Biology subjects

Anderson, M.

Publications and source records attributed to Anderson, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Salience network expansion as a transdiagnostic neural marker for psychopathology risk in adolescence

Increased cortical surface area of the brain's salience network (SAL) has been observed in depression and appears to emerge during early adolescence. However, similar expansion has also been reported in bipolar disorder (BD), obsessive compulsive disorder (OCD), and other atypicalities of salience network function have been broadly implicated across multiple psychiatric conditions. Whether increased SAL surface area is specific to depression or related more generally with psychopathology remains unclear. Using data collected as part of the Adolescent Brain Cognitive Development (ABCD) Study (baseline: N = 7942; ages 9-10; Year 2: N = 5901; ages 11-12), we quantified individual SAL size and examined associations with dimensional symptoms from the Child Behavior Checklist. SAL surface area showed substantial inter-individual variability, with expansion occurring primarily through encroachment into the default mode (DMN), action-mode (AMN), and frontoparietal (FP) networks. Larger SAL size showed a modest positive association with depressive symptoms in the baseline sample, consistent with prior reports; however, this association did not replicate in the year 2 internal replication sample. Instead, associations with total problems were stronger and replicated across both timepoints, suggesting a subtle, dimensional relationship between SAL organization and general psychopathology burden. These findings suggest that individual differences in SAL organization may represent a broader transdiagnostic neural correlate of dimensional psychopathology rather than a disorder-specific neural signature.

neuroscience↗

bioRxiv2026

Knock-in = knock-out: differential fitness effects of cardinal mutations in Anopheles stephensi

The kynurenine pathway metabolizes tryptophan into 3-hydroxykynurenine (3-HK), a precursor for ommochrome eye pigments synthesized via the cardinal (cd) gene in mosquitoes. While cd disruption was presumed neutral, we observed fitness costs in Anopheles stephensi knock-in but not knock-out cd mutants. Here we investigated this anomaly further by assessing survival, fecundity, and midgut integrity across multiple cd mutant lines. Heterozygous knock-in lines, expressing a fluorescent marker and guide RNA for CRISPR/Cas9, exhibited reduced survival post-blood feeding, larva-to-adult survival deficits, and midgut barrier dysfunction, whereas knock-outs showed no such costs. Oral supplementation with xanthurenic acid partially rescued knock-in mortality, implicating oxidative stress linked to 3-HK metabolism. Expression analyses suggest transgene insertion effects, rather than cd disruption, underlie these fitness costs. These findings highlight the importance of evaluating insertional effects in gene drive target selection and support cd as a viable target for genetic control strategies in An. stephensi.

genetics↗

bioRxiv2026

Metastatic Osteosarcoma is Characterized by Loss of Osteoblastic Lineage Fidelity

Osteosarcoma (OS) is a rare and aggressive bone cancer with limited therapeutic progress in several decades. To characterize the transcriptional diversity of malignant cell states in OS, we analyzed single-nucleus RNA sequencing data from 24 tumors, including both primary and metastatic lesions. We identified a canonical osteoblastic cell state that predominated in primary tumor cells, but was dampened in metastases. Integrating tumor data with data from embryonic skeletal development and an experimental osteoblast differentiation model revealed that metastatic OS cells resemble poorly specified mesenchyme enriched for non-osseous programs. Clonal populations in metastatic samples acquired mesenchymal cell states distinct from paired primary tumors. Similar cell state shifts were evident in post-treatment primary tumors relative to paired pre-treatment samples. Our results suggest that localized post-treatment and metastatic OS malignant cells lose osteoblastic lineage fidelity, which may represent a unifying axis of disease evolution and reveal new therapeutic vulnerabilities.

Cancer Biology↗

bioRxiv2026

Structural Evidence for Occupancy-Dependent Inter-Site Coupling in Human Glutathione Synthetase

Human glutathione synthetase (hGS) is a negatively cooperative ATP-grasp enzyme that catalyzes the final step in the biosynthesis of glutathione, a tripeptide antioxidant critical for life. hGS functions as an obligate homodimer with one active site per subunit; the two active sites are separated by [~]40 Angstroms. How ligand binding in one subunit reshapes the distant partner active site has remained a central unresolved question in understanding hGS regulation. This study provides the first atomistic model of ligand-dependent inter-subunit communication underlying negative cooperativity in hGS. Using atomistic simulations and dynamical network analysis, this study reveals how reactant- and product-bound states remodel the empty partner active site, redistribute inter-subunit interactions, and organize long-range communication between the two active sites. The product-bound/partner-empty state displayed a larger and less hydrated empty active site, demonstrating that ligand identity in one subunit alters both the geometry and solvent environment of the opposite site. Changes in ligand-dependent interactions are distributed across the dimer interface, with prominent contributions from the 42-46 interface region, the 11-30 region, and the 212-236 helical/interface region. Suboptimal path analysis shows product- and reactant-bound states share a communication scaffold, with 64.1% of transmission residues common to both pathways, 30.8% product-specific, and 5.1% reactant-specific. Together, the present results establish a detailed structural framework for hGS negative cooperativity in which ligand binding remodels a distributed allosteric network linking substrate-binding loops, the dimer interface, and the partner active site. More broadly, this work demonstrates how atomistic simulations can resolve long-range active-site coupling in multimeric enzymes and provides a foundation for experimental tests of allosteric transmission in hGS.

biophysics↗

bioRxiv2026

The crop pathogen Blumeria hordei exhibits genome-wide pervasive selective and neutral sweepstakes reproduction signatures.

The fungal crop pathogen Blumeria hordei, causal agent of powdery mildew on barley, presents life-history and epidemiological characteristics, as well as and selective pressures due to modern agriculture leading to expected sweepstakes reproduction, that is highly skewed offspring distributions. Using genome-wide polymorphism data and population genomics inferences, we aim to 1) infer the past demographic history and the strength of sweepstakes reproduction in B. hordei, and 2) quantify the contributions of these selective and neutral processes in the genome. An new inference method based on Neural Posterior Estimation and diversity and linkage disequilibrium statistics was developed and tested on simulated and B. hordei genomic data. We confirm that B. hordei exhibits a moderate sweepstakes reproduction (-parameter of 1.6). We highlight that the Site Frequency Spectrum (SFS) appears sensitive to the joint occurrence of sweepstakes and recent demographic changes, which may caution on the reliability of the SFS to infer sweepstakes reproduction. We then scan the genome for selective sweeps, adjusting the significance thresholds of the methods for demographic history and sweepstakes reproduction, thereby yielding a counterintuitive result. When conditioning the significance threshold for sweep detection on simulations under sweepstakes and demography, a very large number of putatively selected regions is found (11.6% of the genome). We suggest that sweepstakes reproduction in B. hordei is due to 1) neutrality (clonal/sexual phases and Boom-and-Bust cycles) generating a genome-wide level of background noise in the coalescent genealogies, and 2) selective sweepstakes due to pervasive positive selection. Our findings have important implications for both population genomic methodology and our understanding of pathogen evolution.

evolutionary biology↗

bioRxiv2026

IL1β/IL1R1/IRAK4 Drives Inflammatory Ovarian Cancer Seeding at the inflamed sites and Is Reversed by an IRAK4 inhibitor UR241-2

Inflammation-driven tumor implantation, such as port-site metastasis (PSM) following laparoscopic gynecologic surgery and peritoneal seeding during post-surgical recurrence, represents an aggressive clinical problem that remains poorly understood and lacks targeted therapies. To address this, we developed a non-surgical Mesothelium-Inflammation/Injury-Metastasis (MIM) model and investigated the role of the IL-1{beta}/IL1R1/MYD88/IRAK1/4 axis and NLRP3 in epithelial ovarian cancer (EOC) seeding at inflamed or injured sites. This model created by a needle injury recapitulates inflammation-driven peritoneal seeding and mimics PSM and inflammation associated dissemination in peritoneum during recurrence. Seeding was dependent on Il1r1 but not Nlrp3, despite its role in regulating IL-1{beta} production, as Il1ra-/- and Nlrp3-/- mice phenocopied wild-type C57BL/6 mice. Given the limited antitumor efficacy of IL-1{beta}-targeting agents such as Anakinra and Canakinumab, we focused on IRAK4 as a therapeutic target. IRAK4 knockdown significantly prolonged survival, reduced tumor cell adhesion, downregulated E-cadherin and Wnt4, and induced S-phase/mitotic arrest. This led to the development of UR241-2, a small-molecule IRAK4 inhibitor, which was validated through molecular simulations, hotspot analysis, nanoBRET, global kinome profiling, and NF-{kappa}{beta} reporter assays. UR241-2 inhibited NF-{kappa}{beta} nuclear translocation and blocked IL-1{beta}-induced IRAK4 phosphorylation. UR241-2 exhibited favorable drug-like properties, including absence of CYP or hERG inhibition, and acceptable CaCo-2 permeability, plasma protein binding, microsomal stability, and pharmacokinetics. In vivo, UR241-2 reduced SKOV3 xenograft growth, suppressed mesothelial seeding, and increased MHC-II macrophages and activated neutrophils in syngeneic high-grade epithelial ovarian HGS3 tumors. RNA-seq revealed enrichment of neutrophil activation signatures and suppression of extracellular matrix (ECM) gene programs. Together, these findings establish a role for the IL-1{beta}/IL1R1/IRAK4 axis in inflammation-driven PSM and peritoneal seeding and ECM regulation in EOC, and demonstrate that IRAK4 inhibition activates antitumor immune responses, providing a therapeutic strategy to block metastatic seeding and improve tumor control.

cancer biology↗

bioRxiv2026

EVEE: Interpretable variant effect prediction from genomic foundation model embeddings

Scientific foundation models learn high-dimensional representations from diverse data modalities, yet what they encode and how to extract that knowledge remain open questions. Here we show that probing the internal representations of Evo 2, a 7-billion-parameter genomic foundation model, enables accurate and interpretable genetic variant effect prediction. We introduce a covariance-based probe that captures second-order structure from Evo 2 sequence embeddings to predict variant pathogenicity across variant types and functional consequences, matching or exceeding specialized predictors within their domains. To ground these predictions in known biological mechanisms, we train a complementary panel of probes on existing annotations to detect which genomic properties are disrupted by a variant. This categorized evidence is then integrated with each variants genomic context through a language model to generate variant-specific mechanistic hypotheses. Our pathogenicity predictions correlate with experimental measures of variant function, clinical penetrance, and biobank disease associations while the mechanistic hypotheses are consistent with expert reviews, known mechanism classes, and downstream molecular readouts. We release pathogenicity scores, disruption profiles, and contextualized interpretations for 4.2 million variants from the ClinVar database as an open resource through the Evo Variant Effect Explorer (EVEE). More broadly, this structured probing approach offers a general framework for interrogating foundation models across scientific disciplines and grounding their outputs in existing domain concepts.

genomics↗

bioRxiv2026

Neurocognitive deficits in controlling aversive memory among insomnia disorders

BackgroundInsomnia disorder is a common sleep disturbance characterized by adverse daytime cognitive and emotional impairments, such as repetitive negative thinking and increased psychological distress. Memory control, a key self-regulatory ability to control or inhibit unwanted thoughts and memories, plays an essential role in supporting cognitive functions and emotional well-being. Here, we delineate the neurocognitive mechanisms underlying memory control among individuals with insomnia. Methods41 participants meeting DSM-5 criteria for insomnia disorder and 40 healthy sleepers completed an emotional Think/No-Think task, during which participants either retrieved (Think) or suppressed the retrieval (No-Think) of aversive memories in response to memory cues while electroencephalograms were recorded. ResultsLinear mixed model analyses with age and depression scores as covariates showed that participants with insomnia exhibited impaired memory control abilities, as evidenced by reduced suppression-induced forgetting in memory recall when compared to healthy sleepers. Electrophysiologically, healthy sleepers showed enhanced right prefrontal theta power in retrieval suppression than in retrieval, indicating elevated needs of inhibitory control during memory control. In sharp contrast, this difference was absent among those with insomnia. Notably, the greater the severity of insomnia symptoms, the smaller the retrieval vs. retrieval suppression theta power differences across participants, linking inefficient top-down control of unwanted memories with low sleep qualities. ConclusionIndividuals with insomnia showed impaired memory control of aversive memories and aberrant electrophysiological activities during retrieval suppression. Future research shall investigate the causal relationship between memory control abilities and insomnia symptoms.

neuroscience↗

bioRxiv2026

Cortical Thickness and Curvature in Autism and ADHD: A Mega-Analysis

BackgroundExisting evidence suggests cortical morphometric alterations occur in people with autism and ADHD. However, these findings remain tentative due to small sample sizes, heterogeneous imaging pipelines, varied statistical approaches, and limited harmonization across acquisition sites. Few studies have applied standardized processing to large, clinically enriched datasets or addressed site-related batch effects. MethodsWe leveraged six large-scale brain imaging datasets (n = 9,647; male=5,835; female=3,812; ages 5-64 years), including 1,533 individuals with ADHD, 1,080 with autism spectrum disorder, and 7,034 matched controls. All imaging data were processed using the validated ABCD-HCP pipeline, with cortical parcellation into 360 regions based on the Human Connectome Project (HCP) atlas, and ComBat harmonization was applied to account for variability across 67 acquisition sites. Group-level differences in cortical thickness and sulcal curvature were examined with ANCOVAs, controlling for covariates and using Bonferroni correction for multiple comparisons. ResultsOur analyses revealed distinct neuroanatomical signatures for both autism and ADHD. Individuals with autism exhibited regionally thinner cortex and curvature alterations particularly in the Cingulo-Opercular network. In contrast, individuals with ADHD displayed regionally thicker cortex, particularly in the default mode and somatomotor networks, alongside curvature differences. Control participants showed intermediate patterns, suggesting that autism and ADHD may represent diverging extremes of cortical maturation. ConclusionsCortical thickness and curvature emerge as potential biomarkers that can advance understanding of neurodevelopmental conditions and disentangle heterogeneity across diagnostic groups. These findings highlight the value of harmonized, large-scale, standardized analyses for resolving inconsistencies in the literature.

neuroscience↗

bioRxiv2025

Gut microbiota as a modulator of circadian neural development in the honey bee model.

Disruption in gut microbiota during the early postnatal period can disrupt normal neural development and result in long-term behavioral alterations1. Similar to other neural systems, the circadian clock mechanism continues to mature after birth2, yet how microbial disturbances in the early period influence the onset of circadian rhythms and the development of central clock mechanisms remains poorly understood. Here we studied whether early-life gut dysbiosis affects the ontogeny of behavioral circadian rhythms and the maturation of clock neurons using the honey bee (Apis mellifera), a model organism that shares features of postnatal development of behavioral circadian rhythm and clock system3-5 with humans6. Our findings demonstrate that antibiotic-treated and gnotobiotic-reared bees display reduced rhythmicity compared to controls. These treatments also impair the development of the circadian pacemaker, marked by fewer Pigment-Dispersing Factor (PDF)-expressing neurons. Additionally, antibiotic exposure increased the expression of the Insulin-like Growth Factor Binding Protein Acid Labile Subunit (IGFALS) in early ages, which stabilizes the IGF-1/27, a hormone important for neurodevelopmental processes42. Together, these results identify gut microbiota as a modulator of circadian development. Our work provides an understanding of how early-life microbial disruptions influence the development of circadian rhythms, providing information that may extend to other animals, including humans.

neuroscience↗

bioRxiv2025

Clinical cure of chronic hepatitis B is dependent on activation and perpetuation of robust CD4+ T cell responses

Chronic infection with hepatitis B virus (HBV), a major global pathogen, often leads to immune-mediated progressive liver injury and liver cancer. While seroclearance of the surface antigen (HBsAg) defines clinical cure and reduces disease-associated risks, HBsAg clearance is rarely observed and remains therapeutically elusive. Here we overcome some of the challenges to studying immune mechanisms of HBsAg clearance in chronic hepatitis B (CHB) using our mouse model of age-dependent HBsAg clearance and persistence, and samples from our BeNEG-DO clinical trial that provided longitudinal PBMCs from patients who either cleared HBsAg or retained stable HBsAg levels after stopping nucleos(t)ide analog therapy. We show that young mice fail to clear HBsAg and have impaired ability to efficiently initiate and sustain HBV-specific CD4+ T cell responses. We also demonstrate a role for CD4+ T cells in hepatic leukocyte organization and cytotoxicity, and in HBV-specific CD8+ T cell cytotoxicity and HBsAg clearance. Upstream of the CD4+ T cell response, we reveal that hepatic dendritic cells, particularly cDC2s, direct effective CD4+ T cell activation and differentiation. Studies in CHB patients identified immune features of HBsAg clearance that overlap with the mouse model, including TH1 and cytotoxic CD4+ T cell activation and CD8+ T cell cytotoxic effector function. These findings identify an essential role for potent CD4+ T cell activation in the clinical cure of CHB and illuminate potential immunotherapeutic targets for enhancing CD4+ T cell responses to achieve greater HBsAg clearance rates. One Sentence SummaryUsing a mouse model of hepatitis B and longitudinal PBMCs from patients with chronic hepatitis B, we identify shared mechanisms of HBsAg seroclearance.

immunology↗

bioRxiv2025

Analyzing the role of a dual-function diguanylate cyclase/phosphodiesterase for attachment and motility in Agrobacterium tumefaciens

Cyclic diguanylate monophosphate (c-di-GMP) is a second messenger that controls the signaling pathway for the motile to sessile transition in many bacteria. Diguanylate cyclases (DGCs), characterized by a GGDEF domain, are responsible for the synthesis of c-di-GMP. c-di-GMP is degraded by EAL and HD-GYP domains that exhibit phosphodiesterase activity (PDE). In Agrobacterium tumefaciens, out of 31 predicted proteins regulating the c-di-GMP levels, this work focuses on the predicted dual-function DGC/PDE, DcpB. We show that DcpB is a cycle-dependent PDE under our experimental conditions, resulting in cell cycle-dependent control of motility and biofilm formation in A. tumefaciens. DcpB also exhibits polar and mid-cell localization. Finally, we identify genetic interactions between dcpB and a LacI-family transcriptional regulators, thuR, suggesting additional regulatory inputs for DcpB-dependent phenotypes. Importancec-di-GMP is a universal secondary messenger known to control various biological processes in bacteria including attachment, motility, virulence, and cell cycle progression. In A. tumefaciens, there are 31 predicted c-di-GMP-metabolizing proteins predicted to affect the c-di-GMP pool, raising the question of why so many proteins are involved and how the activities of these proteins are coordinated. This work describes a cell cycle-dependent PDE activity that helps coordinate cell cycle progression and developmental phenotypes including biofilm formation and motility.

microbiology↗

bioRxiv2025

Examining the heritability of functional brain networks in adolescence

Discovering mechanisms underlying mental illness requires disentangling genetic and environmental factors influencing mental health. Researchers have started investigating the brains role as a potential intermediate biomarker linking genes and environment to mental health; however, understanding how much genetics shapes adolescent brain function remains elusive. Using data from the ABCD study (5,247 unrelated, 330 dizygotic, 248 monozygotic twin subjects), we estimated the heritability of functional connectivity and topography using both SNP and twin data. SNP-based heritability was calculated using genetic correlation and the recently developed AdjHE-RE estimator. We found low SNP heritability for brain functional connectivity (median = 2e-10% Gordon, 5.8e-7% probabilistic) and topography (max = 2%). Twin estimates using ACE models replicated prior findings from the literature (median = 8.9e-6% Gordon, 6% probabilistic, 27% topography). This suggest that additive genetic effects are minimally associated with functional brain features in adolescents highlighting the importance of considering both genetic and environmental factors when studying the development of functional brain networks and their relevance to mental health.

genomics↗

bioRxiv2025

A Cluster of Acidic Residues in the Cytoplasmic Domain of SARS-CoV-2 Spike is Required for Virion-Incorporation and Infectivity

Abstract/SummaryLike all coronaviruses, the infectivity of SARS-CoV-2 virus particles (virions) requires incorporation of the Spike glycoprotein. Yet, the mechanisms that support the virion-incorporation of Spike are incompletely defined. We noted an unusual feature of human sarbecovirus Spike proteins: their cytoplasmic domains (CDs) contain a stretch of acidic amino acids (DEDDSE). This sequence resembles a cluster of acidic residues, or acidic cluster (AC) motif, found in the cytoplasmic domain of the cellular endoprotease Furin. In Furin, the acidic cluster acts as a protein sorting signal, supporting its intracellular localization at the trans-Golgi network (TGN). We tested the contribution of the acidic cluster motif in the Spike CD to protein interactions and to the infectivity of SARS-CoV-2. We used virus-like particles (VLPs) as a model for viral "infection" (transduction). The SARS-CoV2 VLPs were produced by co-expressing Spike (S), Membrane (M), Envelope (E) and Nucleocapsid (N) proteins and deliver an RNA encoding luciferase to target cells expressing the ACE2 receptor. Remarkably, when all five acidic residues of the DEDDSE sequence were replaced with alanines, the VLPs were rendered non-infectious. The N-terminal DE residues provided most of the activity of the acidic cluster. These virologi-cally-impaired Spike mutants were able to reach the cell surface and induce the formation of syncytia, indicating that they are fusogenic and capable of anterograde traffic through the biosynthetic pathway to the plasma membrane. Despite this, they failed to efficiently incorporate into virions. We observed acidic cluster motif-dependent interactions of the Spike CD with several cellular proteins that could potentially support its role in virion-incorporation, including the ERM proteins Ezrin, Radixin, and Moesin; the retromer subunit Vps35, and the medium subunits of the clathrin adaptor complexes AP1 and AP2. While the key cofactor and mechanism of action remains to be defined, this region of acidic residues in the Spike CD appears to be a novel determinant of SARS-CoV-2 infectivity.

molecular biology↗

bioRxiv2025

Ectopic, hepatic GLP-1R agonism enhances the weight loss efficacy of GLP-1 analogues.

ObjectiveUnimolecular triagonists drive substantial weight loss in patients with obesity (PwO) by engaging the glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) receptors to reduce food intake (FI) and the hepatic glucagon (Gcg) receptor to enhance energy expenditure (EE). However, their development has been challenged by deleterious cardiovascular (CV) effects including increased heart rate (HR), elongated QTc, and arrhythmia mediated by GcgR agonism. GLP-1R monoagonists on the other hand improve both obesity and CV outcomes with negligible effects on EE. We sought to imbue peptide GLP-1R agonists with an EE enhancing effect by combining them with ectopic GLP-1R expression and agonism in hepatocytes. MethodsWe used an attenuated adenovirus (AAV) to induce the expression of a functional, liver-specific GLP-1R combined with traditional peptide agonist treatment to drive greater body weight loss via reduced energy intake and increased energy expenditure. ResultsAgonism of the ectopic GLP-1R with either semaglutide, a low internalization GLP-1R agonist (Sema584), or a dual GLP-1R/GIPR agonist in wild-type (WT) diet induced obese (DIO) mice led to enhanced EE and improved weight loss compared to agonist treatment alone. ConclusionsThis represents a novel mechanism for achieving polypharmacy to treat obesity. HighlightsO_LIA Glp1r encoding AAV induces expression of a functional receptor mouse livers. C_LIO_LIEndogenous GLP-1R does not mediate semaglutide clearance. C_LIO_LIEctopic GLP-1R mediates semaglutide clearance. C_LIO_LIEctopic, hepatic Glp1r plus semaglutide enhances weight loss in mice. C_LIO_LIEctopic, hepatic Glp1r plus a dual incretin agonist enhances weight loss in mice. C_LI

zoology↗

bioRxiv2025

IL-1β/IRAK4 Axis Promotes Ovarian Tumor Development at the Mesothelium Injury Sites

Epithelial ovarian cancer (EOC) cells seed at mesothelial inflammation or injury sites. Lack of animal models recapitulating tumor cells seeding at inflamed sites in EOC hinders mechanistic studies and therapy developments. Here, we developed a non-surgical MIM (Mesothelium Inflammation/Injury Metastasis) model that recapitulates tumor cell seeding at inflamed sites. This model captures temporal changes in tumor immune microenvironment and tumor growth allowing for deeper mechanistic and preclinical therapeutic studies of EOC in-vivo. We show here that HGS-3 high-grade murine serous EOC cells seed at needle-induced injury sites in mesothelium/peritoneal wall, forming tumors both internally and protruding outward. Using MIM model, we found that deletion of IL1R1 in mice reduced EOC cell seeding at mesothelium injury/inflamed site in WT but not IL1ra-deficient mice. Treatment of MiM mice with a novel IRAK4 inhibitor we recently developed (UR241-2) revealed an essential role for IRAK4 signaling downstream IL-1{beta}/IL-1R1 in fostering an anti-tumor inflammatory environment, and reduced tumor burden. We conclude that IRAK4 inhibitors can be more effective than IL-1/IL-1R1 targeting agents to control metastasis and peritoneal tumors, an unmet medical need in EOC recurrence. Downregulation of extracellular matrix (ECM), upregulation of neutrophil activation genes, reduced cell adhesion and migration exhibit how UR241-2 corrects ECM and immune disorders in EOC, making it less conducive to metastasis and tumorigenesis.

cancer biology↗

bioRxiv2025

Serotonin signaling in the rat prefrontal cortex is required for Retrieval-Induced Forgetting

Forgetting is a ubiquitous phenomenon actively promoted in many species. The act of remembering some experiences can cause forgetting of others in both humans and rats. We previously found that when rats retrieve a memory to guide exploration, it reduces later retention of other competing memories encoded in that environment. As with humans, this retrieval-induced forgetting (RIF) relies on prefrontal control processes, is competition-dependent, and cue-independent. RIF is thought to be driven by inhibitory control signals from the prefrontal cortex that target areas where memories are stored. Serotonin plays a crucial role in behaviors requiring high cognitive demand, including memory processes, partly through its modulation of prefrontal cortex activity. However, its potential involvement in regulating active forgetting remains unexplored. Here, we had rats perform a task known to induce RIF and pharmacologically manipulated the activity and signaling of serotonin receptors 5-HT1A, 5-HT2A, and 5-HT2C in the medial prefrontal cortex (mPFC), as well as to inhibit downstream effectors. Our findings reveal a specific role for prefrontal serotonin signaling in RIF. Whereas 5-HT2C receptor manipulation had no effect, activating 5-HT1A or blocking 5-HT2A receptors in the mPFC abolished RIF. By contrast, activating 5-HT2A receptors promoted RIF under conditions in which it is normally reduced. Further analyses identified the PI3K/AKT pathway as a downstream effector of 5-HT2A receptor signaling, suggesting a specific molecular mechanism through which serotonin modulates inhibitory control over memory. These results uncover a previously unrecognized serotonergic modulation of adaptive forgetting, identifying specific receptor subtypes that link prefrontal serotonin signaling to inhibitory control over memory competition.

animal behavior and cognition↗

bioRxiv2025

Glucocerebrosidase Deficiency Dysregulates Human Astrocyte Lipid Metabolism

BackgroundDeficiency in the lysosomal enzyme, glucocerebrosidase (GCase), caused by mutations in the GBA1 gene, is the most common genetic risk factor for Parkinsons disease (PD). However, the consequence of reduced enzyme activity within neural cell sub-types remains ambiguous. Thus, the purpose of this study was to define the effect of GCase deficiency specifically in human astrocytes and test their non-cell autonomous influence upon dopaminergic neurons in a midbrain organoid model of PD. MethodsWild-type (GBA+/+), N370S mutant (GBA+/N370), and GBA1 knockout (GBA-/-) astrocytes were rapidly and directly induced from human pluripotent stem cells (hPSCs) via transcription factor-based differentiation. These astrocytes were extensively characterized for GCase-dependent phenotypes using immunocytochemistry, organoid coculture, enzymatic assays, lipid tracers, transcriptomics, and lipidomics. ResultshPSC lines were rapidly induced into astrocytes and enzymatic assays confirmed that GBA-/- astrocytes completely lacked GCase activity, while GBA+/N370 preserved partial activity. GBA-/-, but not GBA+/N370S, exhibited lysosomal alterations, with enlarged lysosomes and glucosylceramide (GlcCer) accumulation. GCase deficiency also exacerbated TNF-alpha-induced secretion of the inflammatory biomarker, CCL2. In midbrain organoids, GCase activity did not modulate the ability of astrocytes to support dopamine neuron production and survival. Lipidomics revealed a GBA-/--specific increase in sphingomyelin, and a decrease of triglycerides. Direct rescue of GCase activity with GBA1 mRNA treatment reduced GlcCer accumulation. Astrocytes exhibited a relatively high uptake and storage of fatty acid analogs as lipid droplets, in comparison to neurons, and this process was impaired in GBA-/- astrocytes. Lastly, GBA-/- astrocytes accumulate neuronal membrane-derived GlcCer. These findings highlight the critical role of astrocytic GCase in lipid metabolism and its neuronal influence. ConclusionGCase deficiency does not inhibit human astrocyte differentiation nor cause a non-cell autonomous neurotoxic effect upon dopaminergic neurons within midbrain organoids. However, it does elicit enhanced inflammatory reactivity, accumulation of GlcCer, and a distinct lipidomic profile, indicating impaired lipid metabolism in astrocytes that can dysregulate neuron-astrocyte intercellular signaling. Overall, these insights underscore dysfunctional astrocyte lipid metabolism as a high priority therapeutic target in Parkinsons disease and related neurodegenerative disorders. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=170 SRC="FIGDIR/small/632210v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@1b1138forg.highwire.dtl.DTLVardef@7b26aborg.highwire.dtl.DTLVardef@127b950org.highwire.dtl.DTLVardef@f74a59_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗