FOXO1 reshapes neutrophils to aggravate acute brain damage and promote late depression after traumatic brain injury

Background:Neutrophils are traditionally viewed as first responders but have a short onset of action in response to traumatic brain injury(TBI).However,the heterogeneity,multifunctionality,and time-dependent modulation of brain damage and outcome mediated by neutrophils after TBI remain poorly understood.Methods:Using the combined single-cell transcriptomics,metabolomics,and proteomics analysis from TBI patients and the TBI mouse model,we investigate a novel neutrophil phenotype and its associated effects on TBI outcome by neurological deficit scoring and behavioral tests.We also characterized the underlying mechanisms both invitro and invivo through molecular simulations,signaling detections,gene expression regulation assessments[including dual-luciferase reporter and chromatin immunoprecipitation(ChIP)assays],primary cultures or co-cultures of neutrophils and oligodendrocytes,intracellular iron,and lipid hydroperoxide concentration measurements,as well as forkhead box protein O1(FOXO1)conditional knockout mice.Results:We identified that high expression of the FOXO1 protein was induced in neutrophils after TBI both in TBI patients and the TBI mouse model.Infiltration of these FOXO1high neutrophils in the brain was detected not only in the acute phase but also in the chronic phase post-TBI,aggravating acute brain inflammatory damage and promoting late TBI-induced depression.In the acute stage,FOXO1 upregulated cytoplasmic Versican(VCAN)to interact with the apoptosis regulator B-cell lymphoma-2(BCL-2)-associated X protein(BAX),suppressing the mitochondrial translocation of BAX,which mediated the antiapoptotic effect companied with enhancing interleukin-6(IL-6)production of FOXO1high neutrophils.In the chronic stage,the“FOXO1-transferrin receptor(TFRC)”mechanism contributes to FOXO1high neutrophil ferroptosis,disturbing the iron homeostasis of oligodendrocytes and inducing a reduction in myelin basic protein,which contributes to the progression of late depression after TBI.Conclusions:FOXO1high neutrophils represent a novel neutrophil phenotype that emerges in response to acute and chronic TBI,which provides insight into the heterogeneity,reprogramming activity,and versatility of neutrophils in TBI.

Effects of interface adhesive and resin cohesive strength on tensile strength of resin sand based on numerical analysis

A plane-strain unit-cell finite element model was proposed to study the effects of resin/sand interface adhesive and resin cohesive strength on the overall tensile strength of resin sand,as well as the fracture modes.The main micro-scale characteristics of the numerical model were extracted from the micrograph of resin sand specimens by three-dimensional X-ray microscopy(3 D-XRM).The extended finite element method(XFEM)and cohesive behavior method were employed to explicitly describe the resin fracture and sand/resin interface debonding,separately.The corresponding experimental observation of micro-scale failure behavior based on the scanning electron microscopy(SEM)was presented for a comparison.The numerical results show that the initial failure of the model occurs at the sand/resin interface,followed by consequent resin failure.Dependent on the resin cohesive strength,the location of resin failure varies from the central zones to resin neck arc zones.A typical mixed mode fracture is observed,which is consistent with the corresponding micro-scale experimental observation.When the resin cohesive strength ranges between 8 and 12 MPa,the resin cracks occur at the central zone of resin bridges and propagate perpendicularly to the tensile direction until through cracks happen.At a higher range(between 12 and 16 MPa),interface cracks cross with resin cracks,bonding bridges of resin sand are broken.The interface adhesive strength has a more significant effect on the overall tensile strength of resin sand than the resin cohesive strength.The overall tensile strength of resin sand increases first then keeps stable with the increase of the resin cohesive strength.This work attempts to establish a numerical model which accurately describes the complicated mixed mode fracture of resin sand,which is beneficial to understand deeply the fracture mechanism of resin sand.