Enhanced potency of an IgM-like nanobody targeting conserved epitope in SARS-CoV-2 spike N-terminal domain.

Almost all the neutralizing antibodies targeting the receptor-binding domain (RBD) of spike (S) protein show weakened or lost efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged or emerging variants, such as Omicron and its sub-variants. This suggests that highly conserved epitopes are crucial for the development of neutralizing antibodies. Here, we present one nanobody, N235, displaying broad neutralization against the SARS-CoV-2 prototype and multiple variants, including the newly emerged Omicron and its sub-variants. Cryo-electron microscopy demonstrates N235 binds a novel, conserved, cryptic epitope in the N-terminal domain (NTD) of the S protein, which interferes with the RBD in the neighboring S protein. The neutralization mechanism interpreted via flow cytometry and Western blot shows that N235 appears to induce the S1 subunit shedding from the trimeric S complex. Furthermore, a nano-IgM construct (MN235), engineered by fusing N235 with the human IgM Fc region, displays prevention via inducing S1 shedding and cross-linking virus particles. Compared to N235, MN235 exhibits varied enhancement in neutralization against pseudotyped and authentic viruses in vitro. The intranasal administration of MN235 in low doses can effectively prevent the infection of Omicron sub-variant BA.1 and XBB in vivo, suggesting that it can be developed as a promising prophylactic antibody to cope with the ongoing and future infection.

Molecular basis of hippopotamus ACE2 binding to SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a wide range of hosts, including hippopotami, which are semi-aquatic mammals and phylogenetically closely related to Cetacea. In this study, we characterized the binding properties of hippopotamus angiotensin-converting enzyme 2 (hiACE2) to the spike (S) protein receptor binding domains (RBDs) of the SARS-CoV-2 prototype (PT) and variants of concern (VOCs). Furthermore, the cryo-electron microscopy (cryo-EM) structure of the SARS-CoV-2 PT S protein complexed with hiACE2 was resolved. Structural and mutational analyses revealed that L30 and F83, which are specific to hiACE2, played a crucial role in the hiACE2/SARS-CoV-2 RBD interaction. In addition, comparative and structural analysis of ACE2 orthologs suggested that the cetaceans may have the potential to be infected by SARS-CoV-2. These results provide crucial molecular insights into the susceptibility of hippopotami to SARS-CoV-2 and suggest the potential risk of SARS-CoV-2 VOCs spillover and the necessity for surveillance. IMPORTANCE: The hippopotami are the first semi-aquatic artiodactyl mammals wherein SARS-CoV-2 infection has been reported. Exploration of the invasion mechanism of SARS-CoV-2 will provide important information for the surveillance of SARS-CoV-2 in hippopotami, as well as other semi-aquatic mammals and cetaceans. Here, we found that hippopotamus ACE2 (hiACE2) could efficiently bind to the RBDs of the SARS-CoV-2 prototype (PT) and variants of concern (VOCs) and facilitate the transduction of SARS-CoV-2 PT and VOCs pseudoviruses into hiACE2-expressing cells. The cryo-EM structure of the SARS-CoV-2 PT S protein complexed with hiACE2 elucidated a few critical residues in the RBD/hiACE2 interface, especially L30 and F83 of hiACE2 which are unique to hiACE2 and contributed to the decreased binding affinity to PT RBD compared to human ACE2. Our work provides insight into cross-species transmission and highlights the necessity for monitoring host jumps and spillover events on SARS-CoV-2 in semi-aquatic/aquatic mammals.

Structural basis for the immune recognition and selectivity of the immune receptor PVRIG for ligand Nectin-2.

Nectin and nectin-like (Necl) co-receptor axis, comprised of receptors DNAM-1, TIGIT, CD96, PVRIG, and nectin/Necl ligands, is gaining prominence in immuno-oncology. Within this axis, the inhibitory receptor PVRIG recognizes Nectin-2 with high affinity, but the underlying molecular basis remains unknown. By determining the crystal structure of PVRIG in complex with Nectin-2, we identified a unique CC' loop in PVRIG, which complements the double-lock-and-key binding mode and contributes to its high affinity for Nectin-2. The association of the corresponding charged residues in the F-strands explains the ligand selectivity of PVRIG toward Nectin-2 but not for Necl-5. Moreover, comprehensive comparisons of the binding capacities between co-receptors and ligands provide innovative insights into the intra-axis immunoregulatory mechanism. Taken together, these findings broaden our understanding of immune recognition and regulation mediated by nectin/Necl co-receptors and provide a rationale for the development of immunotherapeutic strategies targeting the nectin/Necl axis.

Computational Screening of Promising Deep-Ultraviolet Light Emitters.

Deep-ultraviolet (DUV) light sources are technologically highly important, but DUV light-emitting materials are extremely rare; AlN and its alloys are the only materials known so far, significantly limiting the chemical and structural spaces for materials design. Here, we perform a high-throughput computational search for DUV light emitters based on a set of carefully designed screening criteria relating to the sophisticated electronic structure. In this way, we successfully identify 5 promising material candidates that exhibit comparable or higher radiative recombination coefficients than AlN, including BeGeN2, Mg3NF3, KCaBr3, KHS, and RbHS. Further, we unveil the unique features in the atomic and electronic structures of DUV light emitters and elucidate the fundamental genetic reasons why DUV light emitters are extremely rare. Our study not only guides the design and synthesis of efficient DUV light emitters but also establishes the genetic nature of ultrawide-band-gap semiconductors in general.

Small apes adjust rhythms to facilitate song coordination.

Song coordination is a universal characteristic of human music. Many animals also produce well-coordinated duets or choruses that resemble human music. However, the mechanism and evolution of song coordination have only recently been studied in animals. Here, we studied the mechanism of song coordination in three closely related species of wild Nomascus gibbons that live in polygynous groups. In each species, song bouts were dominated by male solo sequences (referred to hereafter as male sequence), and females contributed stereotyped great calls to coordinate with males. Considering the function of rhythm in facilitating song coordination in human music and animal vocalizations, we predicted that adult males adjust their song rhythm to facilitate song coordination with females. In support of this prediction, we found that adult males produced significantly more isochronous rhythms with a faster tempo in male sequences that were followed by successful female great calls (a complete sequence with "introductory" and "wa" notes). The difference in isochrony and tempos between successful great call sequences and male sequences was smaller in N. concolor compared with the other two species, which may make it difficult for females to predict a male's precise temporal pattern. Consequently, adult females of N. concolor produced more failed great call (an incomplete sequence with only introductory notes) sequences. We propose that the high degree of rhythm change functions as an unambiguous signal that can be easily perceived by receivers. In this regard, gibbon vocalizations offer an instructive model to understand the origins and evolution of human music.

Rational design of a 'two-in-one' immunogen DAM drives potent immune response against mpox virus.

The global outbreak of the mpox virus (MPXV) in 2022 highlights the urgent need for safer and more accessible new-generation vaccines. Here, we used a structure-guided multi-antigen fusion strategy to design a 'two-in-one' immunogen based on the single-chain dimeric MPXV extracellular enveloped virus antigen A35 bivalently fused with the intracellular mature virus antigen M1, called DAM. DAM preserved the natural epitope configuration of both components and showed stronger A35-specific and M1-specific antibody responses and in vivo protective efficacy against vaccinia virus (VACV) compared to co-immunization strategies. The MPXV-specific neutralizing antibodies elicited by DAM were 28 times higher than those induced by live VACV vaccine. Aluminum-adjuvanted DAM vaccines protected mice from a lethal VACV challenge with a safety profile, and pilot-scale production confirmed the high yield and purity of DAM. Thus, our study provides innovative insights and an immunogen candidate for the development of alternative vaccines against MPXV and other orthopoxviruses.

Defining a de novo non-RBM antibody as RBD-8 and its synergistic rescue of immune-evaded antibodies to neutralize Omicron SARS-CoV-2.

Currently, monoclonal antibodies (MAbs) targeting the SARS-CoV-2 receptor binding domain (RBD) of spike (S) protein are classified into seven classes based on their binding epitopes. However, most of these antibodies are seriously impaired by SARS-CoV-2 Omicron and its subvariants, especially the recent BQ.1.1, XBB and its derivatives. Identification of broadly neutralizing MAbs against currently circulating variants is imperative. In this study, we identified a "breathing" cryptic epitope in the S protein, named as RBD-8. Two human MAbs, BIOLS56 and IMCAS74, were isolated recognizing this epitope with broad neutralization abilities against tested sarbecoviruses, including SARS-CoV, pangolin-origin coronaviruses, and all the SARS-CoV-2 variants tested (Omicron BA.4/BA.5, BQ.1.1, and XBB subvariants). Searching through the literature, some more RBD-8 MAbs were defined. More importantly, BIOLS56 rescues the immune-evaded antibody, RBD-5 MAb IMCAS-L4.65, by making a bispecific MAb, to neutralize BQ.1 and BQ.1.1, thereby producing an MAb to cover all the currently circulating Omicron subvariants. Structural analysis reveals that the neutralization effect of RBD-8 antibodies depends on the extent of epitope exposure, which is affected by the angle of antibody binding and the number of up-RBDs induced by angiotensin-converting enzyme 2 binding. This cryptic epitope which recognizes non- receptor binding motif (non-RBM) provides guidance for the development of universal therapeutic antibodies and vaccines against COVID-19.

Enhancing the Piezoelectric Properties of 3D Printed PVDF Using Concurrent Torsional Shear Strain.

Extrusion-based polymer 3D printing induces shear strains within the material, influencing its rheological and mechanical properties. In materials like polyvinylidene difluoride (PVDF), these strains stretch polymer chains, leading to increased crystallinity and improved piezoelectric properties. This study demonstrates a 400% enhancement in the piezoelectric property of extrusion-printed PVDF by introducing additional shear strains during the printing process. The continuous torsional shear strains, imposed via a rotating extrusion nozzle, results in additional crystalline ß-phases, directly impacting the piezoelectric behavior of the printed parts. The effect of the nozzle's rotational speed on the amount of ß-phase formation is characterized using FTIR. This research introduces a new direction in the development of polymer and composite 3D printing, where in-process shear strains are used to control the alignment of polymer chains and/or in-fill phases and the overall properties of printed parts.

Cross-species recognition of bat coronavirus RsYN04 and cross-reaction of SARS-CoV-2 antibodies against the virus.

Following the outbreak of coronavirus disease 2019 (COVID-19), several severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related coronaviruses have been discovered. Previous research has identified a novel lineage of SARS-CoV-2-related CoVs in bats, including RsYN04, which recognizes human angiotensin-converting enzyme 2 (ACE2) and thus poses a potential threat to humans. Here, we screened the binding of the RsYN04 receptor-binding domain (RBD) to ACE2 orthologs from 52 animal species and found that the virus showed a narrower ACE2-binding spectrum than SARS-CoV-2. However, the presence of the T484W mutation in the RsYN04 RBD broadened its range. We also evaluated 44 SARS-CoV-2 antibodies targeting seven epitope communities in the SARS-CoV-2 RBD, together with serum obtained from COVID-19 convalescents and vaccinees, to determine their cross-reaction against RsYN04. Results showed that no antibodies, except for the RBD-6 and RBD-7 classes, bound to the RsYN04 RBD, indicating substantial immune differences from SARS-CoV-2. Furthermore, the structure of the RsYN04 RBD in complex with cross-reactive antibody S43 in RBD-7 revealed a potently broad epitope for the development of therapeutics and vaccines. Our findings suggest RsYN04 and other viruses belonging to the same clade have the potential to infect several species, including humans, highlighting the necessity for viral surveillance and development of broad anti-coronavirus countermeasures.

Broad protective RBD heterotrimer vaccines neutralize SARS-CoV-2 including Omicron sub-variants XBB/BQ.1.1/BF.7.

SARS-CoV-2 variants with severe immune evasion are a major challenge for COVID-19 prevention, especially the circulating Omicron XBB/BQ.1.1/BF.7 strains. Thus, the next-generation of broad-spectrum vaccines are urgently needed. Previously, we developed a COVID-19 protein subunit vaccine, ZF2001, based on the RBD-homodimer as the immunogen. To adapt SARS-CoV-2 variants, we developed chimeric RBD-heterodimers to induce broad immune responses. In this study, we further explored the concept of tandem RBD homotrimer and heterotrimer. Prototype SARS-CoV-2 RBD-homotrimer, prototype-Delta-BA.1 (PDO) RBD-heterotrimer and Delta-BA.2-BA.5 (DBA2BA5) RBD-heterotrimer were designed. Biochemical and cryo-EM structural characterization demonstrated total epitope exposure of the RBD-trimers. In mouse experiments, PDO and DBA2BA5 elicited broad SARS-CoV-2 neutralization. Potent protection against SARS-CoV-2 variants was observed in challenge assays and was correlated with neutralizing antibody titer. This study validated the design strategy of tandem RBD-heterotrimers as multivalent immunogens and presented a promising vaccine candidate, DBA2BA5, eliciting broad-spectrum immune responses, including against the circulating XBB/BF.7/BQ.1.1.

Structural basis of white-tailed deer, Odocoileus virginianus, ACE2 recognizing all the SARS-CoV-2 variants of concern with high affinity.

SARS-CoV-2 has been expanding its host range, among which the white-tailed deer (WTD), Odocoileus virginianus, became the first wildlife species infected on a large scale and might serve as a host reservoir for variants of concern (VOCs) in case no longer circulating in humans. In this study, we comprehensively assessed the binding of the WTD angiotensin-converting enzyme 2 (ACE2) receptor to the spike (S) receptor-binding domains (RBDs) from the SARS-CoV-2 prototype (PT) strain and multiple variants. We found that WTD ACE2 could be broadly recognized by all of the tested RBDs. We further determined the complex structures of WTD ACE2 with PT, Omicron BA.1, and BA.4/5 S trimer. Detailed structural comparison revealed the important roles of RBD residues on 486, 498, and 501 sites for WTD ACE2 binding. This study deepens our understanding of the interspecies transmission mechanisms of SARS-CoV-2 and further addresses the importance of constant monitoring on SARS-CoV-2 infections in wild animals. IMPORTANCE Even if we manage to eliminate the virus among humans, it will still circulate among wildlife and continuously be transmitted back to humans. A recent study indicated that WTD may serve as reservoir for nearly extinct SARS-CoV-2 strains. Therefore, it is critical to evaluate the binding abilities of SARS-CoV-2 variants to the WTD ACE2 receptor and elucidate the molecular mechanisms of binding of the RBDs to assess the risk of spillback events.

Interface Healing Between Adjacent Tracks in Fused Filament Fabrication Using In-Process Laser Heating.

Fused filament fabrication is one of the most desired thermal plastic additive manufacturing processes because of its ability to fabricate complex objects with high accessibility. However, due to the extrusion track-based direct write process mechanism, parts built using this method exhibit anisotropic mechanical properties. In this work, an in-process laser heating method is introduced to heal interface adhesion between adjacent deposited tracks by increasing the interface temperature to promote polymer reptation and enhance bonding strength of the interface of adjacent tracks. With the use of laser heating induced interface healing, the measured flexural strength between adjacent tracks in the same layer increased and exceeded that of the control sample tested along the track direction. The effect of laser on interface healing was also verified by investigating the load-displacement curve and morphology analysis of the fractured surface.

Rational design of an influenza-COVID-19 chimeric protective vaccine with HA-stalk and S-RBD.

Highly contagious respiratory illnesses like influenza and COVID-19 pose serious risks to public health. A two-in-one vaccine would be ideal to avoid multiple vaccinations for these diseases. Here, we generated a chimeric receptor binding domain of the spike protein (S-RBD) and hemagglutinin (HA)-stalk-based vaccine for both SARS-CoV-2 and influenza viruses. The S-RBD from SARS-CoV-2 Delta was fused to the headless HA from H1N1 (H1Delta), creating a chimera that forms trimers in solution. The cryo-electron microscopy structure of the chimeric protein complexed with the RBD-targeting CB6 and the HA-stalk-targeting CR9114 antibodies shows that the trimeric protein is stable and accessible for neutralizing antibody binding. Immunization with the vaccine elicited high and long-lasting neutralizing antibodies and effectively protected mice against the challenges of lethal H1N1 or heterosubtypic H5N8, as well as the SARS-CoV-2 Delta or Omicron BA.2 variants. Overall, this study offers a two-in-one universal vaccine design to combat infections caused by both SARS-CoV-2 variants of concern and influenza viruses.

Phase 1 dose-escalation study to evaluate the safety, tolerability, pharmacokinetics, and anti-tumor activity of FCN-159 in adults with neurofibromatosis type 1-related unresectable plexiform neurofibromas.

BACKGROUND: Surgery is a common treatment strategy for patients with neurofibromatosis type 1 (NF1)-related plexiform neurofibroma (PN) and has limited efficacy. FCN-159 is a novel anti-tumorigenic drug via selective inhibition of MEK1/2. This study assesses the safety and efficacy of FCN-159 in patients with NF1-related PN. METHODS: This is a multicenter, open-label, single-arm, phase I dose-escalation study. Patients with NF1-related PN that was non-resectable or unsuitable for surgery were enrolled; they received FCN-159 monotherapy daily in 28-day cycles. RESULTS: Nineteen adults were enrolled in the study, 3 in 4 mg, 4 in 6 mg, 8 in 8 mg, and 4 in 12 mg. Among patients included in dose-limiting toxicity (DLT) analysis, DLTs (grade 3 folliculitis) were reported in 1 of 8 patients (16.7%) receiving 8 mg and 3 of 3 (100%) patients receiving 12 mg. The maximum tolerated dose was determined to be 8 mg. FCN-159-related treatment-emergent adverse events (TEAEs) were observed in 19 patients (100%); most of which were grade 1 or 2. Nine (47.4%) patients reported grade 3 study-drug-related TEAEs across all dose levels, including four experiencing paronychia and five experiencing folliculitis. Of the 16 patients analyzed, all (100%) had reduced tumor size and six (37.5%) achieved partial responses; the largest reduction in tumor size was 84.2%. The pharmacokinetic profile was approximately linear between 4 and 12 mg, and the half-life supported once daily dosing. CONCLUSIONS: FCN-159 was well tolerated up to 8 mg daily with manageable adverse events and showed promising anti-tumorigenic activity in patients with NF1-related PN, warranting further investigation in this indication. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04954001. Registered 08 July 2021.

Research on named entity recognition of adverse drug reactions based on NLP and deep learning.

Introduction: Adverse drug reactions (ADR) are directly related to public health and become the focus of public and media attention. At present, a large number of ADR events have been reported on the Internet, but the mining and utilization of such information resources is insufficient. Named entity recognition (NER) is the basic work of many natural language processing (NLP) tasks, which aims to identify entities with specific meanings from natural language texts. Methods: In order to identify entities from ADR event data resources more effectively, so as to provide valuable health knowledge for people, this paper introduces ALBERT in the input presentation layer on the basis of the classic BiLSTM-CRF model, and proposes a method of ADR named entity recognition based on the ALBERT-BiLSTM-CRF model. The textual information about ADR on the website "Chinese medical information query platform" (https://www.dayi.org.cn) was collected by the crawler and used as research data, and the BIO method was used to label three types of entities: drug name (DRN), drug component (COM), and adverse drug reactions (ADR) to build a corpus. Then, the words were mapped to the word vector by using the ALBERT module to obtain the character level semantic information, the context coding was performed by the BiLSTM module, and the label decoding was using the CRF module to predict the real label. Results: Based on the constructed corpus, experimental comparisons were made with two classical models, namely, BiLSTM-CRF and BERT-BiLSTM-CRF. The experimental results show that the F 1 of our method is 91.19% on the whole, which is 1.5% and 1.37% higher than the other two models respectively, and the performance of recognition of three types of entities is significantly improved, which proves the superiority of this method. Discussion: The method proposed can be used effectively in NER from ADR information on the Internet, which provides a basis for the extraction of drug-related entity relationships and the construction of knowledge graph, thus playing a role in practical health systems such as intelligent diagnosis, risk reasoning and automatic question answering.

In-Process Orbiting Laser-Assisted Technique for the Surface Finish in Material Extrusion-Based 3D Printing.

Material extrusion-based polymer 3D printing, one of the most commonly used additive manufacturing processes for thermoplastics and composites, has drawn extensive attention due to its capability and cost effectiveness. However, the low surface finish quality of the printed parts remains a drawback due to the nature of stacking successive layers along one direction and the nature of rastering of the extruded tracks of material. In this work, an in-process thermal radiation-assisted, surface reflow method is demonstrated that significantly improves the surface finish of the sidewalls of printed parts. It is observed that the surface finish of the printed part is drastically improved for both flat and curved surfaces. The effect of surface reflow on roughness reduction was characterized using optical profilometry and scanning electron microscopy (SEM), while the local heated spot temperature was quantified using a thermal camera.

Design and Application of Vague Set Theory and Adaptive Grid Particle Swarm Optimization Algorithm in Resource Scheduling Optimization.

The purpose of resource scheduling is to deal with all kinds of unexpected events that may occur in life, such as fire, traffic jam, earthquake and other emergencies, and the scheduling algorithm is one of the key factors affecting the intelligent scheduling system. In the traditional resource scheduling system, because of the slow decision-making, it is difficult to meet the needs of the actual situation, especially in the face of emergencies, the traditional resource scheduling methods have great disadvantages. In order to solve the above problems, this paper takes emergency resource scheduling, a prominent scheduling problem, as an example. Based on Vague set theory and adaptive grid particle swarm optimization algorithm, a multi-objective emergency resource scheduling model is constructed under different conditions. This model can not only integrate the advantages of Vague set theory in dealing with uncertain problems, but also retain the advantages of adaptive grid particle swarm optimization that can solve multi-objective optimization problems and can quickly converge. The research results show that compared with the traditional resource scheduling optimization algorithm, the emergency resource scheduling model has higher resolution accuracy, more reasonable resource allocation, higher efficiency and faster speed in dealing with emergency events than the traditional resource scheduling model. Compared with the conventional fuzzy theory emergency resource scheduling model, its handling speed has increased by more than 3.82 times.

De novo design of protein interactions with learned surface fingerprints.

Physical interactions between proteins are essential for most biological processes governing life1. However, the molecular determinants of such interactions have been challenging to understand, even as genomic, proteomic and structural data increase. This knowledge gap has been a major obstacle for the comprehensive understanding of cellular protein-protein interaction networks and for the de novo design of protein binders that are crucial for synthetic biology and translational applications2-9. Here we use a geometric deep-learning framework operating on protein surfaces that generates fingerprints to describe geometric and chemical features that are critical to drive protein-protein interactions10. We hypothesized that these fingerprints capture the key aspects of molecular recognition that represent a new paradigm in the computational design of novel protein interactions. As a proof of principle, we computationally designed several de novo protein binders to engage four protein targets: SARS-CoV-2 spike, PD-1, PD-L1 and CTLA-4. Several designs were experimentally optimized, whereas others were generated purely in silico, reaching nanomolar affinity with structural and mutational characterization showing highly accurate predictions. Overall, our surface-centric approach captures the physical and chemical determinants of molecular recognition, enabling an approach for the de novo design of protein interactions and, more broadly, of artificial proteins with function.

Population pharmacokinetics of FCN-159, a MEK1/2 inhibitor, in adult patients with advanced melanoma and neurofibromatosis type 1 (NF1) and model informed dosing recommendations for NF1 pediatrics.

Objective: FCN-159 is a highly active mitogen-activated extracellular signal-regulated kinase 1/2 (MEK1/2) inhibitor in patients with advanced melanoma and neurofibromatosis type 1 (NF1). We report a population pharmacokinetic (PopPK) model-based analysis of FCN-159 and its application to inform dose selection for NF1 pediatric trials. Methods: PK data collected from patients with advanced melanoma and NF1 in two clinical studies (NCT03932253 and NCT04954001) were analyzed using a non-linear mixed effects model. The adult model was adapted by incorporating allometric scaling for PK projection in 2-17 years old children. Pediatric exposure in different body surface area (BSA) bins was simulated to identify nominal doses (i.e., dose amounts given as integers) and BSA bin cutoffs to achieve exposure comparable to adults' optimal exposure across the entire pediatric BSA range. Results: The final dataset consisted of 45 subjects with a total of 1030 PK samples. The PK of FCN-159 was well-described by a 2-compartment model with first-order linear elimination and delayed first-order absorption. Covariates, including BSA, age, sex, albumin, total protein, and cancer type, were identified as statistically significant predictors of FCN-159 disposition. Simulations based on the final model projected daily doses of 4 mg/m2 QD with optimized BSA bin cutoffs would allow fixed nominal doses within each bin and result in steady state exposure approximating the adult exposure observed at the recommended phase 2 dose (RP2D) in NF1, which is 8 mg QD. Conclusion: The developed population PK model adequately described the PK profile of FCN-159, which was adapted using allometric scaling to inform dose selection for NF1 pediatric trials.