Purpose:To clarify how cardiopulmonary bypass (CPB) affects perioperative immune cell populations and how these changes are associated with postoperative organ dysfunction. Methods:We prospectively recruited 60 consecutive patients who underwent CPB as part of elective valvular surgery and/or coronary artery bypass grafting at our center. Peripheral blood samples were collected before surgery, during rewarming, at the end of CPB, and 24 h after surgery. The populations of neutrophils, monocytes, natural killer (NK) cells, T cells, and B cells were analyzed using flow cytometry, and changes were compared between patients with and without major adverse postoperative events (MAEs) within 30 days after surgery. MAEs included acute kidney injury, neurological dysfunction, liver injury, cardiovascular complications, and respiratory dysfunction. Results:Of the 60 patients analyzed, 10 (16.7%) developed MAEs. CPB was associated with marked perioperative immune changes, with leukocyte and neutrophil counts peaking at 24 h after surgery, whereas lymphocyte counts declined and reached their nadir at the same time point. During rewarming, patients with MAEs had higher proportions of CD56dimCD314⁺ NK cells (96.74 ± 2.41 vs. 88.41 ± 11.75%, P = 0.035) and CD284⁺ non-classical monocytes (71.36 ± 17.95 vs. 49.13 ± 22.42%, P = 0.006), but lower proportions of CD163⁺ classical monocytes (69.46 ± 27.59 vs. 85.04 ± 15.53%, P = 0.035) and CD45RO⁺ T cells (35.62 ± 6.93 vs. 43.22 ± 11.66%, P = 0.023). At the end of CPB, patients with MAEs had higher proportions of CD4⁺CD38⁺ T cells (59.16 ± 15.16 vs. 41.78 ± 18.60%, P = 0.004) and CD274⁺ unswitched memory B cells (42.69 ± 15.29 vs. 23.80 ± 15.04%, P < 0.001). Exploratory receiver operating characteristic curves (ROC) analyses provided descriptive estimates of within-cohort discrimination for several immune subpopulations. In risk-adjusted Firth penalized logistic regression, higher CD284⁺ non-classical monocytes during rewarming [adjusted odds ratio (OR) = 3.118, 95% confidence interval (CI): 1.253-11.613, P = 0.011] and higher CD274⁺ unswitched memory B cells at the end of CPB (adjusted OR=4.516, 95% CI: 1.630-19.508, P = 0.002) remained statistically associated with MAEs. Conclusion:In this single-center study, CPB was associated with dynamic perioperative immune changes, and several immune phenotypes were statistically associated with postoperative MAEs, warranting further validation in larger multicenter studies.

Triclosan (TCS), a widely used antimicrobial agent and known endocrine disruptor, is commonly found in the environment and living organisms, but its neurobehavioral toxicity mechanisms remain unclear. This study integrated computational toxicology with zebrafish experiments to evaluate TCS-induced neurotoxicity. Network toxicology and molecular docking predicted that TCS interacts with neuropsychiatric-related genes including MTOR, TNF, LEP, and NPY, which was verified by RT-qPCR showing upregulation of these genes in zebrafish larvae. In 5-dpf zebrafish larvae, TCS (300 μg/L) caused morphological abnormalities, elevated ROS levels, increased neutrophil and macrophage infiltration (Tg(mpx:EGFP) and Tg(mpeg1:mCherry)), and reduced cerebrovascular branching and vessel diameter (Tg(fli1a:EGFP)). In adult zebrafish (28-day exposure), TCS induced behavioral changes in males, including reduced social interaction (SI), decreased exploration in novel tank test (NTT), shorter center duration in open field test (OFT), and light-dark box test (LDB), accompanied by brain histopathological alterations (granule cell loss, pyknosis, and lighter Nissl staining). Fluoxetine Hydrochloride (FLX) co-treatment partially attenuated these behavioral and histological changes. Females showed similar but weaker trends. These findings indicate that TCS induces neurodevelopmental and behavioral changes in zebrafish via neuroinflammation, oxidative stress, and vascular damage. The observed effects included but were not limited to depressive-like phenotypes and might involve broader neurotoxic mechanisms. This study provided multi-level experimental evidence for TCS neurobehavioral toxicity and highlighted the need for future investigations using lower, more environmentally relevant concentrations and longer exposure designs.

OBJECTIVES:Acute kidney injury (AKI) occurs in 19-42% of patients with cardiac surgery under cardiopulmonary bypass (CPB). Clarifying their landscape of immune cells may help discover the mechanisms and thus the treatment and preventive strategies. METHODS:This prospective, single center study recruited adult patients scheduled for cardiac surgery. The primary outcome was AKI. Blood samples were harvested from the central vein for single-cell RNA sequencing, flow cytometry and protein microarrays to characterize the landscape of immune cells. Here we compared the single-cell RNA sequencing of 42,362 immune cells in the blood of 4 patients before and after cardiac surgery, depending on whether they experienced AKI or not. RESULTS:We observed an increased degree of stronger activation and cytotoxicity of CD8+ and CD4+ T cells, upregulation of CCL5 and downregulation of IL-10 in patients who experienced AKI than those who did not. Analysis of cell-to-cell communication linked AKI to greater postoperative interaction between CCL5 CD8+ T cells and CCR1 on monocytes, as well as between ICAM1 on monocytes and the complex of ITGAL and integrin β2 on T cells. Furthermore, we also found a positive association between AKI and IL-16 signal as well as stronger signaling involving macrophage migration inhibitory factor (MIF). CONCLUSIONS:To our knowledge, this is the first prospective study to integrate single-cell RNA-seq, flow cytometry, and protein microarray in cardiac surgery-related AKI. Our analysis identified distinct immune cells and identified key biomarkers, including CD69, CD28, CCL5, ICAM1, IL-16 and MIF as candidate pathway.

Background: Postoperative delirium (POD) is known to involve systemic inflammatory responses, but the characteristics of the immune cell types involved in these responses are unclear. Methods: In this prospective study, we compared relative abundances and transcriptomes of circulating immune cells between patients who experienced POD (n = 11) or not (n = 109) within 7 days after elective cardiac surgery with cardiopulmonary bypass. Blood was sampled before and at 24 h after surgery; features of immune cells were profiled using multi-channel spectral flow cytometry, 10× single-cell RNA sequencing, and measurement of plasma levels of cytokines. Results: Patients with POD were older and with higher incidence of congestive heart failure than patients without POD, and these risk factors in turn positively correlated with preoperative proportion of CD40+/HLA-DR+ monocytes and CD69+CD8+ T cells. In addition, preoperative activation of antigen presentation in monocytes and chemotaxis in CD8+ T cells, as well as elevated plasma levels of chemokines CCL3 and CXCL8, were detected in patients with POD. After cardiac surgery, activation of antigen presentation and chemotaxis were also found in patients with POD. Conclusions: This study described the perioperative landscape of immune cells in POD and found possible links between preoperative immune dysfunction and risk factors, which may guide future research to explore how the immune system contributes to POD and to design preventive strategies.

Background:Cardiopulmonary bypass (CPB) is associated with activation of pro-inflammatory cells, which infiltrate tissues and cause injury. Here we explored a novel disposable remover to remove inflammatory leukocytes in order to reduce risk of complications after CPB. This is a substudy within a previously registered clinical trial (NCT05400356) that aims to validate a novel disposable remover to remove activated leukocytes generated during CPB. Methods:The device contains an enhanced biocompatible leukocyte membrane (Chinese patent CN202310822538.X) coated with RGD peptide (Arg-Gly-Asp), which binds to specific polypeptide groups on activated leukocytes, leading to their affinity-based adsorption. The device was integrated into a closed extracorporeal circuit containing a blood reservoir, roller pump, and tubes. Blood from seven patients (150 mL per patient) was driven through the circuit for 10 min at 300 mL/min. Counts of leukocytes and their surface molecules were examined before circulation and after 2.5, 5, 7.5, and 10 min of circulation. The types and morphology of blood cells captured on the filter membrane were also examined. Results:Counts of neutrophils and neutrophils expressing the activation markers CD11b, CD54, CD64 or CD181 decreased rapidly by 36-39% during the first 2.5 min of circulation, after which their counts decreased more slowly. In contrast, counts of monocytes or lymphocytes did not change significantly during circulation. After use, the membrane was still smooth and intact, and it contained substantial numbers of intact activated leukocytes, based on immunostaining against activated cells and scanning electron microscopy. Smears of blood samples before and after circulation showed no significant differences in each leukocyte morphology. Conclusion:This novel disposable remover can preferentially remove activated neutrophils from blood ex vivo, with minimal apparent impact on other leukocytes and blood components. Trial Registration:This substudy is part of a prospective cohort study registered at the Clinical Trials Registry (NCT05400356) on 27 May 2022.

[Objective] To explore the relationship between neutrophil activation under cardiopulmonary bypass (CPB) and the incidence of cardiac surgery-associated acute kidney injury (CS-AKI). [Methods] This prospective cohort study enrolled adult patients who scheduled for cardiac surgery under CPB at West China Hospital between May 1, 2022 and March 31, 2023. The primary outcome was acute kidney injury (AKI). Blood samples (5 mL) were obtained from the central vein before surgery, at rewarming, at the end of CPB, and 24 hours after surgery. Neutrophils were labeled with CD11b, CD54 and other markers. To assess the effect of neutrophils activation on AKI, propensity score matching (PSM) was employed to equilibrate covariates between the groups. [Results] A total of 120 patients included into the study, and 17 (14.2%) developed AKI. Both CD11b+ and CD54+ neutrophils significantly increased during the rewarming phase and the increases were kept until 24 hours after surgery. During rewarming, the numbers of CD11b+ neutrophils were significantly higher in AKI compared to non-AKI (4.71×109/L vs 3.31×109/L, Z=-2.14, P<0.05). Similarly, the CD54+ neutrophils counts were also significantly higher in AKI than in non-AKI before surgery (2.75×109/L vs 1.79×109/L, Z=-2.99, P<0.05), during rewarming (3.12×109/L vs 1.62×109/L, Z=-4.34, P<0.05), and at the end of CPB (4.28×109/L vs 2.14×109/L, Z=-3.91, P<0.05). An analysis of 32 matched patients (16 in each group) revealed that CD11b+ and CD54+ neutrophil levels of AKI were 1.74 folds (4.83×109/L vs 2.77×109/L, Z=-2.72, P<0.05) and 2.34 folds (3.32×109/L vs 1.42×109/L, Z=-4.12, P<0.05), respectively, of non-AKI at rewarming phase. [Conclusion] Neutrophils are activated during CPB, and they can be identified by CD11b/CD54 markers. The activated neutrophils of AKI patients are approximately 2 folds of non-AKI during the rewarming phase, with disparity reached peak between groups during rewarming. These findings suggest the removal of 50% of activated neutrophils during the rewarming phase may be effective to reduce the risk of AKI.

Pharmacological agents regarding the most optimal treatments of acute pancreatitis remain. One-carbon metabolism nutrients as therapeutic agents in many diseases might be involved in acute pancreatitis. The roles are acquired exploration in acute pancreatitis. We utilized Mendelian randomization to assess the causal impact of folate, homocysteine, and vitamin B12 (VB12) on acute pancreatitis. Wild-type and corresponding genetically modified mouse models were used to verify the genetic correlating findings. A negative association between genetically predicted serum VB12 levels and risks of acute pancreatitis was identified in human population. The transcobalamin receptor (TCblR)/CD320 gene ablation that decreased cellular VB12 uptake and ATP production in pancreatic tissues promoted necrosis, resulting in much severe pathological changes of induced acute pancreatitis in mice. VB12 pretreatment and posttreatment dramatically increased ATP levels in pancreatic tissues and reduced the necrosis, then the elevated levels of amylase in serum, the levels of CK-19, the activity of trypsin, and T lymphocyte infiltration in pancreatic tissues, prevented the pancreatic gross loss and ameliorated histopathological changes of mouse pancreases with induced acute pancreatitis. The results reveal that VB12 is potential as a therapeutic agent to inhibit tissue injuries and adaptive inflammatory responses in the pancreas in patients with acute pancreatitis.

Previously we have identified that the expression number and levels of oncogenes and antioncogenes are highly positively or negatively associated with major cellular progress in a cancer cell. However, we have not defined any cellular potentials of a human tumor cell at the level of the overall gene expression. Here, we counted the overall number of expression genes and overall counts of mRNA in depth and revealed that the expression levels of mRNA were directly associated with the expression number of genes in a human tumor cell. Gene expression networks revealed steady states of tricarboxylic acid (TCA) cycle and ATP production, differentiation potentials that might be disturbed and blocked by uncertain gene expressing networks, and potential capabilities to undergo epithelial-mesenchymal transition (EMT), neurogenesis, angiogenesis, inflammatory response, immune evasion, and metastasis in a human tumor cell. Our analysis identifies unpredictable gene expression characteristics in human tumor cells. The results might profoundly influence mechanisms how a human tumor cell generates and undergoes its progresses.

Wnt/β-catenin signalling is aberrantly activated in most colorectal cancer (CRC) and is one key driver involved in the initiation and progression of CRC. However, mutations of APC gene in CRC patients retain certain activity of APC protein with decreased β-catenin signalling and DKK4 expression significantly upregulates and represses Wnt/β-catenin signalling in human CRC tissues, suggesting that a precisely modulated activation of the Wnt/β-catenin pathway is essential for CRC formation and progression. The underlying reasons why a specifically reduced degree, not a fully activating degree, of β-catenin signalling in CRC are unclear. Here, we showed that a soluble extracellular inhibitor of Wnt/β-catenin signalling, DKK4, is an independent factor for poor outcomes in CRC patients. DKK4 secreted from CRC cells inactivates β-catenin in fibroblasts to induce the formation of stress fibre-containing fibroblasts and myofibroblasts in culture conditions and in mouse CRC xenograft tissues, resulting in restricted expansion in tumour masses at primary sites and enhanced CRC metastasis in mouse models. Reduced β-catenin activity by a chemical inhibitor MSAB promoted the CRC metastasis. Our findings demonstrate why reduced β-catenin activity is needed for CRC progression and provide a mechanism by which interactions between CRC cells and stromal cells affect disease promotion.

BackgroundWhile a few case-control studies indicated a possible correlation of IgG N-glycosylation patterns with pancreatitis, their restricted sample sizes and methodologies prevented conclusive insights into causality or distinguishing traits across pancreatitis types.MethodWe conducted a two-sample Mendelian Randomization (MR) analysis to investigate the causal relationship between 77 IgG N-glycosylation traits and various types of pancreatitis, including acute pancreatitis (AP), chronic pancreatitis (CP), alcohol acute pancreatitis (AAP), and alcohol chronic pancreatitis (ACP). This analysis utilized summary-level data from genome-wide association studies (GWAS), employing methods such as IVW, MR-Egger, and weighted median. To ensure the robustness of our findings, several sensitivity analyses, including Cochran’s Q statistic, leave-one-out, MR-Egger intercept, and MR-PRESSO global test were conducted.ResultOur study uncovered the causal relationship between specific IgG N-glycosylation traits and various types of pancreatitis. Notably, an increase in genetically predicted IGP7 levels was associated with a decreased risk of developing AP. For CP, our data suggested a protective effect associated with higher levels of both IGP7 and IGP31, contrasting with increased levels of IGP27 and IGP65, which were linked to a heightened risk. Moreover, in the case of AAP, elevated IGP31 levels were causatively associated with a lower incidence, while higher IGP26 levels correlated with an increased risk for ACP.ConclusionThis study establishes causal relationship between specific IgG N-glycosylation patterns and varying risks of different pancreatitis forms, underscoring their potential as predictive biomarkers. These findings necessitate further exploration into the underlying mechanisms, promising to inform more personalized diagnostic and therapeutic strategies in pancreatitis management.

BackgroundGrowing evidence suggests that chronic inflammation, resulting from intricate immune system interactions, significantly contributes to the onset of psychiatric disorders. Observational studies have identified a link between immunoglobulin G (IgG) N-glycosylation and various psychiatric conditions, but the causality of these associations remains unclear.MethodsGenetic variants for IgG N-glycosylation traits and psychiatric disorders were obtained from published genome-wide association studies. The inverse-variance-weighted (IVW) method, MR-Egger, and weighted median were used to estimate causal effects. The Cochran’s Q test, MR-Egger intercept test, leave-one-out analyses, and MR-PRESSO global test were used for sensitivity analyses.ResultsIn the Psychiatric Genomics Consortium (PGC) database, genetically predicted IGP7 showed a protective role in schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP), while elevated IGP34, and IGP57 increased SCZ risk. High levels of IGP21 were associated with an increased risk of post-traumatic stress disorder (PTSD), while elevated levels of IGP22 exhibited a causal association with a decreased risk of attention-deficit/hyperactivity disorder (ADHD). No causal relationship between IgG N-glycan traits and autism spectrum disorder (ASD) and no evidence of reverse causal associations was found.ConclusionHere, we demonstrate that IgG N-glycan traits have a causal relationship with psychiatric disorders, especially IGP7’s protective role, offering new insights into their pathogenesis. Our findings suggest potential strategies for predicting and intervening in psychiatric disorder risk through IgG N-glycan traits.

AIMS:To assess the time-dependent risk of fracture in adults with type 2 diabetes receiving anti-diabetic drugs. MATERIALS AND METHODS:We searched MEDLINE, EMBASE, and Cochrane Library up to 18 November 2021, for randomized controlled trials (RCTs) and propensity-score-matched non-randomized studies (NRSs) comparing all anti-diabetic drugs with standard treatment or with each other on fracture in adults with type 2 diabetes. The study performed a one-stage network meta-analysis using discrete-time hazard regression with reconstructed individual time-to-event data. RESULTS:This network meta-analysis involved seven RCTs (65,051 adults with type 2 diabetes) with a median follow-up of 36 months and three propensity-score-based NRSs (17,954 participants) with a median follow-up of 27.3 months. Among anti-diabetic drugs, thiazolidinediones increased the overall hazard of fracture by 42% (95% credible interval [CrI], 3%-97%) and almost tripled the risk after 4 years (hazard ratio [HR], 2.74; 95% CrI, 1.53-4.80). Credible subgroup analysis suggested that thiazolidinediones increased the hazard of fracture only in females (HR, 2.19; 95% CrI, 1.26-3.74) but not among males (HR, 0.81; 95% CrI, 0.45-1.40). Moderate certainty evidence established that thiazolidinediones increase 92 fractures in five years per 1000 female patients. We did not find the risk of fractures with other anti-diabetic drugs including metformin, sulfonylureas, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors. CONCLUSIONS:Long-term use of thiazolidinediones elevates the risk of fracture among females with type 2 diabetes. There is no evidence eliciting fracture risk associated with other anti-diabetic drugs.

Background: p73, a member of the p53 family, plays diverse roles in angiogenesis and cancer progression, likely due to the heterogeneous functions of its two primary isoforms, TAp73 and DNp73. However, its impact on the endothelial trans-differentiation of colorectal cancer (CRC) stem cells (CoCSCs) remain largely uncharted.Methods: Samples and data from the Stockholm II trial, TCGA and GEO were utilized to investigate the clinical significance of p73. We employed endothelial-specific lineage tracing of CoCSCs, RNA interference, overexpression techniques, mRNA-seq, and both in vitro and in vivo assays to delve into influence of p73 on the endothelial trans-differentiation of CoCSCs, angiogenesis and tumorigenesis. A TAp73-Induced Endothelial Differentiation Signature (TapIEDS)was constructed using 101 combinations of machine-learning algorithms and screened for potential therapeutic agents specific to high TapIEDS.Findings: Unlike DNp73, TAp73 was associated with microvascular density (MVD), and the co-expression of TAp73 and MVD served as a prognostic indicator for CRC patients. Through endothelial-specific cell lineage tracing, we further validated the endothelial trans-differentiation capability of CoCSCs. During this process, TAp73 expression was higher than that of DNp73. Silencing TAp73 inhibited the trans-differentiation of CoCSCs, while its overexpression enhanced this phenotype. However, such effects were not observed with DNp73 overexpression. Xenografts derived from CoCSCs lacking TAp73 exhibited impaired tumorigenesis and reduced vasculogenic potential, originating from both pre-existing vessels and CoCSCs-induced angiogenesis. Furthermore, TAp73 acted as a key regulator of the angiogenic transcriptome during CoCSC endothelial trans-differentiation. The TapIEDS prognostic signature, based on TAp73-regulated genes in CoCSCs endothelial trans-differentiation, was identified as an independent risk factor for patient survival. Lastly, we identified potential therapeutic agents that specifically target high TapIEDS subgroups.Interpretation: Our results emphasize TAp73 pro-angiogenic role in both pre-existing vessels and CoCSCs-induced angiogenesis, which supports tumorigenesis. The overexpression of TAp73 in CRC provides a rationale for its role in the disease and highlights promising avenues for future management strategies, including targeted therapeutic interventions.Funding: This work was supported by grants from Natural Science Foundation of Sichuan Province, China (Grant No. 2022NSFSC0764), Swedish Cancer Foundation (CAN2016/341 and 190322Pj), and Oncology Clinics in Linköping (2020–0331 and 2020–1125), and the Fundamental Research Funds for the Central Universities (Grant No.2022SCU12025 and 2022SCU12020).Declaration of Interest: No potential conflicts of interest were disclosed.Ethical Approval: This study based on patients’ data was conducted in compliance with the ethical guidelines set forth by Linköping University and was approved by the Institutional Review Board (IRB) (Approval Numbers: 2012-107-31, and 2014-79-3). All experiments involving zebrafish were conducted in compliance with the regulations and policies of the Linköping University Animal Care and Use Committee (Dnrs: 104/12, 53/14, 89/15). The study involving mice received ethical approval from the Institutional Review Board of West China Hospital of Sichuan University (Approval Number: 218156A). In accordance with the Declaration of Helsinki, all participating patients provided written informed consent prior to specimen collection.

Background Clinical observation suggests the atheroprotective effect of chloroquine and its derivatives, while its mechanism remains unclear. This study aimed to observe the protective effect of chloroquine against atherosclerosis and explore the underlying mechanism.Methods Ataxia telangiectasia mutated (ATM) wild-type or haploinsufficient apolipoprotein-E-knockout (ATM(+/+)ApoE(-/-) or ATM(+/-)ApoE(-/-)) mice were treated with different dosages of chloroquine. Anti-CD25 antibody was used to deplete natural Tregs in ATM(+/+)ApoE(-/-) mice. The atherosclerotic burden in different groups of mice was comprehensively evaluated by H&E staining and Masson staining. The effect of chloroquine on the regulatory T cells (Tregs) was assessed in vivo and in vitro by flow cytometry and immunohistochemical staining. The expression of related proteins was detected by real-time polymerase chain reaction and western blotting.Results In ATM(+/+)ApoE(-/-) mice, chloroquine alleviated atherosclerotic lesions, stabilized the plaque, and increased Treg counts in the atherosclerotic lesions and spleens. However, in ATM haploinsufficient mice (ATM(+/-)ApoE(-/-)), chloroquine no longer prevented atherosclerosis or impacted Treg counts. Abolishing Treg cells using an anti-CD25 antibody in vivo abrogated the atheroprotective effect of chloroquine. In vitro, chloroquine promoted the differentiation of Tregs from na & iuml;ve T cells, which was accompanied by enhanced ATM/AMP-activated protein kinase (AMPK) activity and reduced downstream mammalian target of rapamycin (mTOR) activity.Discussion These findings suggest that chloroquine ameliorates atherosclerosis and stabilizes plaque by modulating Tregs differentiation through the regulation of the ATM/AMPK/mTOR pathway.

Here we report a new fusion gene, STRN3-RARA, in acute promyelocytic leukemia (APL). It cooperates with UTX deficiency to drive full-blown APL in mice. Although STRN3-RARA leukemia quickly relapses after all-trans retinoic acid treatment, it can be restrained by cepharanthine.

The gene expression networks of a single cell can be used to reveal cell type- and condition-specific patterns that account for cell states, cell identity, and its responses to environmental changes. We applied single cell sequencing datasets to define mRNA patterns and visualized potential cellular capacities among hepatocellular cancer cells. The expressing numbers and levels of genes were highly heterogenous among the cancer cells. The cellular characteristics were dependent strongly on the expressing numbers and levels of genes, especially oncogenes and anti-oncogenes, in an individual cancer cell. The transcriptional activations of oncogenes and anti-oncogenes were strongly linked to inherent multiple cellular programs, some of which oppose and contend against other processes, in a cancer cell. The gene expression networks of multiple cellular programs proliferation, differentiation, apoptosis, autophagy, epithelial-mesenchymal transition, ATP production, and neurogenesis coexisted in an individual cancer cell. The findings give rise a hypothesis that a cancer cell expresses balanced combinations of genes and undergoes a given biological process by rapidly transmuting gene expressing networks.

Loss of function in transport protein particles (TRAPP) links a new set of emerging genetic disorders called "TRAPPopathies". One such disorder is NIBP syndrome, characterized by microcephaly and intellectual disability, and caused by mutations of NIBP/TRAPPC9, a crucial and unique member of TRAPPII. To investigate the neural cellular/molecular mechanisms underlying microcephaly, we developed Nibp/Trappc9-deficient animal models using different techniques, including morpholino knockdown and CRISPR/Cas mutation in zebrafish and Cre/LoxP-mediated gene targeting in mice. Nibp/Trappc9 deficiency impaired the stability of the TRAPPII complex at actin filaments and microtubules of neurites and growth cones. This deficiency also impaired elongation and branching of neuronal dendrites and axons, without significant effects on neurite initiation or neural cell number/types in embryonic and adult brains. The positive correlation of TRAPPII stability and neurite elongation/branching suggests a potential role for TRAPPII in regulating neurite morphology. These results provide novel genetic/molecular evidence to define patients with a type of non-syndromic autosomal recessive intellectual disability and highlight the importance of developing therapeutic approaches targeting the TRAPPII complex to cure TRAPPopathies.