Rebuilding insight into the pathophysiology of Alzheimer’s disease through new blood-brain barrier models

The blood-brain barrier is a unique function of the microvasculature in the brain parenchyma that maintains homeostasis in the central nervous system.Blood-brain barrier breakdown is a common pathology in various neurological diseases,such as Alzheimer’s disease,stroke,multiple sclerosis,and Parkinson’s disease.Traditionally,it has been considered a consequence of neuroinflammation or neurodegeneration,but recent advanced imaging techniques and detailed studies in animal models show that blood-brain barrier breakdown occurs early in the disease process and may precede neuronal loss.Thus,the blood-brain barrier is attractive as a potential therapeutic target for neurological diseases that lack effective therapeutics.To elucidate the molecular mechanism underlying blood-brain barrier breakdown and translate them into therapeutic strategies for neurological diseases,there is a growing demand for experimental models of human origin that allow for functional assessments.Recently,several human induced pluripotent stem cell-derived blood-brain barrier models have been established and various in vitro blood-brain barrier models using microdevices have been proposed.Especially in the Alzheimer’s disease field,the human evidence for blood-brain barrier dysfunction has been demonstrated and human induced pluripotent stem cell-derived blood-brain barrier models have suggested the putative molecular mechanisms of pathological blood-brain barrier.In this review,we summarize recent evidence of blood-brain barrier dysfunction in Alzheimer’s disease from pathological analyses,imaging studies,animal models,and stem cell sources.Additionally,we discuss the potential future directions for blood-brain barrier research.

Blood-brain barrier modeling: challenges and perspectives

The blood-brain barrier （BBB） forms a highly selective inter- face between blood and brain. Extensive research efforts have completely changed our view of the BBB in the last years, from a static, impermeable barrier to a dynamic, highly regulated and specific cellular system. The BBB ultrastructurally consists of specialized brain microvascular endothelial cells （BMEC） characterized by low pinocytic activity,

Targeting brain tumors with innovative nanocarriers:bridging the gap through the blood-brain barrier

Background:Glioblastoma multiforme(GBM)is recognized as the most lethal and most highly invasive tumor.The high likelihood of treatment failure arises fromthe presence of the blood-brain barrier(BBB)and stemcells around GBM,which avert the entry of chemotherapeutic drugs into the tumormass.Objective:Recently,several researchers have designed novel nanocarrier systems like liposomes,dendrimers,metallic nanoparticles,nanodiamonds,and nanorobot approaches,allowing drugs to infiltrate the BBB more efficiently,opening up innovative avenues to prevail over therapy problems and radiation therapy.Methods:Relevant literature for this manuscript has been collected from a comprehensive and systematic search of databases,for example,PubMed,Science Direct,Google Scholar,and others,using specific keyword combinations,including“glioblastoma,”“brain tumor,”“nanocarriers,”and several others.Conclusion:This review also provides deep insights into recent advancements in nanocarrier-based formulations and technologies for GBM management.Elucidation of various scientific advances in conjunction with encouraging findings concerning the future perspectives and challenges of nanocarriers for effective brain tumor management has also been discussed.

Functionalized lipid nanoparticles modulate the blood-brain barrier and eliminate α-synuclein to repair dopamine neurons

The challenge in the clinical treatment of Parkinson's disease lies in the lack of disease-modifying therapies that can halt or slow down the progression. Peptide drugs, such as exenatide (Exe), with potential disease-modifying efficacy, have difficulty in crossing the blood-brain barrier (BBB) due to their large molecular weight. Herein, we fabricate multi-functionalized lipid nanoparticles (LNP) Lpc-BoSA/CSO with BBB targeting, permeability-increasing and responsive release functions. Borneol is chemically bonded with stearic acid and, as one of the components of Lpc-BoSA/CSO, is used to increase BBB permeability. Immunofluorescence results of brain tissue of 15-month-old C57BL/6 mice show that Lpc-BoSA/CSO disperses across the BBB into brain parenchyma, and the amount is 4.21 times greater than that of conventional LNP. Motor symptoms of mice in Lpc-BoSA/CSO-Exe group are significantly improved, and the content of dopamine is 1.85 times (substantia nigra compacta) and 1.49 times (striatum) that of PD mice. α-Synuclein expression and Lewy bodies deposition are reduced to 51.85% and 44.72% of PD mice, respectively. Immunohistochemical mechanism studies show AKT expression in Lpc-BoSA/CSO-Exe is 4.23 times that of PD mice and GSK-3β expression is reduced to 18.41%. Lpc-BoSA/CSO-Exe could reduce the production of α-synuclein and Lewy bodies through AKT/GSK-3β pathway, and effectively prevent the progressive deterioration of Parkinson's disease. In summary, Lpc-BoSA/CSO-Exe increases the entry of exenatide into brain and promotes its clinical application for Parkinson's disease therapy.

Human-induced pluripotent stem cell-derived neural stem cell exosomes improve blood-brain barrier function after intracerebral hemorrhage by activating astrocytes via PI3K/AKT/MCP-1 axis

Cerebral edema caused by blood-brain barrier injury after intracerebral hemorrhage is an important factor leading to poor prognosis.Human-induced pluripotent stem cell-derived neural stem cell exosomes(hiPSC-NSC-Exos)have shown potential for brain injury repair in central nervous system diseases.In this study,we explored the impact of hiPSC-NSC-Exos on blood-brain barrier preservation and the underlying mechanism.Our results indicated that intranasal delivery of hiPSC-NSC-Exos mitigated neurological deficits,enhanced blood-brain barrier integrity,and reduced leukocyte infiltration in a mouse model of intracerebral hemorrhage.Additionally,hiPSC-NSC-Exos decreased immune cell infiltration,activated astrocytes,and decreased the secretion of inflammatory cytokines like monocyte chemoattractant protein-1,macrophage inflammatory protein-1α,and tumor necrosis factor-αpost-intracerebral hemorrhage,thereby improving the inflammatory microenvironment.RNA sequencing indicated that hiPSC-NSC-Exo activated the PI3K/AKT signaling pathway in astrocytes and decreased monocyte chemoattractant protein-1 secretion,thereby improving blood-brain barrier integrity.Treatment with the PI3K/AKT inhibitor LY294002 or the monocyte chemoattractant protein-1 neutralizing agent C1142 abolished these effects.In summary,our findings suggest that hiPSC-NSC-Exos maintains blood-brain barrier integrity,in part by downregulating monocyte chemoattractant protein-1 secretion through activation of the PI3K/AKT signaling pathway in astrocytes.

Activation of the wnt/β-catenin/CYP1B1 pathway alleviates oxidative stress and protects the blood-brain barrier under cerebral ischemia/reperfusion conditions

Accumulating evidence suggests that oxidative stress and the Wnt/β-catenin pathway participate in stroke-induced disruption of the blood-brain barrier.However,the potential links between them following ischemic stroke remain largely unknown.The present study found that cerebral ischemia leads to oxidative stress and repression of the Wnt/β-catenin pathway.Meanwhile,Wnt/β-catenin pathway activation by the pharmacological inhibito r,TWS119,relieved oxidative stress,increased the levels of cytochrome P4501B1(CYP1B1)and tight junction-associated proteins(zonula occludens-1[ZO-1],occludin and claudin-5),as well as brain microvascular density in cerebral ischemia rats.Moreove r,rat brain microvascular endothelial cells that underwent oxygen glucose deprivation/reoxygenation displayed intense oxidative stress,suppression of the Wnt/β-catenin pathway,aggravated cell apoptosis,downregulated CYP1B1and tight junction protein levels,and inhibited cell prolife ration and migration.Overexpression ofβ-catenin or knockdown ofβ-catenin and CYP1B1 genes in rat brain mic rovascular endothelial cells at least partly ameliorated or exacerbated these effects,respectively.In addition,small interfering RNA-mediatedβ-catenin silencing decreased CYP1B1 expression,whereas CYP1B1 knoc kdown did not change the levels of glycogen synthase kinase 3β,Wnt-3a,andβ-catenin proteins in rat brain microvascular endothelial cells after oxygen glucose deprivatio n/reoxygenation.Thus,the data suggest that CYP1B1 can be regulated by Wnt/β-catenin signaling,and activation of the Wnt/β-catenin/CYP1B1 pathway contributes to alleviation of oxidative stress,increased tight junction levels,and protection of the blood-brain barrier against ischemia/hypoxia-induced injury.

Multimodal comparison of plasma proteins associated with blood-brain barrier impairment in Alzheimer’s disease

Background:Vascular impairment is one of the major contributors to dementia.We aimed to identify blood biomarkers suggestive of potential impairment of the blood-brain barrier(BBB)in subjects with Alzheimer’s disease(AD).Methods:We used administrative data from the VA Informatics and Computing Infrastructure Resource Center to study both inpatients and outpatients with AD.Plasma samples from healthy control and AD individuals were analyzed using enzyme-linked immunosorbent assay and proteomics approaches to identify differentially expressed proteins.Bioinformatic analysis was applied to explore significantly enriched pathways.Results:In the same cohort of patients with AD,we found twice number of subjects with cerebral amyloid angiopathy in the two-year period after the onset of AD,compared to the number of subjects with cerebral amyloid angiopathy in the two-year period prior to AD onset.Different pathways related to BBB,like cell adhesion,extracellular matrix organization and Wnt signaling,were activated and differentially expressed proteins such as ADAM22,PDGFR-α,DKK-4,Neucrin and RSOP-1 were identified.Moreover,matrix metalloproteinase-9,which is implicated in causing degradation of basal lamina and BBB disruption,was significantly increased in the plasma of AD patients.Conclusions:Alteration of proteins found in AD subjects could provide new insights into biomarkers regulating permeability and BBB integrity.

Overexpression of mitogen-activated protein kinase phosphatase-1 in endothelial cells reduces blood-brain barrier injury in a mouse model of ischemic stroke

Ischemic stroke can cause blood-brain barrier(BBB)injury,which worsens brain damage induced by stroke.Abnormal expression of tight junction proteins in endothelial cells(ECs)can increase intracellular space and BBB leakage.Selective inhibition of mitogen-activated protein kinase,the negative regulatory substrate of mitogen-activated protein kinase phosphatase(MKP)-1,improves tight junction protein function in ECs,and genetic deletion of MKP-1 aggravates ischemic brain injury.However,whether the latter affects BBB integrity,and the cell type-specific mechanism underlying this process,remain unclear.In this study,we established an adult male mouse model of ischemic stroke by occluding the middle cerebral artery for 60 minutes and overexpressed MKP-1 in ECs on the injured side via lentiviral transfection before stroke.We found that overexpression of MKP-1 in ECs reduced infarct volume,reduced the level of inflammatory factors interleukin-1β,interleukin-6,and chemokine C-C motif ligand-2,inhibited vascular injury,and promoted the recovery of sensorimotor and memory/cognitive function.Overexpression of MKP-1 in ECs also inhibited the activation of cerebral ischemia-induced extracellular signal-regulated kinase(ERK)1/2 and the downregulation of occludin expression.Finally,to investigate the mechanism by which MKP-1 exerted these functions in ECs,we established an ischemic stroke model in vitro by depriving the primary endothelial cell of oxygen and glucose,and pharmacologically inhibited the activity of MKP-1 and ERK1/2.Our findings suggest that MKP-1 inhibition aggravates oxygen and glucose deprivation-induced cell death,cell monolayer leakage,and downregulation of occludin expression,and that inhibiting ERK1/2 can reverse these effects.In addition,co-inhibition of MKP-1 and ERK1/2 exhibited similar effects to inhibition of ERK1/2.These findings suggest that overexpression of MKP-1 in ECs can prevent ischemia-induced occludin downregulation and cell death via deactivating ERK1/2,thereby protecting the integrity of BBB,alleviating brain injury,and improving post-stroke prognosis.

Emerging roles of astrocytes in blood-brain barrier disruption upon amyloid-beta insults in Alzheimer's disease

Blood-brain barrier disruption occurs in the early stages of Alzheimer’s disease.Recent studies indicate a link between blood-brain barrier dysfunction and cognitive decline and might accelerate Alzheimer’s disease progression.Astrocytes are the most abundant glial cells in the central nervous system with important roles in the structural and functional maintenance of the blood-brain barrier.For example,astrocytic cove rage around endothelial cells with perivascular endfeet and secretion of homeostatic soluble factors are two major underlying mechanisms of astrocytic physiological functions.Astrocyte activation is often observed in Alzheimer’s disease patients,with astrocytes expressing a high level of glial fibrillary acid protein detected around amyloid-beta plaque with the elevated phagocytic ability for amyloid-beta.Structural alte rations in Alzheimer’s disease astrocytes including swollen endfeet,somata shrinkage and possess loss contribute to disruption in vascular integrity at capillary and arte rioles levels.In addition,Alzheimer’s disease astrocytes are skewed into proinflammatory and oxidative profiles with increased secretions of vasoactive mediators inducing endothelial junction disruption and immune cell infiltration.In this review,we summarize the findings of existing literature on the relevance of astrocyte alte ration in response to amyloid pathology in the context of blood-brain barrier dysfunction.First,we briefly describe the physiological roles of astrocytes in blood-brain barrier maintenance.Then,we review the clinical evidence of astrocyte pathology in Alzheimer’s disease patients and the preclinical evidence in animal and cellular models.We further discuss the structural changes of blood-brain barrier that correlates with Alzheimer’s disease astrocyte.Finally,we evaluate the roles of soluble factors secreted by Alzheimer’s disease astrocytes,providing potential molecular mechanisms underlying blood-brain barrier modulation.We conclude with a perspective on investigating the therapeutic potential of targeting astrocytes for blood-brain barrier protection in Alzheimer’s disease.

The importance of laminin at the blood-brain barrier

The blood-brain barrier is a unique property of central nervous system blood vessels that protects sensitive central nervous system cells from potentially harmful blood components.The mechanistic basis of this barrier is found at multiple levels,including the adherens and tight junction proteins that tightly bind adjacent endothelial cells and the influence of neighboring pericytes,microglia,and astrocyte endfeet.In addition,extracellular matrix components of the vascular basement membrane play a critical role in establishing and maintaining blood-brain barrier integrity,not only by providing an adhesive substrate for blood-brain barrier cells to adhere to,but also by providing guidance cues that strongly influence vascular cell behavior.The extracellular matrix protein laminin is one of the most abundant components of the basement membrane,and several lines of evidence suggest that it plays a key role in directing blood-brain barrier behavior.In this review,we describe the basic structure of laminin and its receptors,the expression patterns of these molecules in central nervous system blood vessels and how they are altered in disease states,and most importantly,how genetic deletion of different laminin isoforms or their receptors reveals the contribution of these molecules to blood-brain barrier function and integrity.Finally,we discuss some of the important unanswered questions in the field and provide a“to-do”list of some of the critical outstanding experiments.

In vitro model of the blood-brain barrier established by co-culture of primary cerebral microvascular endothelial and astrocyte cells

Drugs for the treatment and prevention of nervous system diseases must permeate the bloodbrain barrier to take effect.In vitro models of the blood-brain barrier are therefore important in the investigation of drug permeation mechanisms.However,to date,no unified method has been described for establishing a blood-brain barrier model.Here,we modified an in vitro model of the blood-brain barrier by seeding brain microvascular endothelial cells and astrocytes from newborn rats on a polyester Transwell cell culture membrane with 0.4-μm pores,and conducted transepithelial electrical resistance measurements,leakage tests and assays for specific bloodbrain barrier enzymes.We show that the permeability of our model is as low as that of the bloodbrain barrier in vivo.Our model will be a valuable tool in the study of the mechanisms of action of neuroprotective drugs.

Mechanisms of imperatorin on regulating Pglycoprotein in blood-brain barrier based on network pharmacology and in vitro experiment

OBJECTIVE To explore mecha⁃nisms of imperatorin on regulating P-glycoprotein(P-gp)in blood-brain barrier(BBB)based on net⁃work pharmacology combined with in vitro experi⁃ment.METHODS Drug targets were predicted using the Pharmapper and Swiss targets data⁃bases;disease targets were obtained through the Genecards database;intersections between drugs and disease targets were screened by Cytoscape software;the obtained core targets were used to construct protein-protein interaction(PPI)network,gene ontology(GO)functions,and Kyoto encyclopedia of genes and genomes(KEGG)pathway enrichment analysis.The effects of imperatorin(20,50,100μmol·L^(-1))on P-gp activity were monitored in hCMEC/D3 in vitro BBB model,and the effects of imperatorin on the expression of target proteins were verified using Western blot method.RESULTS 55 drug targets and 3102 disease targets were obtained from the network pharmacology screening,and 37 core targets were obtained after the combination.Enrichment analysis showed that core targets were closely related to chemical synaptic trans⁃mission regulation,neurotransmitter receptor activity,protein kinase regulation activity,G proteincoupled receptor signaling pathway,neural active ligand receptor interaction pathway,PI3K-Akt sig⁃naling pathway,VEGF signaling pathway,etc..In vitro experimental validation suggested that all tested concentration groups of imperatorin signifi⁃cantly reduced the activity and expression of P-gp,which were achieved by significantly downregu⁃lating the phosphorylation levels of PI3K and Akt,and repressing the expression of VEGFR2 pro⁃tein.CONCLUSION Network pharmacology was used to predict the core targets and signaling pathways of imperatorin on regulating P-gp in BBB and relevant validation was conducted through in vitro experiments,providing a refer⁃ence basis for further exploration of the mecha⁃nisms of imperatorin on regulating P-gp in BBB.

Biochanin A,as the Lrg1/TGF-β/Smad2 pathway blockade,attenuates blood-brain barrier damage after cerebral ischemiareperfusion by modulating leukocyte migration patterns

Background:Biochanin A is an excellent dietary isoflavone that has the concomitant function of both medicine and foodstuff.The attenuation function of biochanin A on blood-brain barrier(BBB)damage induced by cerebral ischemia-reperfusion remains unclear.Methods:C57BL/6 mice were subjected to 1 h middle cerebral artery occlusion(MCAO)followed by 24 h reperfusion.The infarct volume of the brain was stained by TTC,while leakage of the brain was quantitatively stained by Evans blue,and the neurologic deficit score was measured.Microglial-induced morphologic changes were observed via immunofluorescence staining,and rolling and adhering leukocytes in venules were observed via two-photon imaging,while the inner fluorescein isothiocyanate-albumin of venules were compared with those of surrounding interstitial area through venular albumin leakage.Results:The attenuation effect of biochanin A on tight junction injury was compared in ischemia-reperfusion mice or conventional knockdown of leucine-richα2-glycoprotein 1(Lrg1)mice.Biochanin A could ameliorate BBB injury in mice with cerebral ischemiareperfusion in a dose-dependent manner by strengthening the immunostaining volume of occludin,claudin-5,and zonula occludens-1.The amoeba morphologic changes of microglial combined with the elevated expression of Lrg1 could be relieved under the treatment of biochanin A.Biochanin A played a countervailing role on the rolling leukocytes in the vessel,while the leakage of blood vessels was reduced.Biochanin A diminished its functions to further improved attenuation for tight junction injury on conventional Lrg1-knockout mice,as well as the inhibition effects on TGF-β1,and the phosphorylation of suppressor of mothers against decapentaplegic 2(Smad2)/Smad2 via western blot assay.Conclusion:Biochanin A could alleviate tight junction injury induced by cerebral ischemiareperfusion and blocked the Lrg1/TGF-β/Smad2 pathway to modulate leukocyte migration patterns.

The role of fibronectin in multiple sclerosis and the effect of drug delivery across the blood-brain barrier

Remyelination failure is one of the main characteristics of multiple sclerosis and is potentially correlated with disease progression.Previous research has shown that the extracellular matrix is associated with remyelination failure because remodeling of the matrix often fails in both chronic and progressive multiple sclerosis.Fibronectin aggregates are assembled and persistently exist in chronic multiple sclerosis,thus inhibiting remyelination.Although many advances have been made in the mechanisms and treatment of multiple sclerosis,it remains very difficult for drugs to reach pathological brain tissues;this is due to the complexity of brain structure and function,especially the existence of the blood-brain barrier.Therefore,herein,we review the effects of fibronectin aggregates on multiple sclerosis and the efficacy of different forms of drug delivery across the blood-brain barrier in the treatment of this disease.

Synaptic and blood-brain barrier structural changes in a rat epilepsy model induced by coriaria lacton Replication experiment with animals

BACKGROUND： Structural and functional synaptic changes, as well as blood-brain barrier （BBB） changes, affect the micro-environment of nervous tissue and excitation, both of which play an important role in epilepsy. OBJECTIVE： To observe synaptic and BBB ultrastructural changes in the motor cortex of a rat epilepsy model induced by coriaria lacton, and to investigate the synaptic and BBB effects on the mechanism of epilepsy. DESIGN： A randomized controlled animal experiment. SETTING： Department of Histology and Embryology, Luzhou Medical College; and Electron Microscopy Laboratory, Luzhou Medical College. MATERIALS： Twenty healthy male Sprague Dawley rats, aged 8 weeks, were chosen for this study. The rats weighed （280 ± 50） g and were supplied by the Experimental Animal Center of Luzhou Medical College. Experimentation was performed in accordance with the ethical guidelines for the use and care of animals. The animals were randomly divided into a control group and an epilepsy group, with 10 rats in each group. METHODS： This study was performed at the Department of Histology and Embryology, and Electron Microscopy Laboratory, Luzhou Medical College between February and December 2006. According to the protocol, the epilepsy group was injected with 10 μ L/100 g coriaria lacton into the lateral ventricles to establish an epileptic model. The control group rats were not administered anything. Eight days after the model was established, all rats were anesthetized with ether. The motor cortex was removed and sectioned into ultrathin sections. Synaptic and BBB ultrastructural changes were observed by electron microscopy. MAIN OUTCOME MEASURES： （1）Structural changes of three different parts of the synapses, synaptic cleft width, postsynaptic density thickness, proportion of perforation synapses, curvature of synaptic interface, and length of active zones. （2）Capillary and BBB changes （endothelium, basement membrane, pericyte, and the astrocyte endfeet）. RESULTS： （1）Curvature of synaptic interface, length of active zones, thickness of postsynaptic density, and percentage of perforation synapses increased significantly. （2）There was significant edema in the endothelium, basement membrane, and the pericyte of the epilepsy group; the electron density of the basement membrane was reduced. CONCLUSION： （1） The coriaria lacton treatment altered synaptic ultrastructure, as well as BBB characteristics, in the epileptic rat model, and also improved synaptic transmission efficiency, as well as BBB permeability; （2）Synaptic and BBB ultrastructural changes might play an important role in the mechanism of epilepsy.

Current overview of induced pluripotent stem cell-based blood-brain barrier-on-a-chip

BACKGROUND Induced pluripotent stem cells(iPSCs)show great ability to differentiate into any tissue,making them attractive candidates for pathophysiological investigations.The rise of organ-on-a-chip technology in the past century has introduced a novel way to make in vitro cell cultures that more closely resemble their in vivo environments,both structural and functionally.The literature still lacks consensus on the best conditions to mimic the blood-brain barrier(BBB)for drug screening and other personalized therapies.The development of models based on BBB-on-achip using iPSCs is promising and is a potential alternative to the use of animals in research.AIM To analyze the literature for BBB models on-a-chip involving iPSCs,describe the microdevices,the BBB in vitro construction,and applications.METHODS We searched for original articles indexed in PubMed and Scopus that used iPSCs to mimic the BBB and its microenvironment in microfluidic devices.Thirty articles were identified,wherein only 14 articles were finally selected according to the inclusion and exclusion criteria.Data compiled from the selected articles were organized into four topics:(1)Microfluidic devices design and fabrication;(2)characteristics of the iPSCs used in the BBB model and their differentiation conditions;(3)BBB-on-a-chip reconstruction process;and(4)applications of BBB microfluidic three-dimensional models using iPSCs.RESULTS This study showed that BBB models with iPSCs in microdevices are quite novel in scientific research.Important technological advances in this area regarding the use of commercial BBB-on-a-chip were identified in the most recent articles by different research groups.Conventional polydimethylsiloxane was the most used material to fabricate in-house chips(57%),whereas few studies(14.3%)adopted polymethylmethacrylate.Half the models were constructed using a porous membrane made of diverse materials to separate the channels.iPSC sources were divergent among the studies,but the main line used was IMR90-C4 from human fetal lung fibroblast(41.2%).The cells were differentiated through diverse and complex processes either to endothelial or neural cells,wherein only one study promoted differentiation inside the chip.The construction process of the BBB-on-a-chip involved previous coating mostly with fibronectin/collagen Ⅳ(39.3%),followed by cell seeding in single cultures(36%)or co-cultures(64%)under controlled conditions,aimed at developing an in vitro BBB that mimics the human BBB for future applications.CONCLUSION This review evidenced technological advances in the construction of BBB models using iPSCs.Nonetheless,a definitive BBB-on-a-chip has not yet been achieved,hindering the applicability of the models.

A Study of Prospective Barriers,Benefits and Measures for Building Information Modeling(BIM)Adoption in Nepalese AEC Industry

The construction industry needs modern construction methodology and technology to improve sustainability and production performance.Building Information Modelling(BIM)technology supports improving the quality of products by reducing design and construction defects,risks to the health and safety of workers,and reduce overall project cost and delivery time.The BIM has capabilities,but it is still undiscovered and unable to exploit the full scale of its benefits in the Architectural Engineering and Construction(AEC)industry.There is a trend to adopt the BIM level 1,which is limited to 2D and only in a few cases 3D models uses in the design and construction of residential and commercial buildings,particularly in Nepal.Hence,this paper focuses on providing insight into the BIM benefits and identifies the potential barriers while adopting BIM Level 3 in Nepal.This was accomplished by developing a 4DBIM model of a multi-story residential building in Nepal and conducting the industry survey via focus group with the AEC professionals based on the developed 4DBIM model.A comprehensive literature review was conducted and presented the findings of the BIM benefits and barriers while adopting BIM.The study found that commercial and governmental projects can immediately be adopted BIM technology.It is concluded that the unavailability of skilled BIM users and the lack of proper policies for BIM adoption are key barriers in Nepal.Hence,the new policy is required to achieve and exploit the full scale of the BIM benefits and improve the project delivery in terms of quality,cost and time including the health and safety of workers and the sustainability of the AEC industry.

Treadmill exercise improves hippocampal neural plasticity and relieves cognitive deficits in a mouse model of epilepsy

Epilepsy frequently leads to cognitive dysfunction and approaches to treatment remain limited.Although regular exercise effectively improves learning and memory functions across multiple neurological diseases,its application in patients with epilepsy remains controversial.Here,we adopted a 14-day treadmill-exercise paradigm in a pilocarpine injection-induced mouse model of epilepsy.Cognitive assays confirmed the improvement of object and spatial memory after endurance training,and electrophysiological studies revealed the maintenance of hippocampal plasticity as a result of physical exercise.Investigations of the mechanisms underlying this effect revealed that exercise protected parvalbumin interneurons,probably via the suppression of neuroinflammation and improved integrity of blood-brain barrier.In summary,this work identified a previously unknown mechanism through which exercise improves cognitive rehabilitation in epilepsy.

Barriers and Drivers of Sustainable Business Model Innovation:Present and Future Research Perspectiv

Sustainable business model innovation(SBMI)introduced a unique frontier in current business operations and innovation management.Despite the numerous advantages of SBMI to contemporary business strategy,most established firms face challenges in its successful implementation.Through a systematic review process(SRP),the paper attempted to critically evaluate and analyze the previous outcome on the barriers and drivers to SBMI.The research explored 42 prior studies to identify the thematic study areas,highlight the research gaps,and outline future propositions and agendas.The research thoroughly evaluates the state-of-the-art regarding barriers and drivers to implement SBMI.The SRP approach utilized in the study sheds light on the intricacies of SBMI by highlighting six critical barriers:institutional,organizational,strategic,resource allocation,technological,and financial barriers that hinder the successful deployment of SBMI.In addition,the study’s findings indicated that organizational learning,knowledge management,dynamic capabilities resource mobilization,innovative business activities,and human resource development could be a catalyst to the successful implementation of SBMI.Furthermore,the study highlighted some critical gaps and agendas for future research on SBMI.This study contributes to the literature on business model innovation and offers a practical outlook that can facilitate firms and policymakers in developing strategies to improve their business model.

Human induced pluripotent stem cell based in vitro models of the blood-brain barrier： the future standard？

There is an urgent and tremendous need for human dis- ease models in drug development in order to improve pre- clinical predictability. In the case of brain disorders drugs have to cross the blood-brain barrier （BBB） to enter the central nervous system （CNS）. It was estimated that more than 95% of the drugs cannot cross the BBB.