, and students. eScholarship@UMassChan is a service of the Lamar Soutter Library, Worcester, MA, USA. See also our open access journal publishing services.

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  • Apheresis practice variation during the COVID-19 pandemic: Results of a survey

    Tanhehco, Yvette C; Alsammak, Mohamed; Chhibber, Vishesh; Ibeh, Nnaemeka; Li, Yanhua; Stephens, Laura D; Noland, Daniel K; Wu, Ding Wen; Zantek, Nicole D; DeChristopher, Phillip J; et al. (2024-06-01)
    Background: The COVID-19 pandemic affected healthcare delivery across all specialties including apheresis. To describe the changes in apheresis service practices that occurred during the pandemic, the American Society for Apheresis (ASFA) Apheresis Medicine Attending Physician Subcommittee conducted a survey study. Study design and methods: A 32-question survey was designed and distributed to 400 ASFA physician members on September 7, 2022. Attending physicians responded to questions about whether and how apheresis service practices changed during the COVID-19 pandemic compared with the time period prior to the pandemic in terms of: (1) procedure types and volumes, (2) patient consultation workflow, and (3) the use of telemedicine. Descriptive analyses were reported as number and frequency of responses. Results: The survey response rate was 13.8% (55/400). Of these respondents, 96.4% (53/55) were attending physicians. The majority of respondents (42/53, 79.2%) indicated that the types of procedures performed during COVID-19 compared to pre-pandemic did not change. Most frequently for apheresis procedure volume, respondents reported: no change in their monthly inpatient volume (21/47, 44.7%) and a decrease in their monthly outpatient volume (28/46, 60.9%). Prior to COVID-19, 75.0% (30/40) of respondents performed consultations at bedside for inpatients and 67.4% (29/43) performed consultations at bedside for outpatients. Bedside consultations decreased in both settings during the pandemic but were still most frequently performed by attending physicians. At the same time, the use of telemedicine increased for 15.4% of survey respondents during COVID-19. Conclusion: Some, but not all, respondents observed or made changes to their apheresis service during the COVID-19 pandemic. A subset of changes, such as increased utilization of telemedicine, may persist.
  • UMCCTS Newsletter, May 2024

    UMass Center for Clinical and Translational Science (2024-05-06)
    This is the May 2024 issue of the UMass Center for Clinical and Translational Science Newsletter containing news and events of interest.
  • Dominant negative mutations in yeast Hsp90 reveal triage decision mechanism targeting client proteins for degradation [preprint]

    Flynn, Julia M; Joyce, Margot E; Bolon, Daniel N A (2024-04-30)
    Most of the fundamental processes of cells are mediated by proteins. However, the biologically-relevant mechanism of most proteins are poorly understood. Dominant negative mutations have provided a valuable tool for investigating protein mechanisms but can be difficult to isolate because of their toxic effects. We used a mutational scanning approach to identify dominant negative mutations in yeast Hsp90. Hsp90 is a chaperone that forms dynamic complexes with many co-chaperones and client proteins. In vitro analyses have elucidated some key biochemical states and structures of Hsp90, co-chaperones, and clients; however, the biological mechanism of Hsp90 remains unclear. For example, high throughput studies have found that many E3 ubiquitin ligases bind to Hsp90, but it is unclear if these are primarily clients or acting to tag other clients for degradation. We introduced a library of all point mutations in the ATPase domain of Hsp90 into yeast and noticed that 176 were more than 10-fold depleted at the earliest point that we could analyze. There were two hot spot regions of the depleted mutations that were located at the hinges of a loop that closes over ATP. We quantified the dominant negative growth effects of mutations in the hinge regions using a library of mutations driven by an inducible promoter. We analyzed individual dominant negative mutations in detail and found that addition of the E33A mutation that prevents ATP hydrolysis by Hsp90 abrogated the dominant negative phenotype. Pull-down experiments did not reveal any stable binding partners, indicating that the dominant effects were mediated by dynamic complexes. DN Hsp90 decreased the expression level of two model Hsp90 clients, glucocorticoid receptor (GR) and v-src kinase. Using MG132, we found that GR was rapidly destabilized in a proteasome-dependent fashion. These findings provide evidence that the binding of E3 ligases to Hsp90 may serve a quality control function fundamental to eukaryotes.
  • Identifying Therapeutic Oligonucleotide-Induced Neurotoxicity and Methods for Safe Delivery to the Central Nervous System

    Miller, Rachael (2024-04-29)
    Huntington’s disease (HD) is a hereditary neurodegenerative disorder caused by an autosomal dominant mutation in Exon 1 of the Huntingtin gene (Htt). There are no approved treatments for HD. Oligonucleotide therapeutics (ASOs and siRNAs) offer a new strategy to treat genetically defined CNS diseases. These therapeutics aim to attenuate disease pathogenesis by targeting Htt mRNA to reduce the toxic mutant protein. Recent technological advancements now enable robust distribution and efficacy throughout mouse, sheep, and NHP brains. However, oligonucleotides can cause acute neurotoxicity when injected directly into the CSF. This dissertation aims to optimize oligonucleotide delivery for the treatment of HD by addressing safety issues across species. We used electroencephalography (EEG) and electromyography (EMG) in awake animals to confirm that direct CSF injection of oligonucleotides induces seizures. We hypothesized that this was due to the negatively charged oligonucleotides changing the delicate balance of divalent cations in the CSF. To address this issue, we developed an artificial CSF (aCSF) buffer supplemented with Ca2+ alone, Mg2+ alone, or Ca2+ and Mg2+ in the injected solution to prevent the imbalance. Real-time EEG monitoring in awake mice and lambs confirmed the absence of seizures when oligonucleotides were delivered in the new aCSF buffer. In summary, this dissertation identified a potential cause of oligonucleotide-induced acute neurotoxicity, developed a method to safely deliver oligonucleotides to the CNS with Ca2+/Mg2+-enriched buffers, and demonstrated the viability of this formulation in a large animal model. These findings support a new method for safely delivering oligonucleotides to the CNS to treat neurological diseases.
  • Epigenetic Enablers of Meningioma Growth

    Berry, Bethany C (2024-04-26)
    Meningiomas are the most common primary intracranial brain tumor, often causing significant disability and sometimes even death. The most aggressive meningiomas commonly exhibit extensive genomic disruption that can lead to genotoxic and proteotoxic stress, but the mechanisms that enable these tumors to thrive are unknown. To date, meningiomas have no effective chemotherapy. This study used a high-throughput bioactive small molecule screen of established meningioma cell lines and RNA-sequencing of patient meningiomas to identify EHMT2/G9a inhibitors as potent cytotoxic agents in meningioma in vitro. Further, studies using the small molecule EHMT2/G9a inhibitor, UNC0631 demonstrated reduced tumor growth in an orthotopic xenograft mouse model of meningioma in vivo. We used CUT&Tag and transcriptomic analyses of established meningioma cell lines after EHMT2/G9a inhibition to identify the unfolded protein response (UPR) and endoplasmic reticulum (ER) stress apoptotic signaling pathway as key factors in EHMT2/G9a-mediated meningioma cell death. After EHMT2/G9a inhibition, we observed a collapse of heat shock protein expression and hypothesized that downregulation of a deacetylase, Sirtuin 1 (SirT1), may be responsible. Consistent with decreased SirT1 activity, Heat Shock Factor 1 exhibited increased lysine acetylation and decreased DNA binding at the promoters of downregulated heat shock proteins. Overexpression of SirT1 or shRNA-mediated knockdown of the ER stress response mediators, ATF4 or CHOP/DDIT3, decreased meningioma cell death caused by EHMT2/G9a inhibition. The molecular chaperone and ER stress inhibitor, 4-phenylbutyric acid, abrogated meningioma cell death occurring after EHMT2/G9a inhibition. In conclusion, epigenetic maintenance of heat shock protein activity and suppression of the UPR/ER stress apoptotic signaling pathway by EHMT2/G9a and SirT1 are essential for aggressive meningioma growth.
  • Advancing Oligonucleotide Technologies for Malignant Brain Tumors and Other Central Nervous System Diseases

    Sarli, Samantha L (2024-04-26)
    Oligonucleotides are a class of synthetic, nucleic acid-based drugs that modulate the expression of disease-causing genes. These drugs are chemically modified to ensure safe and effective activity in relevant tissues in vivo. However, in complex tissues such as the brain, oligonucleotides can show striking differences in activity across cell types. Determining the activity profile of an oligonucleotide in distinct cell types can inform on mechanism of action and is key in moving these drugs towards the clinic. In this thesis, I broadly focused on developing tools to measure efficacy and improve the safety of gene-silencing oligonucleotides in the central nervous system (CNS). Much of this work was dedicated to glioblastoma multiforme (GBM), a universally lethal brain tumor that is largely resistant to current surgical and drug interventions. To this end, I designed a method to measure gene silencing by oligonucleotides in GBM xenografts versus normal brain tissue in vivo. I assessed the impact of conjugates on oligonucleotide activity patterns in tumor and normal brain cells and identified conjugates with potential GBM applications. In addition, I studied formulation as a strategy to mitigate acute neurotoxicity induced by antisense oligonucleotides (ASOs) delivery to the CNS. I also optimized immunostaining methods for a phosphorothioate-specific antibody to characterize biodistribution of monovalent and multivalent ASOs. In summary, this thesis expands the frameworks used in the rational design of these drugs and further
  • Translation-dependent and -independent mRNA decay occur through mutually exclusive pathways defined by ribosome density during T cell activation

    Mercier, Blandine C; Labaronne, Emmanuel; Cluet, David; Guiguettaz, Laura; Fontrodona, Nicolas; Bicknell, Alicia; Corbin, Antoine; Wencker, Mélanie; Aube, Fabien; Modolo, Laurent; et al. (2024-04-25)
    mRNA translation and decay are tightly interconnected processes both in the context of mRNA quality-control pathways and for the degradation of functional mRNAs. Cotranslational mRNA degradation through codon usage, ribosome collisions, and the recruitment of specific proteins to ribosomes is an important determinant of mRNA turnover. However, the extent to which translation-dependent mRNA decay (TDD) and translation-independent mRNA decay (TID) pathways participate in the degradation of mRNAs has not been studied yet. Here we describe a comprehensive analysis of basal and signal-induced TDD and TID in mouse primary CD4+ T cells. Our results indicate that most cellular transcripts are decayed to some extent in a translation-dependent manner. Our analysis further identifies the length of untranslated regions, the density of ribosomes, and GC3 content as important determinants of TDD magnitude. Consistently, all transcripts that undergo changes in ribosome density within their coding sequence upon T cell activation display a corresponding change in their TDD level. Moreover, we reveal a dynamic modulation in the relationship between GC3 content and TDD upon T cell activation, with a reversal in the impact of GC3- and AU3-rich codons. Altogether, our data show a strong and dynamic interconnection between mRNA translation and decay in mammalian primary cells.
  • BNST GluN2D-containing NMDARs contribute to ethanol intake but not negative affective behaviors in female mice [preprint]

    Doyle, Marie A; Salimando, Gregory J; Altemus, Megan E; Badt, Justin K; Bedenbaugh, Michelle N; Vardy, Alexander S; Adank, Danielle N; Park, Anika S; Winder, Danny G (2024-04-21)
    Alcohol use disorder (AUD) is a chronic, relapsing disease, highly comorbid with anxiety and depression. The bed nucleus of the stria terminalis (BNST), and Crh + neurons in this region are thought to play a key role in chronic ethanol-induced increases in volitional ethanol intake. This role has been hypothesized to be driven by emergent BNST-dependent negative affective behaviors. Indeed, we report here that in female mice undergoing a home cage chronic drinking forced abstinence model (CDFA), excitatory transmission undergoes time-dependent upregulation in BNST Crh + cells. Excitatory NMDA receptors (NMDARs) are a major target of ethanol, and chronic ethanol exposure has been shown to regulate NMDAR function and expression. GluN2D subunit-containing NMDARs have emerged as a target of interest due to their limited distribution and potential roles in affective behavior. We find that knockdown of dorsal BNST (dBNST) GluN2D expression significantly decreases ethanol intake in female, but not male, mice. While BNST Grin2b expression was significantly increased in protracted abstinence following CDFA, no differences in Grin2d expression were observed in dBNST or specifically in dBNST Crh + neurons. Finally, to determine the impact of GluN2D expression on negative affective behaviors, open field, elevated zero maze, and forced swim tasks were used to measure anxiety- and depressive-like behaviors in constitutive and conditional BNST GluN2D knockout mice. Surprisingly, we find that deletion of GluN2D fails to alter negative affect in ethanol-naïve female mice. Together, these data suggest a role for BNST GluN2D-containing NMDARs in ethanol drinking behaviors but not abstinence from ethanol, highlighting potential sex differences and behavioral specificity in the context of AUD behaviors. Overall, these data further suggest roles for BNST synaptic signaling in volitional ethanol intake that are partially independent of actions on affective behavior.
  • Building a Community of Practice to Improve Dissemination of Disability Research

    Wnuk, Jean (2024-04-18)
    A Community of Practice brings together groups of people who share a concern, a set of problems, a passion about a topic, and who deepen their knowledge and expertise in this area by interacting on an ongoing basis. In 2022, the Center on Knowledge Translation for Employment Research (CeKTER) developed of a Community of Practice on "S.M.A.R.T. Social Media for Employment Research Dissemination,” This CoP was developed to respond to NIDILRR disability research grantees who have a collective desire to enhance their social media effectiveness. This CoP continues as of April 2024. Using our experience with the "S.M.A.R.T. Social Media for Employment Research Dissemination" CoP this tip sheet offers others guidance on how to develop and sustain a successful CoP.
  • Microglia phagocytic mechanisms: Development informing disease

    Beiter, Rebecca M; Sheehan, Patrick W; Schafer, Dorothy P (2024-04-16)
    Microglia are tissue-resident macrophages and professional phagocytes of the central nervous system (CNS). In development, microglia-mediated phagocytosis is important for sculpting the cellular architecture. This includes the engulfment of dead/dying cells, pruning extranumerary synapses and axons, and phagocytosing fragments of myelin sheaths. Intriguingly, these developmental phagocytic mechanisms by which microglia sculpt the CNS are now appreciated as important for eliminating synapses, myelin, and proteins during neurodegeneration. Here, we discuss parallels between neurodevelopment and neurodegeneration, which highlights how development is informing disease. We further discuss recent advances and challenges towards therapeutically targeting these phagocytic pathways and how we can leverage development to overcome these challenges.
  • Regulation of Lipolysis by 14-3-3 Proteins on Human Adipocyte Lipid Droplets

    Yang, Qin (2024-04-11)
    Lipid droplets (LDs) in adipocytes are pivotal for systemic lipid metabolism, serving as storage centers during nutritional surplus and as sources of fatty acids when energy is needed. These LDs react to hormonal stimuli like catecholamines and insulin, and their impaired response can lead to dysregulated lipolysis, lipotoxicity, and an increased risk of metabolic diseases. The specific mechanisms behind lipid release in human adipocytes remain largely unexplored. This study aims to elucidate the control of lipid mobilization in human adipocytes. We utilized advanced techniques to generate and differentiate primary progenitor cells on a large scale. Employing proximity labeling with enhanced ascorbate peroxidase (APEX2), we identified the interactome of perilipin 1 (PLIN1), a key LD component protein, under various lipolytic states. Through LC-MS/MS, we discovered 70 proteins interacting specifically with PLIN1. This includes PNPLA2 and LIPE, vital for regulated triglyceride hydrolysis, and four 14-3-3 protein family members (YWHAB, YWHAE, YWHAZ, YWHAG), which are known to regulate diverse signaling pathways. Our functional studies revealed that YWHAB is essential for maximal cyclic adenosine monophosphate (cAMP)-stimulated lipolysis, as its CRISPR-Cas9-mediated knockout mitigates lipolysis through a mechanism independent of insulin signaling. In summary, our use of proximity labeling not only comprehensively mapped the LD proteome in human adipocytes but also unveiled new regulatory mechanisms in adipocyte lipolysis control, specifically involving 14-3-3 proteins.
  • Muscle-Specific Pyruvate Kinase Isoforms, Pkm1 and Pkm2, Regulate Mammalian SWI/SNF Proteins and Histone 3 Phosphorylation During Myoblast Differentiation [preprint]

    Olea-Flores, Monserrat; Sharma, Tapan; Verdejo-Torres, Odette; DiBartolomeo, Imaru; Thompson, Paul R; Padilla-Benavides, Teresita; Imbalzano, Anthony N. (2024-04-11)
    Pyruvate kinase is a glycolytic enzyme that converts phosphoenolpyruvate and ADP into pyruvate and ATP. There are two genes that encode pyruvate kinase in vertebrates; Pkm and Pkl encode muscle- and liver/erythrocyte-specific forms, respectively. Each gene encodes two isoenzymes due to alternative splicing. Both muscle-specific enzymes, Pkm1 and Pkm2, function in glycolysis, but Pkm2 also has been implicated in gene regulation due to its ability to phosphorylate histone 3 threonine 11 (H3T11) in cancer cells. Here, we examined the roles of Pkm1 and Pkm2 during myoblast differentiation. RNA-seq analysis revealed that Pkm2 promotes the expression of Dpf2/Baf45d and Baf250a/Arid1A. Dpf2 and Baf250a are subunits that identify a specific sub-family of the mammalian SWI/SNF (mSWI/SNF) of chromatin remodeling enzymes that is required for activation of myogenic gene expression during differentiation. Pkm2 also mediated the incorporation of Dpf2 and Baf250a into the regulatory sequences controlling myogenic gene expression. Pkm1 did not affect expression but was required for nuclear localization of Dpf2. Additionally, Pkm2 was required not only for the incorporation of phosphorylated H3T11 in myogenic promoters, but also for the incorporation of phosphorylated H3T6 and H3T45 at myogenic promoters via regulation of AKT and protein kinase C isoforms that phosphorylate those amino acids. Our results identify multiple unique roles for Pkm2 and a novel function for Pkm1 in gene expression and chromatin regulation during myoblast differentiation.
  • Eviatar Yemini

    Yemini, Eviatar (2024-04-08)
    Interview with Eviatar Yemini, who studies how neurobehavioral circuits grow and evolve to meet the needs at different stages of development at UMass Chan Medical School.
  • Complement protein signatures in patients with alcohol-associated hepatitis

    Taiwo, Moyinoluwa T; Huang, Emily; Pathak, Vai; Bellar, Annette; Welch, Nicole; Dasarathy, Jaividhya; Streem, David; McClain, Craig J; Mitchell, Mack C; Barton, Bruce A; et al. (2024-04-04)
    Diagnostic challenges continue to impede development of effective therapies for successful management of alcohol-associated hepatitis (AH), thus creating an unmet need to identify and develop non-invasive biomarkers for AH. In murine models of ethanol-induced liver injury, complement activation contributes to hepatic inflammation and injury. Therefore, we hypothesized that complement proteins could be rational diagnostic/prognostic biomarkers in AH. Here, we performed a comparative analysis of data derived from the human hepatic and serum proteome to identify and characterize complement protein signatures in severe AH (sAH). The quantity of multiple complement proteins was perturbed in liver and serum proteome of patients with sAH. Multiple complement proteins differentiated patients with sAH from those with alcohol cirrhosis (AC), alcohol use disorder (AUD) and healthy controls (HCs). Notably, serum collectin 11 and C1q binding protein were strongly associated with sAH and exhibited good discriminatory performance amongst patients with sAH, AC, AUD, and HCs. Furthermore, complement component receptor 1-like protein (CR1L) was negatively associated with pro-inflammatory cytokines. Additionally, lower serum mannose-binding lectin associated serine protease 1 and coagulation factor II were associated with and independently predicted 90-day mortality. In summary, meta-analysis of proteomic profiles from liver and circulation revealed complement protein signatures of sAH, highlighting a complex perturbation of complement and identifying potential diagnostic and prognostic biomarkers for patients with sAH.
  • A Pilot Clinical Trial of an Informatics-Informed Mobile Transitional Care Program: the Paramedic Assisted Community Evaluation after Discharge (PACED) Intervention

    O'Connor, Laurel (2024-04-03)
    Introduction: Early rehospitalization of frail older adults after hospital discharge is detrimental to patients and hospital systems. Implementing effective strategies to execute a feasible and effective transitional care plan is challenging. Mobile integrated health (MIH) programs, which deploy mobile assets into the community to care for patients, may present a possible solution to facilitating effective transitional care back to home environments after hospitalization. However, there have been few previous studies investigating MIH models for transitional care delivery. The objective of this project is to assess the implementation and effectiveness of an informatics-supported paramedic-led MIH transitional care program for frail older adults. Methods: Patients 65 and older preparing for discharge from the hospital with an eFrailty index of 0.24 or greater were enrolled to participate in a structured post-discharge transitional home visit conducted by community paramedics within 72 hours of discharge. Demographic and clinical information, as well as healthcare utilization patterns, were recorded at enrollment and 30 days after the index hospitalization. Additionally, a separate control group of patients that were screened for the intervention but excluded due to geographical location of residence were aggregated and their electronic health record data including demographical and outcomes data was abstracted. Categorical group comparisons were conducted using chi-square tests and continuous variables group comparisons were conducted using the Kruskal–Wallis equality-of-populations rank test. Crude and adjusted binomial regressions were used for comparative outcomes. Results: In total 100 subjects were enrolled in the intervention (median age 81, 64% female) and 47 were included in the control group (median age 80, 55.2% female). The recruitment rate was 18.0%. The complete intervention protocol was completed and documented by paramedics for 90 (90.0%) patients. The crude and relative risk of 30-day rehospitalization was decreased in the PACED group compared to the control (RR=0.40, CI 0.19-0.84, p=0.03). There was a non-significant trend toward decreased risk of 30-day ED visits (RR=0.61, CI=0.37-1.37, p=0.23). Paramedics identified medication errors in 34 (34.0%) of the participants; the errors were remediated during the visit in 31 (91.2%). Additionally, 67 (67.0%) of subjects screened positive for high fall risk and 7 subjects (7.0%) screened positive for delirium. Conclusions: This pilot study of MIH intervention transition care program programs was feasible with high protocol fidelity and yields preliminary evidence that the intervention results in a decreased risk of rehospitalization in frail older adults.
  • Bacterial Patterns of Pathogenesis in Intestinal Immunity

    Tse-Kang, Samantha Y (2024-04-03)
    Mechanisms of pathogen recognition in barrier tissues, which interface with both commensal and virulent bacteria, are critical for health and not fully understood. Here, I define two mechanisms by which the nematode Caenorhabditis elegans identifies an infectious pathogen to activate innate immunity. First, we characterized a central role for lysosome-related organelles in innate immune sensing within intestinal tissues. We found that lysosome-related organelles are actively maintained to limit p38 MAPK activity. We discovered that TIR-1/SARM1, a conserved immune signaling regulator, localized to the membranes of lysosome-related organelles. Upon exposure to a redox active virulence effector produced by Pseudomonas aeruginosa, pyocyanin (PYO), these organelles collapsed and alkalinized in a manner that induced TIR-1/SARM1 aggregation and p38 MAPK activation. Second, we identified the first bacterial pattern recognition receptor in C. elegans. We found that C. elegans detected another toxic phenazine, phenazine-1-carboxamide (PCN), to activate the transcription of innate immune genes. We identified that PCN was a ligand for the nuclear hormone receptor, NHR-86. Binding of PCN to NHR-86 activated an anti-pathogen program in the intestine. In addition, the production of PCN correlated to the virulence of P. aeruginosa strains. Together, these data identify phenazines as bacterial patterns of pathogenesis that are sensed by nematodes to recognize the presence of toxigenic bacteria. C. elegans animals mount distinct innate immune pathways against specific phenazine metabolites to ensure a coordinated and robust response against infectious agents. The findings herein define new mechanisms of pathogen recognition that inform the evolution of innate immune pathways in metazoans.
  • 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.
  • Synaptic injury in the inner plexiform layer of the retina is associated with progression in multiple sclerosis

    Cordano, Christian; Werneburg, Sebastian; Abdelhak, Ahmed; Bennett, Daniel J; Beaudry-Richard, Alexandra; Duncan, Greg J; Oertel, Frederike C; Boscardin, W John; Yiu, Hao H; Jabassini, Nora; et al. (2024-04-03)
    While neurodegeneration underlies the pathological basis for permanent disability in multiple sclerosis (MS), predictive biomarkers for progression are lacking. Using an animal model of chronic MS, we find that synaptic injury precedes neuronal loss and identify thinning of the inner plexiform layer (IPL) as an early feature of inflammatory demyelination-prior to symptom onset. As neuronal domains are anatomically segregated in the retina and can be monitored longitudinally, we hypothesize that thinning of the IPL could represent a biomarker for progression in MS. Leveraging our dataset with over 800 participants enrolled for more than 12 years, we find that IPL atrophy directly precedes progression and propose that synaptic loss is predictive of functional decline. Using a blood proteome-wide analysis, we demonstrate a strong correlation between demyelination, glial activation, and synapse loss independent of neuroaxonal injury. In summary, monitoring synaptic injury is a biologically relevant approach that reflects a potential driver of progression.
  • 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.

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