Deciphering the mechanobiology of microglia in traumatic brain injury with advanced microsystems

Advanced microsystems in traumatic brain injury research:Traumatic brain injury(TBI)results from a mechanical insult to the brain,leading to neuronal and axonal damage and subsequently causing a secondary injury.Within minutes of TBI,a neuroinflammatory response is triggered,driven by intricate molecular and cellular inflammatory processes.

Impact of Zika virus non-structural protein mutations on hippocampal damage

The Zika virus(ZIKV),a member of the Flaviviridae family,attracted worldwide attention for its connection to severe neurological effects,notably microcephaly in newborns,first reported during the 2015 epidemic in Brazil.Yet,its impact goes beyond fetal and neonatal abnormalities,also affecting the central nervous system(CNS)in both children and adults,leading to enduring cognitive and behavioral impairments.

Multiple sclerosis is at a checkpoint: advancing the program

Multiple sclerosis(MS) is a chronic inflammatory and demyelinating disease of the central nervous system(CNS). Patients with MS experience sensory and motor function loss due to myelin and/or axon damage perpetuated by infiltrating immune cells(Hauser and Cree, 2020).

Telencephalic stab wound injury induces regenerative angiogenesis and neurogenesis in zebrafish:unveiling the role of vascular endothelial growth factor signaling and microglia

After brain damage,regenerative angiogenesis and neurogenesis have been shown to occur simultaneously in mammals,suggesting a close link between these processes.However,the mechanisms by which these processes interact are not well understood.In this work,we aimed to study the correlation between angiogenesis and neurogenesis after a telencephalic stab wound injury.To this end,we used zebrafish as a relevant model of neuroplasticity and brain repair mechanisms.First,using the Tg(fli1:EGFP×mpeg1.1:mCherry)zebrafish line,which enables visualization of blood vessels and microglia respectively,we analyzed regenerative angiogenesis from 1 to 21 days post-lesion.In parallel,we monitored brain cell proliferation in neurogenic niches localized in the ventricular zone by using immunohistochemistry.We found that after brain damage,the blood vessel area and width as well as expression of the fli1 transgene and vascular endothelial growth factor(vegfaa and vegfbb)were increased.At the same time,neural stem cell proliferation was also increased,peaking between 3 and 5 days post-lesion in a manner similar to angiogenesis,along with the recruitment of microglia.Then,through pharmacological manipulation by injecting an anti-angiogenic drug(Tivozanib)or Vegf at the lesion site,we demonstrated that blocking or activating Vegf signaling modulated both angiogenic and neurogenic processes,as well as microglial recruitment.Finally,we showed that inhibition of microglia by clodronate-containing liposome injection or dexamethasone treatment impairs regenerative neurogenesis,as previously described,as well as injury-induced angiogenesis.In conclusion,we have described regenerative angiogenesis in zebrafish for the first time and have highlighted the role of inflammation in this process.In addition,we have shown that both angiogenesis and neurogenesis are involved in brain repair and that microglia and inflammation-dependent mechanisms activated by Vegf signaling are important contributors to these processes.This study paves the way for a better understanding of the effect of Vegf on microglia and for studies aimed at promoting angiogenesis to improve brain plasticity after brain injury.

Non-coding RNAs in acute ischemic stroke:from brain to periphery

Acute ischemic stroke is a clinical emergency and a condition with high morbidity,mortality,and disability.Accurate predictive,diagnostic,and prognostic biomarkers and effective therapeutic targets for acute ischemic stroke remain undetermined.With innovations in high-throughput gene sequencing analysis,many aberrantly expressed non-coding RNAs(ncRNAs)in the brain and peripheral blood after acute ischemic stroke have been found in clinical samples and experimental models.Differentially expressed ncRNAs in the post-stroke brain were demonstrated to play vital roles in pathological processes,leading to neuroprotection or deterioration,thus ncRNAs can serve as therapeutic targets in acute ischemic stroke.Moreover,distinctly expressed ncRNAs in the peripheral blood can be used as biomarkers for acute ischemic stroke prediction,diagnosis,and prognosis.In particular,ncRNAs in peripheral immune cells were recently shown to be involved in the peripheral and brain immune response after acute ischemic stroke.In this review,we consolidate the latest progress of research into the roles of ncRNAs(microRNAs,long ncRNAs,and circular RNAs)in the pathological processes of acute ischemic stroke–induced brain damage,as well as the potential of these ncRNAs to act as biomarkers for acute ischemic stroke prediction,diagnosis,and prognosis.Findings from this review will provide novel ideas for the clinical application of ncRNAs in acute ischemic stroke.

Targeting tau in Alzheimer's disease:from mechanisms to clinical therapy

Alzheimer’s disease is the most prevalent neurodegenerative disease affecting older adults.Primary features of Alzheimer’s disease include extra cellular aggregation of amyloid-βplaques and the accumulation of neurofibrillary tangles,fo rmed by tau protein,in the cells.While there are amyloid-β-ta rgeting therapies for the treatment of Alzheimer’s disease,these therapies are costly and exhibit potential negative side effects.Mounting evidence suggests significant involvement of tau protein in Alzheimer’s disease-related neurodegeneration.As an important microtubule-associated protein,tau plays an important role in maintaining the stability of neuronal microtubules and promoting axonal growth.In fact,clinical studies have shown that abnormal phosphorylation of tau protein occurs before accumulation of amyloid-βin the brain.Various therapeutic strategies targeting tau protein have begun to emerge,and are considered possible methods to prevent and treat Alzheimer’s disease.Specifically,abnormalities in post-translational modifications of the tau protein,including aberrant phosphorylation,ubiquitination,small ubiquitin-like modifier(SUMO)ylation,acetylation,and truncation,contribute to its microtubule dissociation,misfolding,and subcellular missorting.This causes mitochondrial damage,synaptic impairments,gliosis,and neuroinflammation,eventually leading to neurodegeneration and cognitive deficits.This review summarizes the recent findings on the underlying mechanisms of tau protein in the onset and progression of Alzheimer’s disease and discusses tau-targeted treatment of Alzheimer’s disease.

Autophagy in neuroinflammation after traumatic brain injury

Traumatic brain injury(TBI)is an acquired injury of the brain caused by the impact of external forces on the brain(Maas et al.,2008).It is a major cause of death and disability among people of all ages(Maas et al.,2008).The primary mechanical injury to the brain initiates a cascade of secondary biochemical events that lead to acute and chronic neurodegeneration and activation of inflammatory pathways(Maas et al.,2008).Both brain-resident microglia and blood-derived myeloid cells-macrophages and monocytes that infiltrate the brain due to injury-induced blood-brain barrier damage,contribute to the inflammatory responses after TBI(Morganti et al.,2015).

Mechanical responses of anchoring structure under triaxial cyclic loading

Dynamic load on anchoring structures(AS)within deep roadways can result in cumulative damage and failure.This study develops an experimental device designed to test AS under triaxial loads.The device enables the investigation of the mechanical response,failure mode,instability assessment criteria,and anchorage effect of AS subjected to combined cyclic dynamic-static triaxial stress paths.The results show that the peak bearing strength is positively correlated with the anchoring matrix strength,anchorage length,and edgewise compressive strength.The bearing capacity decreases significantly when the anchorage direction is severely inclined.The free face failure modes are typically transverse cracking,concave fracturing,V-shaped slipping and detachment,and spallation detachment.Besides,when the anchoring matrix strength and the anchorage length decrease while the edgewise compressive strength,loading rate,and anchorage inclination angle increase,the failure intensity rises.Instability is determined by a negative tangent modulus of the displacement-strength curve or the continued deformation increase against the general downward trend.Under cyclic loads,the driving force that breaks the rock mass along the normal vector and the rigidity of the AS are the two factors that determine roadway stability.Finally,a control measure for surrounding rock stability is proposed to reduce the internal driving force via a pressure relief method and improve the rigidity of the AS by full-length anchorage and grouting modification.

A review of reservoir damage during hydraulic fracturing of deep and ultra-deep reservoirs

Deep and ultra-deep reservoirs have gradually become the primary focus of hydrocarbon exploration as a result of a series of significant discoveries in deep hydrocarbon exploration worldwide.These reservoirs present unique challenges due to their deep burial depth(4500-8882 m),low matrix permeability,complex crustal stress conditions,high temperature and pressure(HTHP,150-200℃,105-155 MPa),coupled with high salinity of formation water.Consequently,the costs associated with their exploitation and development are exceptionally high.In deep and ultra-deep reservoirs,hydraulic fracturing is commonly used to achieve high and stable production.During hydraulic fracturing,a substantial volume of fluid is injected into the reservoir.However,statistical analysis reveals that the flowback rate is typically less than 30%,leaving the majority of the fluid trapped within the reservoir.Therefore,hydraulic fracturing in deep reservoirs not only enhances the reservoir permeability by creating artificial fractures but also damages reservoirs due to the fracturing fluids involved.The challenging“three-high”environment of a deep reservoir,characterized by high temperature,high pressure,and high salinity,exacerbates conventional forms of damage,including water sensitivity,retention of fracturing fluids,rock creep,and proppant breakage.In addition,specific damage mechanisms come into play,such as fracturing fluid decomposition at elevated temperatures and proppant diagenetic reactions at HTHP conditions.Presently,the foremost concern in deep oil and gas development lies in effectively assessing the damage inflicted on these reservoirs by hydraulic fracturing,comprehending the underlying mechanisms,and selecting appropriate solutions.It's noteworthy that the majority of existing studies on reservoir damage primarily focus on conventional reservoirs,with limited attention given to deep reservoirs and a lack of systematic summaries.In light of this,our approach entails initially summarizing the current knowledge pertaining to the types of fracturing fluids employed in deep and ultra-deep reservoirs.Subsequently,we delve into a systematic examination of the damage processes and mechanisms caused by fracturing fluids within the context of hydraulic fracturing in deep reservoirs,taking into account the unique reservoir characteristics of high temperature,high pressure,and high in-situ stress.In addition,we provide an overview of research progress related to high-temperature deep reservoir fracturing fluid and the damage of aqueous fracturing fluids to rock matrix,both artificial and natural fractures,and sand-packed fractures.We conclude by offering a summary of current research advancements and future directions,which hold significant potential for facilitating the efficient development of deep oil and gas reservoirs while effectively mitigating reservoir damage.

Frequency Domain Fatigue Evaluation on SCR Girth-Weld Based on Structural Stress

The Steel Catenary Riser(SCR)is a vital component for transporting oil and gas from the seabed to the floating platform.The harsh environmental conditions and complex platform motion make the SCR’s girth-weld prone to fatigue failure.The structural stress fatigue theory and Master S-N curve method provide accurate predictions for the fatigue damage on the welded joints,which demonstrate significant potential and compatibility in multi-axial and random fatigue evaluation.Here,we propose a new frequency fatigue model subjected to welded joints of SCR under multiaxial stress,which fully integrates the mesh-insensitive structural stress and frequency domain random process and transforms the conventional welding fatigue technique of SCR into a spectrum analysis technique utilizing structural stress.Besides,a full-scale FE model of SCR with welds is established to obtain the modal structural stress of the girth weld and the frequency response function(FRF)of modal coordinate,and a biaxial fatigue evaluation about the girth weld of the SCR can be achieved by taking the effects of multi-load correlation and pipe-soil interaction into account.The research results indicate that the frequency-domain fatigue results are aligned with the time-domain results,meeting the fatigue evaluation requirements of the SCR.

Impact of spatially varying rock disturbance on rock slope stability

Degradation of rock mass produced by rock blasting,stress relief,and other causes is an important factor in the assessment of rock strength.Quantified as a disturbance factor,such degradation varies depending on blasting control,stress state and stress relief,and rock mass quality.This study focuses on the impact of disturbance on the safety of slopes.The disturbance in the rock mass is characterized by the geometry of the disturbed zone,its size,the magnitude,and the decaying rate with the distance away from the slope surface.A method accounting for decay of rock disturbance is presented.A study of the impact of rock disturbance characteristics on the quantitative stability measures of slopes was carried out.These characteristics included disturbed zone geometry,its thickness,the maximum magnitude of the disturbance factor,and the rate of disturbance decaying.The thickness of the disturbed zone and the maximum factor of disturbance were found to have the greatest impact.For example,the factor of safety for a 45slope in low-quality rock mass can decrease from 1.96 to 1.09 as the thickness of the disturbed zone increases from 1/4 of slope height H to the double of H and the maximum disturbance factor increases from 0.5 to 1.Uniform thickness of a disturbed zone was found to yield more conservative outcomes than the triangular zones did.The critical failure surfaces were found to be shallow for high rates of disturbance decay,and they were the deepest for spatially uniform disturbance factors.

The action mechanism by which C1q/tumor necrosis factor-related protein-6 alleviates cerebral ischemia/reperfusion injury in diabetic mice

Studies have shown that C1q/tumor necrosis factor-related protein-6 (CTRP6) can alleviate renal ischemia/reperfusion injury in mice. However, its role in the brain remains poorly understood. To investigate the role of CTRP6 in cerebral ischemia/reperfusion injury associated with diabetes mellitus, a diabetes mellitus mouse model of cerebral ischemia/reperfusion injury was established by occlusion of the middle cerebral artery. To overexpress CTRP6 in the brain, an adeno-associated virus carrying CTRP6 was injected into the lateral ventricle. The result was that oxygen injury and inflammation in brain tissue were clearly attenuated, and the number of neurons was greatly reduced. In vitro experiments showed that CTRP6 knockout exacerbated oxidative damage, inflammatory reaction, and apoptosis in cerebral cortical neurons in high glucose hypoxia-simulated diabetic cerebral ischemia/reperfusion injury. CTRP6 overexpression enhanced the sirtuin-1 signaling pathway in diabetic brains after ischemia/reperfusion injury. To investigate the mechanism underlying these effects, we examined mice with depletion of brain tissue-specific sirtuin-1. CTRP6-like protection was achieved by activating the sirtuin-1 signaling pathway. Taken together, these results indicate that CTRP6 likely attenuates cerebral ischemia/reperfusion injury through activation of the sirtuin-1 signaling pathway.

Creep constitutive model considering nonlinear creep degradation of fractured rock

Stability analysis of underground constructions requires a model study of rock masses’ long-term performance. Creep tests under different stress conditions was conducted on intact granite and granite samples fractured at 30° and 45° angles. The experimental results indicate that the steady creep strain rates of intact and fractured rock present an exponential increase trend with the increase of stress level. A nonlinear creep model is developed based on the experimental results, in which the initial damage caused by fracture together with the damage caused by constant load have been taken into consideration. The fitting analysis results indicated that the model proposed is more accurate at identifying the full creep regions in fractured granite, especially the accelerated stage of creep deformation. The least-square fit error of the proposed creep model is significantly lower than that of Nishihara model by almost an order of magnitude. An analysis of the effects of elastic modulus, viscosity coefficient, and damage factors on fractured rock strain rate and creep strain is conducted. If no consideration is given to the effects of the damage, the proposed nonlinear creep model can degenerate into to the classical Nishihara model.

The secondary injury cascade after spinal cord injury:an analysis of local cytokine/chemokine regulation

After spinal cord injury,there is an extensive infiltration of immune cells,which exacerbates the injury and leads to further neural degeneration.Therefore,a major aim of current research involves targeting the immune response as a treatment for spinal cord injury.Although much research has been performed analyzing the complex inflammatory process following spinal cord injury,there remain major discrepancies within previous literature regarding the timeline of local cytokine regulation.The objectives of this study were to establish an overview of the timeline of cytokine regulation for 2 weeks after spinal cord injury,identify sexual dimorphisms in terms of cytokine levels,and determine local cytokines that significantly change based on the severity of spinal cord injury.Rats were inflicted with either a mild contusion,moderate contusion,severe contusion,or complete transection,7 mm of spinal cord centered on the injury was harvested at varying times post-injury,and tissue homogenates were analyzed with a Cytokine/Chemokine 27-Plex assay.Results demonstrated pro-inflammatory cytokines including tumor necrosis factorα,interleukin-1β,and interleukin-6 were all upregulated after spinal cord injury,but returned to uninjured levels within approximately 24 hours post-injury,while chemokines including monocyte chemoattractant protein-1 remained upregulated for days post-injury.In contrast,several anti-inflammatory cytokines and growth factors including interleukin-10 and vascular endothelial growth factor were downregulated by 7 days post-injury.After spinal cord injury,tissue inhibitor of metalloproteinase-1,which specifically affects astrocytes involved in glial scar development,increased more than all other cytokines tested,reaching 26.9-fold higher than uninjured rats.After a mild injury,11 cytokines demonstrated sexual dimorphisms;however,after a severe contusion only leptin levels were different between female and male rats.In conclusion,pro-inflammatory cytokines initiate the inflammatory process and return to baseline within hours post-injury,chemokines continue to recruit immune cells for days post-injury,while anti-inflammatory cytokines are downregulated by a week post-injury,and sexual dimorphisms observed after mild injury subsided with more severe injuries.Results from this work define critical chemokines that influence immune cell infiltration and important cytokines involved in glial scar development after spinal cord injury,which are essential for researchers developing treatments targeting secondary damage after spinal cord injury.

Modulation of p75 neurotrophin receptor mitigates brain damage following ischemic stroke in mice

Stroke is a significant leading cause of death and disability in the United States(Tsao et al.,2022).Approximately 87% of strokes fall into the ischemic category,mainly caused by arterial blockage(Jayaraj et al.,2019).Although the only FDA-approved effective medication is tissue plasminogen activator(tPA),it should be administrated within 4.5 hours of ischemic stroke.Furthermore,tPA has been an integral part of managing acute ischemic stro ke.

Prediction of Renal Function by Urinary Lead and Cadmium - Based on Classification Decision Tree and Logistic Regression Model

It is estimated that chronic kidney disease(CKD)will be the fifth leading cause of death in the world by 2040[1].Early recognition and intervention for kidney damage are essential.Estimated glomerular filtration rate(eGFR)can be calculated by measuring blood creatinine to evaluate glomerular function,and urinary N-acetyl-β-δ-glucosaminidase(UNAG)level is generally recognized as a marker of renal tubular injury.Exposure to lead(Pb)and cadmium(Cd)can damage renal function,leading to a decrease in eGFR and an increase in UNAG[2].Both Pb and Cd are easily accumulated in the body and then slowly released by the kidneys and excreted.So,urinary Pb(UPb)and Cd(UCd)levels can be used as biomarkers of exposure[3,4].

Rockburst criterion and evaluation method for potential rockburst pit depth considering excavation damage effect

Excavation-induced disturbances in deep tunnels will lead to deterioration of rock properties and formation of excavation damaged zone(EDZ).This excavation damage effect may affect the potential rockburst pit depth.Taking two diversion tunnels of Jinping II hydropower station for example,the relationship between rockburst pit depth and excavation damage effect is first surveyed.The results indicate that the rockburst pit depth in tunnels with severe damage to rock masses is relatively large.Subsequently,the excavation-induced damage effect is characterized by disturbance factor D based on the Hoek-Brown criterion and wave velocity method.It is found that the EDZ could be further divided into a high-damage zone(HDZ)with D=1 and weak-damage zone(WDZ),and D decays from one to zero linearly.For this,a quantitative evaluation method for potential rockburst pit depth is established by presenting a three-element rockburst criterion considering rock strength,geostress and disturbance factor.The evaluation results obtained by this method match well with actual observations.In addition,the weakening of rock mass strength promotes the formation and expansion of potential rockburst pits.The potential rockburst pit depth is positively correlated with HDZ and WDZ depths,and the HDZ depth has a significant contribution to the potential rockburst pit depth.

Micro-macro evolution of mechanical behaviors of thermally damaged rock:A state-of-the-art review

The influence of thermal damage on macroscopic and microscopic characteristics of different rocks has received much attention in the field of rock engineering.When the rocks are subjected to thermal treatment,the change of macroscopic characteristics and evolution of micro-structure would be induced,ultimately resulting in different degrees of thermal damage in rocks.To better understand the thermal damage mechanism of different rocks and its effect on the rock performance,this study reviews a large number of test results of rock specimens experiencing heating and cooling treatment in the laboratory.Firstly,the variations of macroscopic behaviors,including physical parameters,mechanical parameters,thermal conductivity and permeability,are examined.The variations of mechanical parameters with thermal treatment variables(i.e.temperature or the number of thermal cycles)are divided into four types.Secondly,several measuring methods for microstructure,such as polarizing microscopy,fluorescent method,scanning electron microscopy(SEM),X-ray computerized tomography(CT),acoustic emission(AE)and ultrasonic technique,are introduced.Furthermore,the effect of thermal damage on the mechanical parameters of rocks in response to different thermal treatments,involving temperature magnitude,cooling method and thermal cycle,are discussed.Finally,the limitations and prospects for the research of rock thermal damage are proposed.

Enhanced structural damage behavior of liquid-filled tank by reactive material projectile impact

A series of ballistic experiments were performed to investigate the damage behavior of high velocity reactive material projectiles(RMPs) impacting liquid-filled tanks,and the corresponding hydrodynamic ram(HRAM) was studied in detail.PTFE/Al/W RMPs with steel-like and aluminum-like densities were prepared by a pressing/sintering process.The projectiles impacted a liquid-filled steel tank with front aluminum panel at approximately 1250 m/s.The corresponding cavity evolution characteristics and HRAM pressure were recorded by high-speed camera and pressure acquisition system,and further compared to those of steel and aluminum projectiles.Significantly different from the conical cavity formed by the inert metal projectile,the cavity formed by the RMP appeared as an ellipsoid with a conical front.The RMPs were demonstrated to enhance the radial growth velocity of cavity,the global HRAM pressure amplitude and the front panel damage,indicating the enhanced HRAM and structural damage behavior.Furthermore,combining the impact-induced fragmentation and deflagration characteristics,the cavity evolution of RMPs under the combined effect of kinetic energy impact and chemical energy release was analyzed.The mechanism of enhanced HRAM pressure induced by the RMPs was further revealed based on the theoretical model of the initial impact wave and the impulse analysis.Finally,the linear correlation between the deformation-thickness ratio and the non-dimensional impulse for the front panel was obtained and analyzed.It was determined that the enhanced near-field impulse induced by the RMPs was the dominant reason for the enhanced structural damage behavior.

Multiscale modeling of gas-induced fracturing in anisotropic clayey rocks

In the context of repositories for nuclear waste,understanding the behavior of gas migration through clayey rocks with inherent anisotropy is crucial for assessing the safety of geological disposal facilities.The primary mechanism for gas breakthrough is the opening of micro-fractures due to high gas pressure.This occurs at gas pressures lower than the combined strength of the rock and its minimum principal stress under external loading conditions.To investigate the mechanism of microscale mode-I ruptures,it is essential to incorporate a multiscale approach that includes subcritical microcracks in the modeling framework.In this contribution,we derive the model from microstructures that contain periodically distributed microcracks within a porous material.The damage evolution law is coupled with the macroscopic poroelastic system by employing the asymptotic homogenization method and considering the inherent hydro-mechanical(HM)anisotropy at the microscale.The resulting permeability change induced by fracture opening is implicitly integrated into the gas flow equation.Verification examples are presented to validate the developed model step by step.An analysis of local macroscopic response is undertaken to underscore the influence of factors such as strain rate,initial damage,and applied stress,on the gas migration process.Numerical examples of direct tension tests are used to demonstrate the model’s efficacy in describing localized failure characteristics.Finally,the simulation results for preferential gas flow reveal the robustness of the two-scale model in explicitly depicting gas-induced fracturing in anisotropic clayey rocks.The model successfully captures the common behaviors observed in laboratory experiments,such as a sudden drop in gas injection pressure,rapid build-up of downstream gas pressure,and steady-state gas flow following gas breakthrough.