Maternal Immune Activation imprints translational dysregulation and differential MAP2 phosphorylation in descendant neural stem cells.

Alterations induced by maternal immune activation (MIA) during gestation impact the subsequent neurodevelopment of progeny, a process that in humans, has been linked to the development of several neuropsychiatric conditions. To undertake a comprehensive examination of the molecular mechanisms governing MIA, we have devised an in vitro model based on neural stem cells (NSCs) sourced from fetuses carried by animals subjected to Poly I:C treatment. These neural progenitors demonstrate proliferative capacity and can be effectively differentiated into both neurons and glial cells. Transcriptomic, proteomic, and phosphoproteomic analyses conducted on these cellular models, in conjunction with counterparts from control treatments, revealed discernible shifts in the expression levels of a specific subset of proteins implicated in neuronal function. Noteworthy, we found an absence of congruence between these alterations at the transcriptomic level, suggesting that differences in protein translation contribute to the observed dysregulation. Furthermore, the phosphoproteomic data highlighted a discernible discrepancy in the basal phosphorylation of proteins between differentiated cells from both experimental groups, particularly within proteins associated with cytoskeletal architecture and synaptic functionality, notably those belonging to the MAP family. Observed alterations in MAP phosphorylation were found to potentially have functional consequences as they correlate with changes in neuronal plasticity and the establishment of neuronal synapses. Our data agrees with previous published observations and further underscore the importance of MAP2 phosphorylation state on its function and the impact that this protein has in neuronal structure and function.

Portal vein thrombosis in a patient with severe hemophilia B: A challenging balanced management.

Key Clinical Message: The increased life expectancy in patients with hemophilia (PwH) over the last years has raised the incidence of comorbidities, including thromboembolic events. Thromboembolic events are rare in PwH and most of them occur in the presence of exogenous risk factors. There is still scarce scientific evidence on the optimal antithrombotic treatment and management approach in this population. Abstract: In the hemophilic population thromboembolic events are rare. Most of them are often multifactorial and occur in the presence of both exogenous (orthopedic surgery, intensive replacement therapy, use of central venous catheters…) and endogenous (cardiovascular diseases) risk factors. We describe the case of a 43-year-old patient with severe hemophilia B (sHB) receiving prophylaxis with eftrenonacog alfa (rFIXFc) and antithrombotic treatment due to portal vein thrombosis. The patient was treated with extended half- life factor IX (EHL-FIX) prophylaxis maintaining higher trough levels to avoid new bleeding episodes associated to the underlying disease and the use of antithrombotic therapy with low molecular weight heparin. EHL-FIX concentrates allow prolonged intervals between intravenous infusions and higher hemostatic protection thanks to increased factor trough levels. This current case report provides clinical evidence in antithrombotic management in a patient with severe hemophilia B.

Macular vessel density in the superficial plexus is not a proxy of cerebrovascular damage in non-demented individuals: data from the NORFACE cohort.

INTRODUCTION: Optical coherence tomography angiography (OCT-A) is a novel tool that allows the detection of retinal vascular changes. We investigated the association of macular vessel density (VD) in the superficial plexus assessed by OCT-A with measures of cerebrovascular pathology and atrophy quantified by brain magnetic resonance imaging (MRI) in non-demented individuals. METHODS: Clinical, demographical, OCT-A, and brain MRI data from non-demented research participants were included. We analyzed the association of regional macular VD with brain vascular burden using the Fazekas scale assessed in a logistic regression analysis, and the volume of white matter hyperintensities (WMH) assessed in a multiple linear regression analysis. We also explored the associations of macular VD with hippocampal volume, ventricle volume and Alzheimer disease cortical signature (ADCS) thickness assessed in multiple linear regression analyses. All analyses were adjusted for age, sex, syndromic diagnosis and cardiovascular variables. RESULTS: The study cohort comprised 188 participants: 89 with subjective cognitive decline and 99 with mild cognitive impairment. No significant association of regional macular VD with the Fazekas categories (all, p > 0.111) and WMH volume (all, p > 0.051) were detected. VD in the nasal quadrant was associated to hippocampal volume (p = 0.007), but no other associations of macular VD with brain atrophy measures were detected (all, p > 0.05). DISCUSSION: Retinal vascular measures were not a proxy of cerebrovascular damage in non-demented individuals, while VD in the nasal quadrant was associated with hippocampal atrophy independently of the amyloid status.

Imaging Delay Following Liver-Directed Therapy Increases Progression Risk in Early- to Intermediate-Stage Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related deaths in the world. Patients with early-stage HCC are treated with liver-directed therapies to bridge or downstage for liver transplantation (LT). In this study, the impact of HCC care delay on HCC progression among early-stage patients was investigated. Early-stage HCC patients undergoing their first cycle of liver-directed therapy (LDT) for bridge/downstaging to LT between 04/2016 and 04/2022 were retrospectively analyzed. Baseline variables were analyzed for risk of disease progression and time to progression (TTP). HCC care delay was determined by the number of rescheduled appointments related to HCC care. The study cohort consisted of 316 patients who received first-cycle LDT. The HCC care no-show rate was associated with TTP (p = 0.004), while the overall no-show rate was not (p = 0.242). The HCC care no-show rate and HCC care delay were further expanded as no-show rates and rescheduled appointments for imaging, laboratory, and office visits, respectively. More than 60% of patients experienced HCC care delay for imaging and laboratory appointments compared to just 8% for office visits. Multivariate analysis revealed that HCC-specific no-show rates and HCC care delay for imaging (p < 0.001) were both independently associated with TTP, highlighting the importance of minimizing delays in early-stage HCC imaging surveillance to reduce disease progression risk.

Lineage-specific regulation of PD-1 expression in early-stage hepatocellular carcinoma following 90yttrium transarterial radioembolization - Implications in treatment outcomes.

BACKGROUND: Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related deaths in the world. Liver-directed therapies, including 90Yttrium (90Y) radioembolization, play an integral role in the management of HCC with excellent response rates. This has led to clinical trials of immunotherapy in combination with 90Y. Elevated PD-1 expression and lymphopenia were recently shown as risk factors for disease progression in early-stage HCC treated with liver-directed therapies. The aim of this study was to investigate PD-1 expression dynamics in bridge/downstage to transplant in HCC patients receiving first-cycle 90Y and evaluate the impact of these changes on response rates and time-to-progression (TTP). METHODS: Patients with HCC receiving first-cycle 90Y as a bridge to liver transplantation (n = 99) were prospectively enrolled. Blood specimens were collected before 90Y and again during routine imagining follow-up to analyze PD-1 expression via flow cytometry. Complete and objective response rates (CR and ORR) were determined using mRECIST. RESULTS: In 84/88 patients with available follow-up imaging, 83% had a localized ORR with 63% having localized CR. For overall response, 71% and 54% experienced ORR and CR, respectively. Post-90Y PD-1 upregulation in CD8 + associated with HCC progression and decreased TTP. Treatment with 90Y was associated with an anticipated significant post-treatment drop in lymphocytes (P < 0.001) that was independent of PD-1 expression for either CD4+ or CD8+ T cells (P = 0.751 and P = 0.375) and not associated with TTP risk. The change in lymphocytes was not correlated with PD-1 expression following treatment nor TTP. CONCLUSIONS: Elevated PD-1 expression on peripheral T cells is associated with increased risk of HCC progression and shorter time to progression in bridging/downstaging to transplant HCC patients undergoing first-cycle 90Y. Treatment-induced lymphopenia was not associated with treatment response, or increased progression risk, suggesting this anticipated adverse event does not impact short-term HCC outcomes.

Benefits of rIX-FP prophylaxis in patients with Haemophilia B: real-world evidence from a Spanish reference centre.

Standard FIX prophylaxis for PWHB require frequent injections, which has led to the development of extended half-life products like rIX-FP (albutrepenonacog alfa) that has shown good efficacy in clinical studies. This ambispective study aims to report a real-world experience with rIX-FP in a Spanish centre with PWHB who switched from SHL-FIX or began prophylaxis with rIX-FP. Five PWHB were included in this study, Four PTP switched to rIX-FP with prophylaxis every 7 days whilst one PUP started with an every-14-days regimen. 3 PTPs extended their dosing intervals to every 14 days or every 21 days. In all PTPs, median annualized spontaneous and joint bleeding rates were maintained at 0.00 and median (range) of ABR was 0.92 (0.00-2.77) after switch to rIX-FP. Mean trough level with previous product was 3.68% (SD = 2.06), while it was 7.08% (SD = 3) with all rIX-FP dosing intervals. After switching to rIX-FP, all PTP reduced their annual infusion rate between 50 and 84% and their annual FIX consumption by 61% (59-67%). This is the first reported real-world experience with albutrepenonacog alfa in a small cohort in Spain and demonstrates good bleeding control together with a reduction of the infusion rate, factor consumption and higher through factor level than previous treatment.

VHrare study: Prevalence, clinical features and management of severe rare bleeding disorders in a large cohort.

INTRODUCTION: Rare bleeding disorders (RBD) constitute 5% of total hereditary bleeding disorders, although the number could be higher, due to the presence of undiagnosed asymptomatic patients. The objective of this study was to analyze the prevalence and characteristics of patients with severe RBDs in our area. MATERIAL AND METHODS: We analyzed the patients with RBD followed at a tertiary-level hospital between January 2014 and December 2021. RESULTS: A total of 101 patients were analyzed, with a median age at diagnosis of 27.67 years (range 0-89), of which 52.47% were male. The most frequent RBD in our population was FVII deficiency. Regarding the diagnostic reason, the most frequent cause was a preoperative test and only 14.8% reported bleeding symptoms at the time of diagnosis. A genetic study was carried out in 63.36% of patients and the most frequent mutation type found was finding a missense mutation. CONCLUSIONS: The distribution of RBDs in our centre is similar to the one reported in the literature. The majority of RBDs were diagnosed from a preoperative test and this allowed preventive treatment prior to invasive procedures to avoid bleeding complications. 83% of patients did not have a pathological bleeding phenotype according to ISTH-BAT.

Manejo ambulatorio de pacientes con amiloidosis cardiaca por cadenas livianas / Outpatient management of patients with cardiac light chain amyloidosis

Resumen La amiloidosis primaria o de cadenas livianas (AL) es la forma más común de amiloidosis y se caracteriza por presentar una población clonal de células plasmáticas que producen una cadena ligera monoclonal de tipo lambda o kappa. En algunos sujetos, dicha cadena se deposita en forma de amiloide en los órganos y tejidos, dando lugar a manifestaciones clínicas, como proteinuria o síndrome nefrótico, miocardiopatía restrictiva y hepatomegalia. Aunque se considera una enfermedad rara, datos recientes sugieren que la amiloidosis cardíaca se subestima como una causa de enfermedades o síndromes cardíacos comunes. En la amiloidosis AL, tanto la respuesta hematológica como la de los órganos después del tratamiento son importantes para mejorar el resultado clínico, especialmente, si mejora la función cardíaca que es uno de los aspectos clave en el pronóstico de la amiloidosis AL. Se presenta el caso y la revisión de un paciente de sexo femenino, de 67 años de edad, que en la pesquisa diagnóstica de anemia e insuficiencia cardiaca (IC) se concluye en el diagnóstico de mieloma múltiple y amiloidosis cardiaca (AC) por depósito de cadenas livianas.

Abstract Primary or light chain (AL) amyloidosis is the most common form of amyloidosis and is characterized by a clonal population of plasma cells that produce a monoclonal lambda or kappa-type light chain, which in some subjects this chain is deposited as amyloid in the organs and tissues, giving rise to clinical manifestations such as proteinuria or nephrotic syndrome, restrictive cardiomyopathy and hepatomegaly. Although considered a rare disease, recent data suggest cardiac amyloidosis is underestimated as cause of common heart diseases or syndromes. In AL amyloidosis, both the hematologic and organ response after treatment, are important to improve clinical outcome. Especially if it improves cardiac function is one of the key aspects in the prognosis of AL amyloidosis. We present the case and review of a 67-year-old female patient, who in the investigation diagnoses anemia and heart failure concludes in the diagnosis of multiple myeloma and cardiac amyloidosis due to light chain deposition.

Periarticular injection and hamstring block versus placebo for pain control in anterior cruciate ligament reconstruction: A randomized controlled trial.

PURPOSE: To study the effectiveness of periarticular infiltration (PI), including the proximal donor site vs. placebo in anterior cruciate ligament (ACL) reconstruction. METHOD: A total of 44 patients were randomized in two groups assigned to receive PI or placebo. The perioperative protocol was the same for both groups. The principal outcome was pain measured at 8 and 24 h by a visual analog scale (VAS). The pain was registered in the knee and the proximal donor site. Pain scores were also assessed to determine whether the VAS improvement would reach the threshold values reported for the minimal clinically significant difference. The secondary outcome was the need for opioid rescue medication. RESULTS: Patients receiving PI exhibited lower pain values in the knee at 8 h (mean PI 35.00 ± 5.76 vs. placebo 60.23 ± 4.52 p = 0.01) and at 24 h (mean PI 37.23 ± 5.62 vs. placebo 55.55 ± 3.41 p = 0.008). These results were above the threshold for clinical significance. No improvements were found in proximal donor site pain and consumption of opioid rescue medication. Complications were comparable between the two groups. CONCLUSION: PI significantly reduced pain in the knee vs. placebo after ACL reconstruction with hamstring autograft at 8 and 24 h after surgery. The instillation of part of the mixture in the proximal hamstring stump did not result in any improvement LEVEL OF EVIDENCE I: Level I, randomized controlled trial.

Technical Feasibility of Suction Thrombectomy Using a Large-Bore Aspiration System in the Portomesenteric Venous System.

PURPOSE: To assess technical feasibility and safety of portal vein thrombectomy with suction thrombectomy using a large-bore thrombectomy device for portomesenteric venous thrombosis (PMVT). MATERIALS AND METHODS: After receiving approval from institutional review board, patients undergoing PMVT treatment using a large-bore aspiration thrombectomy device (Inari FlowTriever or ClotTriever) between July 2019 and June 2021 were identified at 2 medical centers. Charts were reviewed for demographic information, imaging findings, and procedural details. PMVT was categorized using the Yerdel grading system. The thrombectomy procedure was performed via transjugular access through the existing or a new transjugular intrahepatic portosystemic shunt (TIPS) or transsplenic or transhepatic approach. Technical success was defined as successful clot reduction and restoration of portal venous flow at the conclusion of the procedure. Patient outcomes based on clinical presentation, adverse events, and thrombectomy-associated adverse events were recorded. RESULTS: Twenty patients, with a median age of 58 years (range, 23-72 years), underwent large-bore aspiration thrombectomy, which was technically successful in 19 of 20 (95%) patients. In 9 of 20 (45%) patients, 9 of 20 (45%) patients, and 2 of 20 (10%) patients, the 20-F, 16-F, and 24-F devices were used, respectively. Fourteen patients had a pre-existing TIPS, and 6 patients had a TIPS created. In 5 of 20 (25%) patients, overnight lysis was performed in conjunction with Inari thrombectomy. Thrombus resolution with restoration of flow was achieved in 19 of 20 (95%) cases. There were no thrombectomy-associated adverse events. The mean follow-up time was 70 days (±113) at which time primary patency of the portal venous system was present in 16 of 20 (80%) patients. CONCLUSIONS: Large-bore aspiration portal vein thrombectomy is feasible for PMVT.

A Cofactor-Based Mechanism for the Origin of the Genetic Code.

The origin of the genetic code is probably the central problem of the studies on the origin of life. The key question to answer is the molecular mechanism that allows the association of the amino acids with their triplet codons. We proposed that the codon-anticodon duplex located in the acceptor stem of primitive tRNAs would facilitate the chemical reactions required to synthesize cognate amino acids from simple amino acids (glycine, valine, and aspartic acid) linked to the 3' acceptor end. In our view, various nucleotide-A-derived cofactors (with reactive chemical groups) may be attached to the codon-anticodon duplex, which allows group-transferring reactions from cofactors to simple amino acids, thereby producing the final amino acid. The nucleotide-A-derived cofactors could be incorporated into the RNA duplex (helix) by docking Adenosine (cofactor) into the minor groove via an interaction similar to the A-minor motif, forming a base triple between Adenosine and one complementary base pair of the duplex. Furthermore, we propose that this codon-anticodon duplex could initially catalyze a self-aminoacylation reaction with a simple amino acid. Therefore, the sequence of bases in the codon-anticodon duplex would determine the reactions that occurred during the formation of new amino acids for selective binding of nucleotide-A-derived cofactors.

Filter-Assisted Shunt Embolization of Large Portosystemic Shunts: Technical Feasibility, Safety, and Outcomes.

PURPOSE: To describe the feasibility and outcomes of filter-assisted shunt embolization in patients with acquired large portosystemic shunts. METHODS: Two-center HIPAA compliant retrospective study of all patients who underwent filter-assisted shunt embolization between 03/2015-03/2021. Initial clinical evaluation, including demographic information, shunt sizing, and procedural details, was reviewed. Technical success was defined as successful occlusion of the targeted shunt. RESULTS: Eight patients (55 ± 10 years/88% male) had a large acquired portosystemic shunt which was suitable for filter-assisted shunt embolization. Indications for the procedure: 3 = pre-transplantation optimization, 2 = overt hepatic encephalopathy (HE), 1 = post-transplant thrombosis, 1 = portal vein thrombosis and encephalopathy, 1 = encephalopathy and variceal bleeding. Portosystemic shunts occurred between splenic and renal veins, inferior mesenteric and gonadal veins, and coronary veins. Mean shunt diameter was 27 ± 5 mm. The technical success of the procedure was 8/8 (100%). In 7 patients, a transjugular intrahepatic portosystemic shunt (TIPS) was also placed at the time of the shunt embolization due to either pre-transplant indication or sluggish portal flow. There were no intraprocedural complications from filter placement. OUTCOMES: 3 = currently listed for transplant, 2 = resolution of HE, 1 = made CMO, 1 patient with patent post-transplant vasculature. 1 = died as a complication related to TIPS placement (SIR Class F Complication). CONCLUSION: Filter-assisted shunt embolization is a technically feasible and safe technique to reduce or embolize large portosystemic shunts.

Neurosurgery in a patient with severe hemophilia B: an experience using eftrenonacog alfa as perioperative management.

Extended half-life FIX (EHL-FIX) concentrates have been developed with the purpose of reducing the frequency of infusions in patients with severe or moderate hemophilia B. We describe the case of a 63-year-old patient with severe hemophilia B (sHB) treated with FIX-Fc fusion protein (rFIXFc) who underwent neurosurgery.

A semi-industrial scale AnMBR for municipal wastewater treatment at ambient temperature: performance of the biological process.

A semi-industrial scale AnMBR plant was operated for more than 600 days to evaluate the long-term operation of this technology at ambient temperature (ranging from 10 to 27 ○C), variable hydraulic retention times (HRT) (from 25 to 41 h) and influent loads (mostly between 15 and 45 kg COD·d-1). The plant was fed with sulfate-rich high-loaded municipal wastewater from the pre-treatment of a full-scale WWTP. The results showed promising AnMBR performance as the core technology for wastewater treatment, obtaining an average 87.2 ± 6.1 % COD removal during long-term operation, with 40 % of the data over 90%. Five periods were considered to evaluate the effect of HRT, influent characteristics, COD/SO42--S ratio and temperature on the biological process. In the selected periods, methane yields varied from 70.2±36.0 to 169.0±95.1 STP L CH4·kg-1 CODinf, depending on the influent sulfate concentration, and wasting sludge production was reduced by between 8 % and 42 % compared to conventional activated sludge systems. The effluent exhibited a significant nutrient recovery potential. Temperature, HRT, SRT and influent COD/SO42--S ratio were corroborated as crucial parameters to consider in maximizing AnMBR performance.

A cloud-based platform to predict wind pressure coefficients on buildings.

Natural ventilation (NV) is a key passive strategy to design energy-efficient buildings and improve indoor air quality. Therefore, accurate modeling of the NV effects is a basic requirement to include this technique during the building design process. However, there is an important lack of wind pressure coefficients (C p ) data, essential input parameters for NV models. Besides this, there are no simple but still reliable tools to predict C p data on buildings with arbitrary shapes and surrounding conditions, which means a significant limitation to NV modeling in real applications. For this reason, the present contribution proposes a novel cloud-based platform to predict wind pressure coefficients on buildings. The platform comprises a set of tools for performing fully unattended computational fluid dynamics (CFD) simulations of the atmospheric boundary layer and getting reliable C p data for actual scenarios. CFD-expert decisions throughout the entire workflow are implemented to automatize the generation of the computational domain, the meshing procedure, the solution stage, and the post-processing of the results. To evaluate the performance of the platform, an exhaustive validation against wind tunnel experimental data is carried out for a wide range of case studies. These include buildings with openings, balconies, irregular floor-plans, and surrounding urban environments. The C p results are in close agreement with experimental data, reducing 60%-77% the prediction error on the openings regarding the EnergyPlus software. The platform introduced shows being a reliable and practical C p data source for NV modeling in real building design scenarios. Electronic Supplementary Material ESM: The appendix is available in the online version of this article at 10.1007/s12273-021-0881-9.

A Multiscale Approach for the Numerical Simulation of Turbulent Flows with Droplets.

A multiscale approach for the detailed simulation of water droplets dispersed in a turbulent airflow is presented. The multiscale procedure combines a novel representative volume element (RVE) with the Pseudo Direct Numerical Simulation (P-DNS) method. The solution at the coarse-scale relies on a synthetic model, constructed using precomputed offline RVE simulations and an alternating digital tree, to characterize the non-linear dynamic response at the fine-scale. A set of numerical experiments for a wide range of volume fractions, particle distribution sizes, and external shear forces in the RVE are carried out. Quantitative results of the statistically stationary turbulent state are obtained, and the turbulence modulation phenomenon due to the presence of droplets is discussed. The developed synthetic model is then employed to solve global scale simulations of flows with airborne droplets via the P-DNS method. Improved predictions are obtained for flow conditions where turbulence modulation is noticeable.

Possible Ancestral Functions of the Genetic and RNA Operational Precodes and the Origin of the Genetic System.

The origin of genetic systems is the central problem in the study of the origin of life for which various explanatory hypotheses have been presented. One model suggests that both ancestral transfer ribonucleic acid (tRNA) molecules and primitive ribosomes were originally involved in RNA replication (Campbell 1991). According to this model the early tRNA molecules catalyzed their own self-loading with a trinucleotide complementary to their anticodon triplet, while the primordial ribosome (protoribosome) catalyzed the transfer of these terminal trinucleotides from one tRNA to another tRNA harboring the growing RNA polymer at the 3´-end.Here we present the notion that the anticodon-codon-like pairs presumably located in the acceptor stem of primordial tRNAs (Rodin et al. 1996) (thus being and remaining, after the code and translation origins, the major contributor to the RNA operational code (Schimmel et al. 1993)) might have originally been used for RNA replication rather than translation; these anticodon and acceptor stem triplets would have been involved in accurately loading the 3'-end of tRNAs with a trinucleotide complementary to their anticodon triplet, thus allowing the accurate repair of tRNAs for their use by the protoribosome during RNA replication.We propose that tRNAs could have catalyzed their own trinucleotide self-loading by forming catalytic tRNA dimers which would have had polymerase activity. Therefore, the loading mechanism and its evolution may have been a basic step in the emergence of new genetic mechanisms such as genetic translation. The evolutionary implications of this proposed loading mechanism are also discussed.

His452Tyr polymorphism in the human 5-HT2A receptor affects clozapine-induced signaling networks revealed by quantitative phosphoproteomics.

Antipsychotic drugs remain the current standard for schizophrenia treatment. Although they directly recognize the orthosteric binding site of numerous monoaminergic G protein-coupled receptors (GPCRs), these drugs, and particularly second-generation antipsychotics such as clozapine, all have in common a very high affinity for the serotonin 5-HT2A receptor (5-HT2AR). Using classical pharmacology and targeted signaling pathway assays, previous findings suggest that clozapine and other atypical antipsychotics behave principally as 5-HT2AR neutral antagonists and/or inverse agonists. However, more recent findings showed that antipsychotics may also behave as pathway-specific agonists. Reversible phosphorylation is a common element in multiple signaling networks. Combining a quantitative phosphoproteomic method with signaling network analysis, we tested the effect of clozapine treatment on the overall level of protein phosphorylation and signal transduction cascades in vitro in mammalian cell lines induced to express either the human 5-HT2AR or the H452Y variant of the gene encoding the 5-HT2AR receptor. This naturally occurring variation within the 5-HT2AR gene was selected because it has been repeatedly associated with schizophrenia patients who do not respond to clozapine treatment. Our data show that short time exposure (5 or 10 min) to clozapine (10-5 M) led to phosphorylation of numerous signaling components of pathways involved in processes such as endocytosis, ErbB signaling, insulin signaling or estrogen signaling. Cells induced to express the H452Y variant showed a different basal phosphoproteome, with increases in the phosphorylation of mTOR signaling components as a translationally relevant example. However, the effect of clozapine on the functional landscape of the phosphoproteome was significantly reduced in cells expressing the 5-HT2AR-H452Y construct. Together, these findings suggest that clozapine behaves as an agonist inducing phosphorylation of numerous pathways downstream of the 5-HT2AR, and that the single nucleotide polymorphism encoding 5-HT2AR-H452Y affects these clozapine-induced phosphorylation-dependent signaling networks.