Biology subjects

Simon, J.

Publications and source records attributed to Simon, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Targeting Microbial Bile Salt Hydrolase Reprograms Bile Acid Metabolism and Ameliorates Metabolic Dysfunction-Associated Steatohepatitis in Mice

Microbial bile salt hydrolase (BSH) plays a central role in shaping bile acid composition and gut-liver metabolic signaling, yet its therapeutic potential in metabolic dysfunction-associated steatohepatitis (MASH) remains incompletely defined. Here, we evaluated the efficacy of the non-absorbable BSH inhibitor GR-7 in a diet induced mouse model of steatohepatitis using early and late intervention strategies with different dosing regimens. GR-7 reduced food intake and exerted stage- and dose-dependent therapeutic effects, with early intervention robustly suppressing hepatic fibrosis even at low dose, whereas late-stage administration of high-dose GR-7 markedly reduced hepatic steatosis and inflammation, as evidenced by decreased liver weight, hepatic triglyceride and cholesterol levels, and plasma ALT. Although late intervention did not result in statistically significant histological reversal of fibrosis, a trend toward improvement was observed, together with suppression of fibrogenic gene expression, suggesting that prolonged treatment may further enhance antifibrotic efficacy. Mechanistically, GR-7 effectively inhibited microbial BSH activity in vivo, leading to reduced cecal unconjugated primary and secondary bile acids--including deoxycholic acid and lithocholic acid, which was associated with improved gut barrier integrity and reduced hepatic inflammation. In parallel, BSH inhibition reprogrammed hepatic bile acid metabolism toward activation of the alternative CYP27A1-mediated synthesis pathway, accompanied by reduced food intake, thereby contributing to improved hepatic lipid accumulation. Furthermore, late-stage high-dose treatment selectively remodeled the hepatic immune landscape rather than fully restoring homeostasis, highlighting immune recalibration as a key component of therapeutic response. Together, these findings identify microbial BSH inhibition as a promising microbiome-targeted therapeutic strategy for MASH. HighlightsO_LIThe non-absorbable BSH inhibitor GR-7 improves steatosis, inflammation, and fibrosis in of Western diet-induced steatohepatitis model in mice in a dose-dependent manner. C_LIO_LIGR-7 reduces food intake and body weight gain. C_LIO_LIGR-7 reduces cytotoxic secondary bile acids, including DCA and LCA. C_LIO_LIGR-7 reprograms hepatic bile acid metabolism and immune responses. C_LI

pharmacology and toxicology↗

bioRxiv2026

Senescence-directed nanotherapy ameliorates fibrosis and overcomes immune exclusion in cancer

Fibrotic remodeling of tissues and tumors establishes immunosuppressive microenvironments that drive organ dysfunction and, in cancer, limit response to immunotherapy. Senescent-like cells are conserved drivers of fibrosis and therapeutic targets, yet their functional heterogeneity complicates therapeutic intervention. Here, we show that P-selectin is expressed by a subset of senescent-like cells in fibrotic tissues and tumors. Leveraging fucoidan-based nanoparticles that bind P-selectin, we developed senescence-modulating nanoparticles (SMNPs) to selectively target these disease-associated states. SMNPs exerted potent antifibrotic and immunomodulatory effects while improving therapeutic index. Mechanistically, we identified a pathogenic, immunosuppressive macrophage population as a functional target in vivo. In fibrotic tumors, niche remodeling restored immune infiltration and sensitized tumors to immune-checkpoint-based therapies. These findings establish SMNPs as a generalizable strategy to target pathogenic senescent cell subsets across fibrosis and cancer.

cancer biology↗

bioRxiv2025

Peracetic Acid Efficacy and Decay Kinetics in Poultry Processing under Chiller Conditions

Pathogens on poultry products continue to pose critical public health risks. Despite significant literature examining sanitizer impact on bacterial pathogens during chilling, the mechanisms of sanitizer efficacy in terms of pathogen and organic load, sanitizer levels, and exposure duration are not well understood. To assess these, we report on experimentally-informed-mechanistic-modeling to describe pathogen dynamics during poultry chilling. The shedding and survival of a five-strain cocktail of poultry-plant derived Salmonella enterica serovars, at high and low loads, with exposure to peracetic acid (PAA; 0 - 200 mg{middle dot}L-1) for up to 60 min in 10-L chiller tanks, in the presence or absence of whole chicken carcass/parts, were measured. Process water parameters versus time were simultaneously monitored. Results suggest that total dissolved solids (TDS) predict PAA decay more consistently than chemical oxygen demand (COD). A mathematical model for PAA decay and pathogen shedding/inactivation was developed. This model accurately predicted PAA level changes in the pre/main chiller of a high-speed poultry processing plant in North America. Without PAA, Salmonella shedding from chicken thighs is influenced by rinse time and number of rinses. Without organic load, residual PAA (1 mg{middle dot}L-1) inactivated bacteria given sufficient exposure time, although PAA levels > 5 mg{middle dot}L-1 were essential for rapid inactivation. With organic load, initial PAA concentration (> 40 mg{middle dot}L-1) and exposure time (> 2 min) were critical for bacterial inactivation, with model results connecting process conditions to dominate modes of bacterial inactivation on chicken. The insights from such experimental-modeling studies provide key tools for processors to improve pathogen control during chilling.

microbiology↗

bioRxiv2024

Rational Design of Unsaturated, Thioether Ionizable Lipids for Enhanced In vivo mRNA Delivery

Therapies based on mRNA technology have offered hope to millions of patients worldwide by disrupting the way we treat diseases. The safe and functional delivery of the delicate mRNA molecules to the target tissue is a crucial step in the development of effective vaccines and therapeutic interventions. Lipid nanoparticles (LNP) are the most clinically advanced delivery vehicles for mRNA drugs. Key to the success of LNP is the inclusion of an ionizable cationic lipid. However, the structure-function relationships between ionizable lipids and efficient in-vivo mRNA delivery are still poorly understood. In this work, we focused on the rational design and sequential structural optimization of previously identified ionizable lipids that performed well in vitro, but not in vivo. Through two distinct iterative optimization cycles -- one targeting the lipid tail and the other the headgroup -- we aimed to understand how the fusogenicity and apparent pKa of the ionizable lipid contribute to LNP delivery performance in vivo. By engineering unsaturated lipids with more hydrophobic, less protonatable amino headgroups with longer alkyl group at the tertiary nitrogen, we achieved both significant improvement of protein expression in vitro, reduced hemolysis risk, and more than 200-fold improvement of in vivo mRNA delivery. When compared head-to-head to a market-approved LNP benchmark, the newly developed ionizable lipids/LNP resulted in equally highly efficient in vivo mRNA delivery, with strong liver and spleen tropism upon intravenous injection, while matching the safety of the approved platform. Our findings are pivotal for the development of next-generation mRNA-LNP therapies and vaccines.

bioengineering↗

bioRxiv2024

Single-cell transcriptomics predict novel potential regulators of acute epithelial restitution in the ischemia-injured intestine

Intestinal ischemic injury damages the epithelial barrier predisposes patients to life-threatening sepsis unless that barrier is rapidly restored. There is an age-dependency of intestinal recovery in that neonates are the most susceptible to succumb to disease of the intestinal barrier versus older patients. We have developed a pig model that demonstrates age-dependent failure of intestinal barrier restitution in neonatal pigs which can be rescued by the direct application of juvenile pig mucosal tissue, but the mechanisms of rescue remain undefined. We hypothesized that by identifying a subpopulation of restituting enterocytes by their expression of cell migration transcriptional pathways, we can then predict novel upstream regulators of age-dependent restitution response programs. Superficial mucosal epithelial cells from recovering ischemic jejunum of juvenile pigs were processed for single cell RNA sequencing analysis, and predicted upstream regulators were assessed in a porcine intestinal epithelial cell line (IPEC-J2) and banked tissues. A subcluster of absorptive enterocytes expressed several cell migration pathways key to restitution. Differentially expressed genes in this subcluster predicted their upstream regulation included colony stimulating factor-1 (CSF-1). We validated age-dependent induction of CSF-1 by ischemia and documented that CSF-1 and CSF1R co-localized in ischemic juvenile, but not neonatal, wound-adjacent epithelial cells and in the restituted epithelium of juveniles and rescued (but not control) neonates. Further, the CSF1R inhibitor BLZ945 reduced restitution in scratch wounded IPEC-J2 cells. These studies validate an approach to inform potential novel therapeutic targets, such as CSF-1, to improve outcomes in neonates with intestinal injury in a unique pig model. NEW & NOTEWORTHYThese studies validate an approach to identify and predict upstream regulation of restituting epithelium in a unique pig intestinal ischemic injury model. Identification of potential molecular mediators of restitution, such as CSF-1, will inform the development of targeted therapeutic interventions for medical management of patients with ischemia-mediated intestinal injury.

cell biology↗

bioRxiv2024

Metastatic site influences driver gene function in pancreatic cancer

Driver gene mutations can increase the metastatic potential of the primary tumor1-3, but their role in sustaining tumor growth at metastatic sites is poorly understood. A paradigm of such mutations is inactivation of SMAD4 - a transcriptional effector of TGF{beta} signaling - which is a hallmark of multiple gastrointestinal malignancies4,5. SMAD4 inactivation mediates TGF{beta}s remarkable anti-to pro-tumorigenic switch during cancer progression and can thus influence both tumor initiation and metastasis6-14. To determine whether metastatic tumors remain dependent on SMAD4 inactivation, we developed a mouse model of pancreatic ductal adenocarcinoma (PDAC) that enables Smad4 depletion in the pre-malignant pancreas and subsequent Smad4 reactivation in established metastases. As expected, Smad4 inactivation facilitated the formation of primary tumors that eventually colonized the liver and lungs. By contrast, Smad4 reactivation in metastatic disease had strikingly opposite effects depending on the tumors organ of residence: suppression of liver metastases and promotion of lung metastases. Integrative multiomic analysis revealed organ-specific differences in the tumor cells epigenomic state, whereby the liver and lungs harbored chromatin programs respectively dominated by the KLF and RUNX developmental transcription factors, with Klf4 depletion being sufficient to reverse Smad4s tumor-suppressive activity in liver metastases. Our results show how epigenetic states favored by the organ of residence can influence the function of driver genes in metastatic tumors. This organ-specific gene-chromatin interplay invites consideration of anatomical site in the interpretation of tumor genetics, with implications for the therapeutic targeting of metastatic disease.

cancer biology↗

bioRxiv2024

Effect of pH on the thermostability and redox properties of cytochrome c552 from Wolinella succinogenes

Cytochrome c552 from Wolinella succinogenes is one of the few examples of a low reduction potential class I c-type cytochrome with a mixture of high/low spin state populations observed in its visible spectrum. Analysis of its structural model suggests that the heme is Met/His coordinated and highly solvent-exposed. This supports the hypothesis that it is the solvent accessibility of the propionate groups that controls the reduction potential of small c-type cytochromes. The visible spectra obtained at different pH values reveal the presence of a protonable group with a pKa of 7.3, which also influences the reduction potential of this small cytochrome c552 (Em0 of 97 {+/-} 5 mV, pH 7.0) and can be either an H2O/OH- group distantly coordinating the heme iron, or one of the propionate groups. The thermostability of cytochrome c552 has been studied by circular dichroism and differential scanning calorimetry, indicating a highly stable protein at pH 5-7 (90 {degrees}C to 77 {degrees}C).

biochemistry↗

bioRxiv2024

Alveolar macrophages play a key role in tolerance to ozone

Acute exposure to ozone (O3) causes pulmonary inflammation and injury in humans and animal models. In rodents, acute O3-induced inflammation and injury can be mitigated by pre-exposure to relatively low concentration O3, a phenomenon referred to as tolerance. While tolerance was described long ago, the underlying mechanisms are not known, though upregulation of antioxidants has been proposed. To identify new mechanisms for O3 tolerance, we generated a mouse model in which female C57BL6/NJ mice were pre-exposed to filtered air (FA) or 0.8 ppm O3 for four days (4 hours/day), then challenged with 2 ppm O3 (3 hours) 2 days later, and phenotyped for airway inflammation and injury 6 or 24 hours thereafter. As expected, pre-exposure to O3 resulted in significantly reduced airway inflammation and injury at 24 hours, as well as reduced induction of antioxidant genes. Like previous studies in rats, tolerance was associated with changes in the frequency and proliferation of alveolar epithelial cells, but was not associated with upregulation of antioxidants, CCSP (SCGB1A1), or mucus. We found that alveolar macrophages (AMs) play a critical role in tolerance, as depletion of AMs using clodronate in mice pre-exposed to O3 restored many responses to acute O3 challenge. Further, AMs of O3 tolerized mice exhibited decreased expression of genes involved in cellular signaling via Toll-like receptors, MYD88, and NF-kB, and proinflammatory cytokine production. We conclude that O3 tolerance is highly, but not exclusively, dependent on AMs, and that further studies investigating how repeated O3 exposure induces hypo-responsiveness in AMs are warranted.

pharmacology and toxicology↗

bioRxiv2023

Anterior cingulate cortex neurons in macaques encode social image identities

The anterior cingulate cortex gyrus (ACCg) has been implicated in prosocial behaviors involving complex reasoning about social cues. While this indicates that the ACCg is involved in social behavior, it remains unclear whether ACCg neurons also encode social information during goal-directed actions without social consequences. To address this, we assessed how social information is processed by ACCg neurons in a reward localization task. Two rhesus monkeys performed the task using either social or nonsocial visual guides to locate rewarding targets. We found that monkeys can use both sets of guides, and many neurons in the ACCg distinguished social from nonsocial trials. Yet, this encoding was no more common in ACCg than in the prearcuate cortex (PAC), which has not been strongly linked to social behavior. However, unlike PAC, ACCg neurons were more likely to encode the unique identity of social visual guides compared to nonsocial, even though identity was irrelevant to the reward localization task. This suggests that ACCg neurons are uniquely sensitive to social information that differentiates individuals, which may underlie its role in complex social reasoning.

neuroscience↗

bioRxiv2022

Single-cell dynamics of core pluripotency factors in human pluripotent stem cells

The human transcription factors OCT4, SOX2, and NANOG form a core signaling network critical for maintaining stem cell pluripotency and self-renewal potential. The spatiotemporal expression dynamics of these pluripotency factors throughout differentiation is unclear, limiting our understanding of stem cell fate decisions. Here, we combined CRISPR/Cas9-mediated gene editing with microraft array technology to generate human embryonic stem cell lines with endogenously tagged fluorophores for OCT4, SOX2, and NANOG. Fluorescence time-lapse imaging revealed that pluripotent stem cells show gastrulation-like patterning without direct chemical induction. Directed differentiation to the three primary germ layers--endoderm, mesoderm, and ectoderm--revealed distinct spatiotemporal patterns of SOX2 and NANOG expression in single cells. Finally, we captured dynamic changes in cell morphology during ectoderm differentiation corresponding to the formation of neural rosettes. This study provides a robust method for generating live-cell reporters in human stem cells and describes the single-cell dynamics of human pluripotency factors during differentiation.

developmental biology↗

bioRxiv2022

Chromosome 9p21.3 Coordinates Cell Intrinsic and Extrinsic Tumor Suppression

Somatic chromosomal deletions are prevalent in cancer, yet their functional contributions remain ill-defined. Among the most prominent of these events are deletions of chromosome 9p21.3, which disable a cell intrinsic barrier to tumorigenesis by eliminating the CDKN2A/B tumor suppressor genes. However, half of 9p21.3 deletions encompass a cluster of 16 type I interferons (IFNs) whose co-deletions have not been functionally characterized. To dissect how 9p21.3 and other genomic deletions impact cancer, we developed MACHETE (Molecular Alteration of Chromosomes with Engineered Tandem Elements), a genome engineering strategy that enables flexible modeling of megabase-sized deletions. Generation of 9p21.3-syntenic deletions in a mouse model of pancreatic cancer revealed that concomitant loss of Cdkn2a/b and the IFN cluster led to immune evasion and metastasis compared to Cdkn2a/b-only deletions. Mechanistically, IFN co-deletion disrupted type I IFN signaling, altered antigen-presenting cells, and facilitated escape from CD8+ T cell surveillance in a cell extrinsic manner requiring loss of interferon epsilon (Ifne). Our results establish co-deletions of the IFN cluster as a pervasive route to tumor immune evasion and metastasis, revealing how deletions can disable physically linked cell intrinsic and extrinsic tumor suppression. Our study establishes a framework to dissect the functions of genomic deletions in cancer and beyond.

cancer biology↗

bioRxiv2022

EZH2 inhibition remodels the inflammatory senescence-associated secretory phenotype to potentiate pancreatic cancer immune surveillance

T cell-activating immunotherapies that produce durable and even curative responses in some malignancies have failed in pancreatic ductal adenocarcinoma (PDAC) due to rampant immune suppression and poor tumor immunogenicity. We and others have demonstrated that induction of cellular senescence and its accompanying senescence-associated secretory phenotype (SASP) can be an effective approach to activate not only T cell but also cytotoxic Natural Killer (NK) cell-mediated anti-tumor immunity. Here we found that the pancreas tumor microenvironment (TME) suppresses NK and T cell surveillance following therapy-induced senescence through EZH2-mediated repression of pro-inflammatory SASP genes. Genetic or pharmacological inhibition of EZH2 or its methyltransferase activity stimulated the production of pro-inflammatory SASP chemokines CCL2 and CXCL9/10 that led to enhanced NK and T cell infiltration and tumor eradication in preclinical PDAC mouse models. EZH2 activity was also associated with suppression of SASP-associated inflammatory chemokines and cytotoxic lymphocyte immunity and reduced overall survival in a PDAC patient cohort. These results demonstrate that EZH2 mediates epigenetic repression of the pro-inflammatory SASP in the pancreas TME, and that EZH2 blockade in combination with senescence-inducing therapies could be a powerful means to potentiate NK and T cell surveillance in PDAC to achieve immune-mediated tumor control.

cancer biology↗

bioRxiv2022

Somatic mouse models of gastric cancer reveal genotype-specific features of metastatic disease

Metastatic gastric carcinoma is a highly lethal cancer that responds poorly to conventional and molecularly targeted therapies. Despite its clinical relevance, the mechanisms underlying the behavior and therapeutic response of this disease are poorly understood owing, in part, to a paucity of tractable models that faithfully recapitulate different subtypes of the human disease. To close this gap, we developed methods to somatically introduce different oncogenic lesions directly into the stomach epithelium and show that genotypic configurations observed in patients produce metastatic gastric cancers that recapitulate the histological, molecular, and clinical features of all non-viral molecular subtypes of the human disease. Applying this platform to both wild-type and immune-deficient mice revealed previously unappreciated links between the genotype, organotropism and immune surveillance of metastatic cells that produced distinct patterns of metastasis that were mirrored in patients. Our results establish and credential a highly portable platform for producing autochthonous cancer models with flexible genotypes and host backgrounds, which can unravel mechanisms of gastric tumorigenesis or test new therapeutic concepts aimed at improving outcomes in gastric cancer patients.

cancer biology↗

bioRxiv2022

Basal forebrain cholinergic circuits orchestrate diverse cell types in the adult dentate gyrus to support neural stem cell function and spatial memory

Dentate gyrus (DG) is a critical structure involved in spatial memory and adult neurogenesis, two distinct processes dynamically regulated by local circuits comprising diverse populations of DG cells. It remains unknown how these DG cells are orchestrated to regulate these distinct hippocampal functions. Here we report activation of a cholinergic circuit from the Diagonal Band of Broca to DG promotes quiescent radial neural stem cell (rNSC) activation and spatial memory. Furthermore, single-nucleus RNA-sequencing reveals broad transcriptomic changes across DG mature and adult-born cells in response to cholinergic-circuit activation. Notably, neuronal populations exhibit cholinergic-activity-induced molecular changes related to synaptic functions crucial for spatial memory; while rNSCs exhibit changes related to structural remodeling and neurogenic proliferation crucial for hippocampal neurogenesis. Electrophysiology and NicheNet analyses reveal granule cells, endothelial cells, and astrocytes as potential intermediaries for cholinergic regulation of rNSCs. Our findings reveal cell-type-specific signaling mechanisms underlying cholinergic regulation of distinct DG functions.

neuroscience↗

bioRxiv2022

Identification of novel basil downy mildew resistance genes using de novo comparative transcriptomics

O_LISweet basil (Ocimum basilicum L.) production is threatened by the oomycete pathogen Peronospora belbahrii causing basil downy mildew (BDM); BDM resistant cultivar Mrihani (MRI) was identified in a germplasm screen, and fertile progeny were produced through a breeding program with BDM-susceptible Newton (SB22), but the molecular mechanisms conferring resistance in MRI and progeny remained unknown C_LIO_LIComparative transcriptomics was performed to identify candidate resistance genes and potential mechanisms for BDM resistance; RNA samples from BDM-infected MRI and SB22 plants were harvested at 4 time points during the first 3 days of infection to differentiate interactions in resistant and susceptible plants. C_LIO_LIThree categories of genes uniquely induced in resistant MRI upon pathogen challenge were identified: nucleotide-binding leucine rich repeat proteins (NLRs), multi-functional receptor-like kinases (RLKs), and secondary metabolic enzymes; validation of the top resistance candidate NLR gene confirmed its unique presence in MRI as well as in two of four resistant MRIxSB22 F2 progeny. C_LIO_LIIn MRI, pathogen challenge also upregulated transcripts in the salicylic acid synthesis pathway, suggesting its role in BDM resistance, and demonstrating the application of using comparative transcriptomics to identify resistance genes and mechanisms in non-model crops for marker-assisted breeding approaches. C_LI

plant biology↗

bioRxiv2022

ER translocation of suboptimal targeting sequences depends on Sec61β/Sbh1 and its phosphorylation

The endoplasmic reticulum (ER) protein translocation channel subunit Sec61{beta}/Sbh1 is non-essential, but contains multiple phosphorylation sites suggesting a regulatory role in ER protein import. We show here that mutating two N-terminal, proline-flanked, phosphorylation sites in the Sbh1 cytosolic domain phenocopies the temperature-sensitivity of a yeast strain lacking SBH1/SBH2, and results in reduced translocation into the ER of an Sbh1-dependent substrate, Gls1. In a microscopic screen we show that about 12% of GFP-tagged secretory proteins depend on Sbh1 for translocation. Sbh1-dependent proteins have targeting sequences with less pronounced hydrophobicity and often no or an inverse charge bias. A subset of these proteins was dependent on N-terminal phosphorylation of Sbh1 and on the phospho-S/T-specific proline isomerase Ess1 (PIN1 in mammals) for ER import. We conclude that Sbh1 promotes ER translocation of substrates with suboptimal targeting sequences and that its activity is regulated by a conformational change induced by N-terminal phosphorylation.

biochemistry↗

bioRxiv2021

Profiling of the drug resistance of thousands of Src tyrosine kinase mutants uncovers a regulatory network that couples autoinhibition to the dynamics of the catalytic domain

Kinase inhibitors are effective cancer therapies but resistance often limits clinical efficacy. Despite the cataloguing of numerous resistance mutations, our understanding of kinase inhibitor resistance is still incomplete. Here, we comprehensively profiled the resistance of [~]3500 Src tyrosine kinase mutants to four different ATP-competitive inhibitors. We found that ATP-competitive inhibitor resistance mutations are distributed throughout Srcs catalytic domain. In addition to inhibitor contact residues, residues that participate in regulating Srcs phosphotransferase activity were prone to the development of resistance. Unexpectedly, we found that a resistance-prone cluster of residues located on the top face of the N-terminal lobe of Srcs catalytic domain contributes to autoinhibition by reducing catalytic domain dynamics, and mutations in this cluster led to resistance by lowering inhibitor affinity and promoting kinase hyperactivation. Together, our studies demonstrate how drug resistance profiling can be used to define potential resistance pathways and uncover new mechanisms of kinase regulation.

biochemistry↗

bioRxiv2021

Rescue of behavioral and electrophysiological phenotypes in a Pitt-Hopkins syndrome mouse model by genetic restoration of Tcf4 expression

Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder caused by monoallelic mutation or deletion in the transcription factor 4 (TCF4) gene. Individuals with PTHS typically present in the first year of life with developmental delay and exhibit intellectual disability, lack of speech, and motor incoordination. There are no effective treatments available for PTHS, but the root cause of the disorder, TCF4 haploinsufficiency, suggests that it could be treated by normalizing TCF4 gene expression. Here we performed proof-of-concept viral gene therapy experiments using a conditional Tcf4 mouse model of PTHS and found that postnatally reinstating Tcf4 expression in neurons improved anxiety-like behavior, activity levels, innate behaviors, and memory. Postnatal reinstatement also partially corrected EEG abnormalities, which we characterized here for the first time, and the expression of key TCF4-regulated genes. Our results support a genetic normalization approach as a treatment strategy for PTHS, and possibly other TCF4-linked disorders.

neuroscience↗