bioRxiv : the preprint server for biology最新文献

{"title":"Eukaryotic domestication of a bacterial immune protein following horizontal transfer.","authors":"Edward M Culbertson, Emily Cruz-Lorenzo, Jocelyn Leon Padilla, Megan Halfmann, James R Drurey, Jeffrey J Lange, Yao Li, Neha Garlapati, Harshitha Gompa, Benjamin R Morehouse, Randal Halfmann, Tera C Levin","doi":"10.64898/2026.04.30.722052","DOIUrl":"https://doi.org/10.64898/2026.04.30.722052","url":null,"abstract":"<p><p>Many components of eukaryotic innate immunity originated from bacterial immune systems. However, it has been unclear how eukaryotes acquire these genes, why eukaryotes have sampled only certain families of bacterial proteins, and how these components become domesticated into eukaryotic physiology. Here, we discovered a recent instance of bacteria-eukaryote horizontal transfer and used it to characterize the genetic and biochemical changes that accompanied HGT. We focus on TIR domains, which are widespread yet potentially costly immune modules that are commonly associated with inflammation and/or cell death. By generating an atlas of TIR diversity across the tree of life, we phylogenetically categorized the domains and uncovered highly diverged TIR families found in eukaryotes. This analysis also allowed us to identify the TirBCD protein family of amoeba, which has been horizontally acquired and is closely related to the bacterial immune protein TIR-STING. Across their short eukaryotic history, the amoeba genes have acquired introns, evolved distinct patterns of gene expression, and engaged in evolutionary patterns of duplication and divergence typical of eukaryotic immune genes. While the TIR domain was transferred into amoebae, the genomic locus did not contain other components of a bacterial operon nor were regulatory domains transferred into the TIR protein. Nevertheless, TirC retains biochemical and physiological similarities to TIR-STING. TirC is a highly potent NADase, capable of spontaneously oligomerizing into large complexes and depleting cellular NAD even at very low protein concentrations. When expressed in yeast or E. coli, TirC is spontaneously active and highly toxic, illustrating the dangers of autoimmunity following TIR protein movement into novel hosts. In contrast, amoebae tolerated high TirC expression with no disruption in cell size, growth, or behavior. Single, double, and triple knock out mutants of amoeba tirBCD are viable and display modest defects in their ability to phagocytose bacteria, implying that the co-opted bacterial TIR domain may regulate eukaryotic host-microbe interactions. Overall, this study uncovers an informative example of recent eukaryotic TIR evolution that captures features of both bacterial and eukaryotic immunity. In addition, we expect that the TIR domain atlas will be useful to researchers in many model systems as they explore the vast diversity of TIR molecular and cellular functions.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13142454/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147848722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Linking human brain functional connectivity to underlying neurotransmission.","authors":"Leon D Lotter, Golia Shafiei, Daouia Larabi, Abhay Koushik, Ottavia Dipasquale, Mitul Mehta, Mara Cercignani, Arjun Sethi, Neil Harrison, Štefan Holiga, Daniel Umbricht, Igor Yakushev, Suresh Muthukumaraswamy, Anna Forsyth, Joerg F Hipp, Bratislav Misic, Svenja Caspers, Julian Koenig, Kaustubh R Patil, Casey Paquola, Simon B Eickhoff, Juergen Dukart","doi":"10.64898/2026.04.28.721294","DOIUrl":"https://doi.org/10.64898/2026.04.28.721294","url":null,"abstract":"<p><p>The human brain is organized into interacting functional systems. Their underlying neurobiological mechanisms remain difficult to study in vivo ^1,2 . Here, we adopt a topological framework to quantify the association between neurobiology and brain functional connectivity derived from both resting-state functional magnetic resonance imaging (rsfMRI) and magnetic encephalography (MEG). Across six healthy adult cohorts (n = 19-112), regional variation in rsfMRI connectivity robustly aligns with the distribution of neurotransmitter receptors and transporters. We find that low-frequency functional synchronization measured by rsfMRI is predominantly modulated by decreased regional availability of multiple receptors and transporters. These patterns are present in every single subject, replicate across all cohorts, and are mirrored in MEG, where high-frequency synchronization increases with availability of the same receptors and transporters. Most prominently, we observe noradrenergic modulation of functional connectivity in a sensorimotor-posterior-insular network that is consistently detected across individuals and is linked to autonomic arousal. In pharmacological and clinical samples, the associations are sensitive to manipulation of the respective neurotransmitter systems and are altered in patients with early psychosis, aligning with clinical symptomatology. These findings provide biological insight into typical and atypical functional organization of the human brain using a framework linking underlying neurobiology to the functional connectome (NEOFC).</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13142320/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147848771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spectrotemporal signatures of driving and modulatory circuits across cortical and subcortical networks.","authors":"Monica N O'Connell, Annamaria Barczak, Chase A Mackey, Tammy McGinnis, Kieran Mackin, John Smiley, Cynthia Bleiwas, Peter A Lakatos, Charles E Schroeder","doi":"10.64898/2026.04.29.721627","DOIUrl":"https://doi.org/10.64898/2026.04.29.721627","url":null,"abstract":"<p><p>Sensory processing depends on interactions between neural circuits that convey and regulate information across cortical and subcortical networks. Classical frameworks distinguish driving inputs, which transmit sensory content via suprathreshold activation, from modulatory inputs, which alter neuronal excitability without directly eliciting spiking. However, physiological signatures of these circuit types that generalize widely across distributed brain regions remain unclear. Here, we functionally differentiate driving and modulatory circuits in the awake macaque brain by jointly quantifying suprathreshold multiunit activity (MUA) and oscillatory phase coherence (inter-trial coherence, ITC) across eight cortical and thalamic structures during auditory, visual, and motor sampling conditions. Preferred sensory stimuli elicited broadband ITC increases accompanied by robust MUA, yielding relatively uniform spectral distributions across adjacent frequency bands, consistent with driving inputs. In contrast, non-preferred sensory and motor-related events produced narrowband, frequency-specific ITC modulation without concurrent firing, and was characterized by dominant peaks at stimulation or event rates, which is consistent with modulatory inputs. This narrowband ITC modulation is indicative of coordinated phase alignment, capable of dynamically regulating information transfer, mediated by driving inputs, across thalamocortical circuits. These response types were observed within individual regions, revealing two separable modes of neural activity. These findings identify distinct spectrotemporal signatures of driving and modulatory activity and demonstrate that subthreshold oscillatory modulation is a widespread mechanism for coordinating multisensory and motor influences on perception.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13142446/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147848756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Do Symptom Domains Have Similar Cellular Underpinnings Across Psychiatric Diagnoses: Evidence from 3D Hippocampal MR Spectroscopy.","authors":"Eugene Ruby, Oded Gonen, Eyal Lotan, Assaf Tal, Henry Rusinek, Jose C Clemente, Jessica Robinson-Papp, Katherine H Karlsgodt, Dolores Malaspina","doi":"10.64898/2026.04.27.721016","DOIUrl":"https://doi.org/10.64898/2026.04.27.721016","url":null,"abstract":"<p><strong>Introduction: </strong>The NIMH Research Domain Criteria (RDoC) posits similar cellular pathologies for particular symptom domains across diagnostic categories. Conversely, knowledge that these differ could advance treatment discovery, especially for affective and non-affective psychoses, as studies usually intermix them.</p><p><strong>Methods: </strong>We tested this by comparing metabolite biomarker concentrations for cellular pathologies from whole hippocampal proton magnetic spectroscopic imaging (1H MRSI) with symptoms from the original and five factor PANSS, and the Hamilton Depression and Young Mania Scales. Participants were 26 healthy controls; 22 non-psychotic affective cases (NP-aff); and 33 with psychosis (including 20 schizophrenia (Scz) and 13 affective psychosis (aff-P) cases).</p><p><strong>Results: </strong>PANSS activation factor was related to reductions in all cellular component biomarkers in Scz, including glia, membrane turnover, neural integrity, glutaminergic neurotransmission, and energy metabolism (p's<.05), but only to energy metabolism in NP-aff (p=.03). Biomarkers for mood symptoms also varied across categories, suggesting gliosis for mania and depression in HC (p's≤.025), but increased membrane turnover for mania in aff-P (p=.015), and decreased neural integrity and energy metabolism for depression in Scz (p's<.05). In contrast, negative symptoms and autistic preoccupation were related to reduced glia in both NP-aff and aff-P (p's<.05). Autistic preoccupation in Scz was related to both reduced glia and membrane turnover (p's<.05). Only Scz showed a significant finding for positive symptoms, specifically reduced membrane turnover (p=.018).</p><p><strong>Discussion: </strong>These results suggest both distinct and similar cellular pathologies for symptoms across diagnoses, including affective and non-affective psychoses. The differences support categorizing disorders and stratifying different psychoses in research rather than transdiagnostic approaches.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13142384/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147848638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Third Trimester-Equivalent Alcohol Exposure Induces Sex-Dependent Alterations in Locomotor Activity, Anxiety-Risky Behaviors, and Enhances Mechanical Allodynia in Adulthood.","authors":"Estrella Villicana, Melody S Sun, Haojie Chen, Luis E Paez-Beltran, Carissa J Milliken, Erik J Balmer, Russell A Morton, Erin D Milligan, C Fernando Valenzuela, Tou Yia Vue","doi":"10.64898/2026.04.28.721494","DOIUrl":"https://doi.org/10.64898/2026.04.28.721494","url":null,"abstract":"<p><p>Prenatal alcohol exposure (PAE) causes fetal alcohol spectrum disorders (FASDs), which are neurodevelopmental conditions characterized by behavioral dysregulation, learning deficits, and cognitive inflexibilities. Alcohol exposure is harmful at all stages of human gestation, including the third trimester. This developmental window, characterized by rapid brain growth, myelination, and neural circuit formation, may be particularly vulnerable, yet the long-lasting behavioral and sensory consequences of exposure during this period remain poorly understood. In this study, neonatal mouse pups were exposed to ethanol (EtOH) or Air vapor from postnatal day (P) 4 to P8, which is equivalent to a third-trimester alcohol exposure (TTAE) in humans. Blood ethanol concentrations measured at P8 reached approximately 250 mg/dL, consistent with binge-level exposure. Air- and EtOH-exposed mice were then assessed as adults at 5-6 months of age for locomotor activity, anxiety-related risky behaviors, recognition memory, and increased susceptibility to peripheral neuropathy, as indicated by sensitization to light touch following minor chronic constriction injury (mCCI) of the sciatic nerve. We found that TTAE was sufficient to produce long-lasting behavioral outcomes in a sex-dependent manner. Notably, EtOH-exposed males exhibited increased spontaneous locomotor activity and risky behavior, whereas EtOH-exposed females showed minimal or decreased changes compared to their respective controls. However, both EtOH-exposed male and female mice exhibited marked increases in light-touch sensitization, referred to as mechanical allodynia, following mCCI, a response absent in air-exposed controls. Together, these findings reveal that TTAE is highly detrimental to behavioral regulation and creates a vulnerability to developing neuropathic pain in adulthood.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13142522/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147848757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Translation Inhibiting Antibiotics Induce a Strain Specific asRNA Regulating Purine Metabolism in S. pneumoniae TIGR4.","authors":"İrem Özkan, Tim van Opijnen, Michelle M Meyer","doi":"10.64898/2026.04.28.721496","DOIUrl":"https://doi.org/10.64898/2026.04.28.721496","url":null,"abstract":"<p><p>Translation inhibiting antibiotics (TIA) are an important class of antibiotics that elicit a wide variety of transcriptional responses. In this work we characterize the transcriptional responses of S. pneumoniae TIGR4, via RNA-seq, 5'-, and 3'-end mapping, to sub-MIC levels of three TIA, chloramphenicol, tetracycline, and kasugamycin. We find that kasugamycin (initiation inhibitor) displays a distinct transcriptomic profile compared to chloramphenicol and tetracycline (elongation inhibitors). However, genes in nucleotide metabolism were consistently downregulated. We also detected a TIA induced antisense transcript complementary to downregulated genes for purine metabolism, which we term SP_0835as. Mutating the promoter for SP_0835as eliminates both induction of SP_0835as, and repression of the complementary genes in response to chloramphenicol. The mutated strain also displays slower growth rates than control strains in conditions that strongly induce SP_0835as, implying biologically relevant activity. Furthermore, the SP_0835as promoter straddles the boundary between SP_0835 and an insertion sequence (IS3) immediately downstream. A survey of diverse S. pneumoniae genomes shows that the promoter is identified in another clinical strain. However, other laboratory strains of S. pneumoniae lack this insertion sequence, SP_0835as expression, and TIA repression of the complementary genes. Thus, SP_0835as represents a nascent RNA regulator that significantly remodels the metabolic response to TIA.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13142319/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147848214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Artificial intelligence aided design of peptides with custom secondary structure motifs and reduced amino acid alphabets.","authors":"Sean M Brown, Ashley B Cohen, Scott N Dean","doi":"10.64898/2026.04.29.721096","DOIUrl":"https://doi.org/10.64898/2026.04.29.721096","url":null,"abstract":"<p><p>Proteins are highly diverse functional polymers where the specific sequence of amino acids, selected from a standard genetically-encoded alphabet of twenty (C20), determines the structure and ultimately the function of the resulting folded protein. This standard alphabet has been identified to be non-randomly distributed in physicochemical properties crucial to both structure-formation and function, often referred to as coverage theory. While machine learning models have drastically improved protein structure prediction, protein design has yet to have similar development. Here we therefore bridge contemporary biological theory with recent advancements in artificial intelligence (AI) to develop and evaluate a generative AI protein design model, trained on hundreds of thousands of proteins within the RSCB PDB, for custom secondary structure motifs using reduced amino acid alphabets. Results indicate an overall success in designing novel proteins with desired secondary structure motifs for a broad range of amino acid alphabets. Interestingly this tool often captures the full three-dimensional tertiary structure of a target protein despite training only on physicochemical sequence space and DSSP secondary structure. The development of this model advances research across multiple disciplines, from general scientific AI/ML architecture development to protein design for biotechnology, astrobiology, and early-Earth evolutionary biology.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13142411/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147848204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optoretinography in R9AP-bradyopsia reveals the essential role of G-protein signaling in the human cone elongation response.","authors":"Connor E Weiss, Teng Liu, Vimal Prabhu Pandiyan, Yan Cao, Debarshi Mustafi, Joseph Carroll, Kirill Martemyanov, Edward N Pugh, Ramkumar Sabesan","doi":"10.64898/2026.04.28.721497","DOIUrl":"https://doi.org/10.64898/2026.04.28.721497","url":null,"abstract":"<p><p>Human cone and rod outer segments exhibit a rapid shrinkage followed by a slower elongation in response to light, forming the basis of the optoretinogram. The molecular basis of this optical assay of photoreceptor function remains incompletely understood. In mouse rods, the elongation response requires transducin, the G-protein α-subunit activated in the initial amplifying step of the phototransduction cascade. Here, we measured human cone outer segment responses in subjects with bradyopsia arising from a triple-deletion mutation in R9AP, the anchor and transport protein for the GTPase-activating protein (GAP) RGS9. Immunoprecipitation showed that the mutant R9AP has greatly reduced affinity for RGS9, predictably reducing the level of RGS9 in the outer segment. The bradyopsia subjects' elongation responses had normal activation kinetics, amplitude and photosensitivity, but markedly slowed recovery. These results indicate that normal levels of RGS9 are required for deactivation of the cone elongation response, situating the underlying molecular mechanism within the G-protein cascade at or prior to formation of the GAP complex. The recovery of the cone elongation response, measured in a paired-flash paradigm for stimuli isomerizing up to 75% of opsin, revealed that elongation requires a substrate that is depleted and recovers in a bleach-dependent manner. In particular, recovery from the highest bleaching exposure (75%) tracked the time course of cone opsin regeneration, implying that unregenerated cone opsin produces \" <i>dark light</i> \", known in rods to arise from constitutive activation of G-protein. Taken together, the results from controls and bradyopsia identify the inactive (GDP-bound) transducin complex as the essential substrate for the human cone elongation response. Suppression of the elongation response in the paired-flash paradigm further revealed the complete profile of the initial fast cone outer segment shrinkage response and reinforced its origin in opsin structural changes. Overall, these results identify key mechanistic elements of the optoretinogram and enable its use as a molecularly interpretable, non-invasive assay of cone function in disease and therapeutic response.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13142400/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147848836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"How Phosphorylation of How Phosphorylation of alpha/beta-Tubulin Perturbs Microtubule Structure: A Computational Study.","authors":"Annemarie Ianos, Ahmed Osman, Krishna Mahavadi, Baofu Qiao, Susan A Rotenberg","doi":"10.64898/2026.04.29.721677","DOIUrl":"https://doi.org/10.64898/2026.04.29.721677","url":null,"abstract":"<p><p>Microtubules are cytoskeletal structures composed of polymers of alpha-beta-tubulin heterodimers. They play a central role in cell division and motility by a stochastic process of alternating polymerization and depolymerization episodes (dynamic instability) that can be modulated by phosphorylation. Protein kinase Calpha and cyclin-dependent kinase 1 are known to phosphorylate Ser165 of alpha-tubulin (alpha:Ser165) and Ser172 of beta-tubulin, (alpha:Ser172), respectively. Using all-atom molecular dynamics simulations of 6-mer alpha/beta-tubulin systems modeled on the cryo-EM structure of a microtubule (PDB 3J6E), the impact of phosphorylation at each site is explored in terms of secondary structures (alpha:helix H8/loop T7 segment and beta:loops T3/T5) that lie at the inter-dimer cleft near the E-site beta:GTP. If properly aligned, alpha:Glu254 (helix H8) hydrolyzes beta:GTP to GDP thereby triggering the transition from a polymerizing to a depolymerizing microtubule. alpha-Tubulin phosphorylated at alpha:Ser165 displaces helix H8 (alpha:Glu254/alpha:Gln256) and loop T5 towards the gamma-phosphate of beta:GTP. This movement coincides with a shift of the beta:GTP nucleotide by 4.5-5.5 A, stabilization of the gamma-P of beta-GTP by additional H-bonding and weakened inter-dimer interactions. In a phosphorylated beta:Ser172 system, loop T5 is displaced toward beta:GTP and coincides with stabilization of inter-dimer interactions. Therefore, phosphorylation of either alpha- or beta-tubulin generates a distinct profile of intramolecular rearrangements that remodel the inter-dimer cleft and modulate dynamic instability. These profiles may provide a useful reference for screening mutations identified in tumor genomes.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13142500/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147848552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PARP inhibition with 3-aminobenzimide attenuates behavioral, cardiovascular, and neuroinflammatory effects of chronic stress.","authors":"Liza Judith Wills, Hui Wang-Heaton, Aaron J Polichnowski, Kristy L Thomas, Benjamin E Jewett, Seth Jewett, Grayson Aldridge, Gregory A Ordway, Russell W Brown, Michelle J Chandley","doi":"10.64898/2026.04.28.721400","DOIUrl":"https://doi.org/10.64898/2026.04.28.721400","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Major depressive disorder (MDD) affects approximately 20% of the population, with over 30% of cases demonstrating treatment resistance. Postmortem analyses have revealed increased poly (ADP-ribose) polymerase 1 (PARP-1) expression in prefrontal cortical white matter of individuals with MDD, suggesting PARP-1 as a potential therapeutic target. Chronic stress, a major risk factor for depression, affects multiple physiological domains including behavior, cardiovascular function, neuroinflammation, and gut-brain axis signaling.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We conducted a comprehensive multi-system investigation of PARP inhibition effects on stress-induced pathophysiology using the social defeat stress/chronic unpredictable stress (SDS+CUS) rodent model. In the primary study, male Sprague-Dawley rats (N=32) underwent 10 days of SDS+CUS while receiving daily treatment with the PARP inhibitor 3-aminobenzamide (3-AB; 40mg/kg), selective serotonin reuptake inhibitor fluoxetine (FLX; 10mg/kg), or saline (0.9% NaCl), with non-stressed controls included. Behavioral outcomes were assessed via sucrose preference and social interaction tests. Neurobiological analyses examined PARP-1 expression, microglial morphology, and proinflammatory cytokine levels (IL-1β, TNF-α, IL-6) in relevant brain regions. In a parallel cardiovascular study, a separate cohort of stressed rats (N=8) received either saline or 3-AB treatment while hemodynamic parameters were monitored via telemetry before, during, and after stress exposure. Exploratory gut microbiome analyses were also conducted (see Supplemental Materials).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Saline-treated stressed rats demonstrated significantly elevated anhedonia and social avoidance compared to all other groups, while 3-AB treatment prevented these behavioral deficits. Cardiovascular monitoring revealed that stressed saline-treated rats developed significant elevations in systolic and mean blood pressure with decreased heart rate compared to baseline, whereas 3-AB treatment prevented these hemodynamic changes. Neurobiological analyses showed that FLX-treated stressed rats unexpectedly exhibited elevated PARP-1 expression in prefrontal cortical gray matter. Microglial morphological analysis revealed significantly more prolate (activated) microglia in the saline-treated stressed rats compared to all other treatment groups. Saline-treated stressed rats exhibited significantly increased hippocampal proinflammatory cytokines, with 3-AB treatment specifically normalizing TNF-α levels.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;PARP inhibition with 3-AB provides multi-system protection against chronic stress effects, preventing behavioral deficits, cardiovascular dysfunction, and neuroinflammation. These findings establish PARP-1 as a key mediator in the systemic pathophysiology of chronic stress and highlight PARP inhibition as a promising therapeutic approach for stress-related disorders with treat","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13142347/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147848598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}