Brain-X最新文献

{"title":"Revolutionary delivery system enables precise protein transportation","authors":"Qian Zhang,&nbsp;Kun Zhang","doi":"10.1002/brx2.21","DOIUrl":"https://doi.org/10.1002/brx2.21","url":null,"abstract":"<p>The capacity to transport customized proteins into certain cell types has enormous implications for life science research and disease therapy. However, challenges associated with cell targeting and protein transportation through cellular membranes still exist, necessitating the creation of complex systems that can continuously carry payload proteins into cells.<span>¹</span>. In gene editing especially, achieving accurate targeted delivery is an intricate problem that warrants addressing. Endosymbiotic bacteria have developed complex delivery systems that enable them to interact with the host organism,<span>²</span> wherein secreted contractile injection systems (CISs), which are analogous to bacteriophage tails, can be harnessed as nanodevices.<span>³</span>. These macromolecular complexes consist of a solid tubular structure encompassed in a compressible sheath that is attached to a baseplate and sharpened by a spike protein. It is hypothesized that payloads are packed into the lumen of the inner tube behind the spike, which upon recognition by the target cell are pushed into the target cell through the membrane via sheath contraction.<span>⁴</span></p><p>Inspired by previous reports regarding CISs, recently, a team led by Professor Feng Zhang at the Broad Institute developed a redesigned protein delivery system; the corresponding results have been published in <i>Nature</i>.<span>⁵</span> Therein, extracellular contractile injection systems (eCISs), syringe-like nanomachines mimicking bacteriophage tails that can transport payloads independently and extracellularly, served as a new tool to solve a long-standing problem, that is, how to deliver therapeutic molecules to specific types of human cells precisely and efficiently (Figure 1). The structural composition of eCISs originating from the <i>Photorhabdus</i> virulence cassette (PVC) is such that the tail fibers on the outside of one end recognize specific receptors on the cell surface and anchor to host cells; thus, in their study, the researchers speculated that modifying the structure of these tail fibers may enable them to recognize different cells. Given that the action and targeting mechanisms of eCISs in human cells remain a mystery, the team used AlphaFold, an artificial intelligence protein design platform that can predict protein structures from amino acid sequences, to redesign the injector of PVC to shift the targeting objective from insect cells to human cells. Cellular studies demonstrated that after modification, the syringe, carrying a variety of protein cargoes, could detect human and mouse cells. Further research on protein delivery to cultivated cells was carried out, and the modified PVC was proved to exhibit specific targeting toward epidermal growth factor receptor (EGFR) after genetic engineering.</p><p>The most promising application of the precise delivery based on such PVC-derived eCISs is the specific targetin","PeriodicalId":94303,"journal":{"name":"Brain-X","volume":"1 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/brx2.21","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50152847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SPEAC-seq: A new method to investigate astrocyte-microglia crosstalk","authors":"Yao Tang,&nbsp;Fuchen Liu","doi":"10.1002/brx2.22","DOIUrl":"https://doi.org/10.1002/brx2.22","url":null,"abstract":"<p>Multicellular organisms rely on cellular communication to function. Numerous biological activities depend on the dynamic communication networks created by cellular communication. In neuroinflammation, crosstalk between astrocytes and microglia plays a crucial role. Aberrant interactions between these two sub-types of glial cells have been implicated in several neuroimmunological diseases, such as multiple sclerosis (MS)—a chronic inflammatory disorder of the central nervous system (CNS)—and its preclinical model, experimental autoimmune encephalomyelitis (EAE).<span>¹</span> As is known, specific cell signaling pathways are activated by receptors via selective detection and interaction with signal molecules (ligands). This results in the conversion of these molecules into intracellular messages. Accordingly, analysis of ligand-receptor pair interactions forms the basis for understanding cell behavior.<span>²</span> However, current methods fail to establish causal links between cellular interactions and molecular states. Furthermore, despite the CRISPR-Cas9 system serving as a powerful tool for gene identification, there are noted limitations relating to high-throughput co-culture and screening of the perturbation of single cells.<span>³</span> Recently, Professor Francisco J. Quintana's team developed a novel technique to identify forward genetic screens of cell–cell interaction mechanisms, which they call systematic perturbation of encapsulated associated cells followed by sequencing (SPEAC-seq). It combines CRISPR-Cas9 perturbations, co-culture of cells in droplets, and fluorescence-activated droplet sorting based on microfluidics (Figure 1).<span>⁴</span></p><p>The researchers established a preliminary microfluidic platform for studying cell-cell interactions. Firstly, a microfluidic co-flow system using two aqueous suspensions (one for each cell type) and oil was used to generate picoliter water-in-oil droplets containing cell pairs. For subsequent studies of cellular interactions, detection and selection were performed using a custom three-color optical system and dielectrophoretic microfluidic sorter. Next, the study was extended to cell pairs to determine if the cues generated by one cell were sufficient to alter the cellular state of cells co-cultured in the same droplet. Multiple labeling using a fluorescent dye with cell permeability was used for spiking and detection of cell pairs in the droplets. Results showed the upregulation of EGFP expression in NF-κB-labeled astrocytes paired with activated macrophages, as initially detected in isolated reporter cell pairs and following optimization of droplet sorting parameters. The above indicates that the researchers have successfully established an oil-in-droplet-based co-culture system. Subsequently, based on the microdroplet co-culture system combined with CRISPR-Cas9 perturbations, SPEAC-seq was developed as a forward genetic screening platfo","PeriodicalId":94303,"journal":{"name":"Brain-X","volume":"1 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/brx2.22","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50146616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A new mechanism of consciousness recovery from anesthesia regulated by K+-Cl– cotransporter KCC2","authors":"Jinwei Zhang","doi":"10.1002/brx2.19","DOIUrl":"https://doi.org/10.1002/brx2.19","url":null,"abstract":"<p>Neuroscience faces a puzzle in understanding the mechanism of general anesthesia. In the past, it was widely believed that recovery from anesthesia was a passive process caused by the breakdown of anesthetic agents. However, recent studies have challenged this view. For instance, activating specific neural circuits can promote the recovery of consciousness,<span>¹</span> indicating that these circuits is related to consciousness recovery and could play a crucial role in promoting it. However, prior to the recent work of Hu et al.,<span>²</span> research had not yet examined the core of consciousness recovery.</p><p>Hu et al. presented findings indicating that consciousness recovery is an active, not passive, process.<span>³</span> So-called passive recovery is merely an easily observable, intuitive, and superficial phenomenon and is not the essence of consciousness recovery. The authors used a combination of the traditional righting reflex test and a newly established scale to assess the level of consciousness in animals during the loss of consciousness following anesthetic administration. In mice, the administration of propofol, pentobarbital, or ketamine via intraperitoneal injection resulted in loss of the righting reflex (LORR) within 1 min and a righting reflex score of less than 3 within 15–20 min. The authors defined the state of mice with a consciousness score of less than 3 as the minimal response state (MRS) (Figure 1A). They then found that the active process of consciousness recovery is driven by inherent dynamics within the brain, initiated by a neurochemical reaction triggered by the ubiquitin degradation of the K⁺-Cl⁻ cotransporter-2 (KCC2), mediated by ubiquitin ligase Fbxl4 (F-box and leucine-rich repeat protein 4), in the ventral posteromedial nucleus (VPM) of the thalamus. Interestingly, the total amount of KCC2 (tKCC2) was observed to decrease from the awake state to MRS and increase from MRS to the recovery of the righting reflex (RRR), and with opposite changes in the amount of KCC2 Thr1007 phosphorylation (pKCC2) in the thalamus and hypothalamus (Figure 1B). The decreased tKCC2 and increased pKCC2 during MRS resulted in lower KCC2 activity, leading to elevated intraneuronal Cl⁻ levels [Cl⁻]_{\u0000 <i>i</i>\u0000}. This facilitated γ-aminobutyric acid (GABA)-driven Cl⁻ output, which in turn led to GABA_A receptor-mediated depolarization in VPM neurons (Figure 1C). Further in vitro experiments have shown that the interaction between KCC2 and Fbxl4 depends on the phosphorylation of KCC2 at Thr1007, which plays a critical role in the ubiquitination of KCC2 during propofol anesthesia. As a result, VPM neurons are disinhibited through GABA_A receptor-mediated signaling, which accelerates the recovery of excitability and consciousness arousal.</p><p>Hu et al. discovered that ubiquitin degradati","PeriodicalId":94303,"journal":{"name":"Brain-X","volume":"1 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/brx2.19","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50115615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The oscillating mystery: The effects of forty-hertz entrainment in treating Alzheimer's disease","authors":"Chuanliang Han","doi":"10.1002/brx2.14","DOIUrl":"https://doi.org/10.1002/brx2.14","url":null,"abstract":"<p>Imagine standing at crossroads unable to find your way home or gazing into the eyes of your loved one without remembering their name. For some, this is not merely imagination but the reality of Alzheimer's disease (AD). AD is a neurodegenerative disease that predominantly affects the elderly and stands as the leading cause of dementia. However, its etiology and pathogenesis remain poorly understood. One hallmark of AD is the accumulation of abnormal proteins in the brain, including amyloid-beta (Aβ) and tau. These proteins can disrupt the normal functioning of neurons and lead to their eventual death.</p><p>Since 2016, a series of studies<span>¹</span> have demonstrated that 40-Hz stimulation effectively improves the cognitive abilities of AD model mice. This improvement is attributed to the reduction of accumulated amyloid-β (Aβ) proteins and the enhancement of microglial function, both of which are associated with the disease. However, these findings have been challenged by recent research<span>²</span> conducted by Prof. Buzsáki and published in <i>Nature Neuroscience</i>. In this study, the research team utilized two AD mouse models, specifically APP/PS1 and 5xFAD, to explore the effects of both acute and chronic 40-Hz light stimulation on Aβ, microglia, and gamma oscillations. Firstly, they discovered that 40-Hz light stimulation had no effect on the level of Aβ deposition or the morphology of microglia, whether tested in vitro or in vivo. Subsequently, they demonstrated that the entrainment does not activate native gamma oscillations in the targeted brain regions (visual cortex, hippocampus, and entorhinal cortex). Furthermore, they observed that 40-Hz light stimulation induced aversion and avoidance behavior in mice. This was evident from the duration the mice spent in the compartment with 40-Hz light compared to the one with continuous light. Given the absence of experiments assessing cognitive functions before and after 40-Hz entrainment, the observed inconsistencies in pathological changes in AD following acute or chronic exposure should be considered with caution. For example, the inability to replicate the beneficial effects of flickering light stimulation on Aβ and microglia may be attributed to variations in the experimental parameters. Although both animal models and human subjects have shown improvements in cognitive functions (such as memory) after 40-Hz entrainment, the underlying mechanisms driving these changes remain elusive. Nevertheless, this study successfully eliminated one potential mechanism for reducing AD symptoms—namely, the entrainment of natural gamma-band oscillations. The search for alternative mechanisms continues.</p><p>Given the notable behavioral improvement resulting from 40-Hz stimulation, it is indisputable that the underlying mechanism must have a significant association with gamma-band activity (30–100 Hz). The broad frequency band comprises multiple sub-gamma oscillations, each ","PeriodicalId":94303,"journal":{"name":"Brain-X","volume":"1 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/brx2.14","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50155888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Waking up neural stem cells through inhibition of mitochondrial pyruvate import","authors":"Yajiao Shi,&nbsp;You Wan,&nbsp;Jie Zheng","doi":"10.1002/brx2.13","DOIUrl":"https://doi.org/10.1002/brx2.13","url":null,"abstract":"<p>Neurogenesis declines sharply in adulthood, partly because neural stem and progenitor cells (NSPCs) increasingly return to a dormant state as they age. However, innate NSPC pools are preserved in specific brain regions throughout an individual's lifetime. Petrelli et al.<span>¹</span> recently reported that inhibiting mitochondrial pyruvate import stimulated NSPCs to transition from a quiescent state to an active state, thereby promoting neurogenesis in both young and middle-aged mice. These findings indicate a novel approach for pro-neurogenic treatments.</p><p>Most neurogenesis in the brain is completed during embryonic development, with only small pools of NSPCs remaining to generate new neurons postnatally. These NSPCs are primarily found in the hippocampal dentate gyrus and the subventricular zone. This biological process, particularly adult hippocampal neurogenesis (AHN), plays a crucial role in specific functions such as pattern separation, learning and memory, and emotional regulation. The pool of NSPCs in the adult brain gradually diminishes but is maintained at a certain level throughout life due to the self-renewal of neural stem cells during symmetric cell division.</p><p>However, the extent of AHN declines much more sharply compared with the age-dependent depletion of the NSC pool. One of the most significant causes for this decline is the increasing rate at which NSCs in the adult brain transition from an active to a dormant state, remaining quiescent and refusing to proliferate to initiate neurogenesis. Thus, activating these dormant quiescent NSCs is pivotal for restoring neurogenesis.</p><p>The mitochondrial pyruvate carrier (MPC) on the inner mitochondrial membrane is responsible for transporting the glycolytic end-product pyruvate from the cytosol into the mitochondria, thereby linking glycolysis to the tricarboxylic acid cycle and oxidative phosphorylation. Given that glycolysis plays a critical role in determining the activity state of NSCs, Petrelli et al.<span>¹</span> recently found that MPC expression was highest in quiescent NSPCs, as opposed to those that were active or proliferating.</p><p>Moreover, both pharmacological blockage of MPC in vitro using the specific membrane-penetrating inhibitor UK5099 and selective deletion of the <i>Mpc1</i> gene in NSPCs led to the proliferation of these quiescent NSPCs. Subsequently, the authors aimed to investigate the underlying metabolic mechanism. They ruled out the contribution of lactate elevation resulting from MPC loss-of-function as neither lactate supplementation nor downregulation affected the proliferation of NSPCs.</p><p>Instead, they discovered that the elevated intracellular aspartate, presumed to be due to the upregulation of glutamic-oxaloacetic transaminase activity or enhanced mitochondrial aspartate import, played a significant role in activating quiescent NSPCs. In contrast to quiescent NSPCs, inhibiting MPCs did not affect the proliferat","PeriodicalId":94303,"journal":{"name":"Brain-X","volume":"1 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/brx2.13","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50147946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel mechanism of DNA repair in neurons opens promising avenues for combatting neurodegenerative diseases and brain aging","authors":"Conglin Wang,&nbsp;Xintong Ge,&nbsp;Wenqiang Xin,&nbsp;Ping Lei","doi":"10.1002/brx2.9","DOIUrl":"https://doi.org/10.1002/brx2.9","url":null,"abstract":"<p>A recent study, titled “A NPAS4-NuA4 Complex Couples Synaptic Activity to DNA Repair,” reveals an exciting new mechanism by which neurons maintain genomic stability in response to external stimuli. Published in Nature on February 23, 2023,<span>¹</span> this paper provides valuable insights into the molecular mechanisms underlying neurodegenerative diseases and brain aging that pave the way for the development of new therapeutic strategies. This commentary reviews the research findings and their potential for future applications.</p><p>The brain is a highly dynamic and plastic organ that relies on neurons to modify their gene expression under a variety of pathophysiological conditions. Excessive or prolonged neuronal response to external stimuli can lead to DNA damage and genomic instability, thereby being harmful to the brain. Cumulative DNA damage in the neuronal genome is also a hallmark of neurodegeneration and brain aging. Until recently, the molecular mechanism by which neurons repair DNA and maintain genomic stability in response to external stimuli remained unclear.</p><p>Neuronal PAS Domain Protein 4 (NPAS4) is an activity-induced transcription factor that is selectively expressed in neurons following membrane depolarization and subsequent calcium signaling. Through a series of biochemical and genomic experiments on mice, the researchers first determined that NPAS4 exists as part of a 21-protein complex called NPAS4-NuA4. They then measured DNA damage using γH2AX ChIP-seq, sBLISS-seq, END-seq and SAR-seq, which indicated that NPAS4 preferentially binds to active DNA breaking-induced sites in neurons. These advanced techniques can be used to analyze the binding sites of transcription factors,<span>²</span> provide whole-genome maps with DNA double-strand breaks,<span>³</span> monitor DNA terminal excision,<span>⁴</span> and localize DNA repair synthesis in vivo and in various cell types.<span>⁵</span> Thus, they could contribute greatly to future research in neuroscience and other biomedical fields.</p><p>In addition, the NPAS4-NuA4 complex serves as a critical mediator in the mechanism underlying neurodegenerative diseases and aging in the brain. Activated in response to neuronal activity driven by changes in sensory experience, NPAS4-NuA4 binds to periodically damaged transcriptional regulatory elements and recruits DNA repair machinery to prevent age-dependent somatic mutation accumulation. Furthermore, impaired NPAS4-NuA4 leads to a range of cellular defects that result in a shortened lifespan, including dysregulation of neuronal activity-dependent transcriptional responses, loss of somatic inhibition of pyramidal neurons, impaired localization of protective repair machinery, and genomic instability.</p><p>One of the most exciting aspects of this study is its discovery of a link between damage and neuronal activity-dependent regulatory elements and neuronal dysfunction in neuro","PeriodicalId":94303,"journal":{"name":"Brain-X","volume":"1 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/brx2.9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50138113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"3D printing-based full-scale human brain for diverse applications","authors":"Weijian Hua,&nbsp;Cheng Zhang,&nbsp;Lily Raymond,&nbsp;Kellen Mitchell,&nbsp;Lai Wen,&nbsp;Ying Yang,&nbsp;Danyang Zhao,&nbsp;Shu Liu,&nbsp;Yifei Jin","doi":"10.1002/brx2.5","DOIUrl":"10.1002/brx2.5","url":null,"abstract":"<p>Surgery is the most frequent treatment for patients with brain tumors. The construction of full-scale human brain models, which is still challenging to realize via current manufacturing techniques, can effectively train surgeons before brain tumor surgeries. This paper aims to develop a set of three-dimensional (3D) printing approaches to fabricate customized full-scale human brain models for surgery training as well as specialized brain patches for wound healing after surgery. First, a brain patch designed to fit a wound's shape and size can be easily printed in and collected from a stimuli-responsive yield-stress support bath. Then, an inverse 3D printing strategy, called “peeling-boiled-eggs,” is proposed to fabricate full-scale human brain models. In this strategy, the contour layer of a brain model is printed using a sacrificial ink to envelop the target brain core within a photocurable yield-stress support bath. After crosslinking the contour layer, the as-printed model can be harvested from the bath to photo crosslink the brain core, which can be eventually released by liquefying the contour layer. Both the brain patch and full-scale human brain model are successfully printed to mimic the scenario of wound healing after removing a brain tumor, validating the effectiveness of the proposed 3D printing approaches.</p>","PeriodicalId":94303,"journal":{"name":"Brain-X","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/brx2.5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41224669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"3-hydroxybutyrate in the brain: Biosynthesis, function, and disease therapy","authors":"Bing-Long Wang,&nbsp;Jian-Fei Wu,&nbsp;Da Xiao,&nbsp;Bo Wu,&nbsp;Dai-Xu Wei","doi":"10.1002/brx2.6","DOIUrl":"https://doi.org/10.1002/brx2.6","url":null,"abstract":"<p>3-hydroxybutyrate (3HB), or BHB, is an anionic small molecule acid metabolite with a hydroxyl group. 3HB is the major ketone body that is distributed in the human brain and its primary energy source when glucose is absent. A better understanding of 3HB and how to adapt neuronal response mechanisms is expected to facilitate the development of new interventions to promote cognitive brain function and prevent neurodegenerative diseases. It provides important concepts for the clinical application of 3HB therapy. This review summarizes the distribution of 3HB in the brain, its properties, and its mechanism in brain and nerve regulation. We focus on 3HB biosynthesis in natural human cells and engineered bacteria via synthetic biology platforms and 3HB treatment in various brain and nerve diseases, including epilepsy, multiple sclerosis, stroke, Parkinson's disease, Alzheimer's disease, Huntington's disease, depressive disorder, and schizophrenia. Ultimately, this review explores the future development trend of 3HB as a potential small-molecule drug for brain and nerve diseases.</p>","PeriodicalId":94303,"journal":{"name":"Brain-X","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/brx2.6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50145576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nucleic acid delivery by ionizable nanocarriers for brain disease treatment","authors":"Ruru Xiong,&nbsp;Guixia Ling,&nbsp;Yuqi Zhang,&nbsp;Jibin Guan,&nbsp;Peng Zhang","doi":"10.1002/brx2.7","DOIUrl":"https://doi.org/10.1002/brx2.7","url":null,"abstract":"<p>The successful application of messenger RNA vaccines in the market has demonstrated the potential of gene therapy in treating various diseases, including infectious diseases, autoimmune disorders, brain diseases, and other cancers. However, gene therapy faces great challenges in treating brain diseases such as brain tumors, infections, and strokes because the limitations of the blood-brain barrier make it difficult for nucleic acid drugs to be delivered safely and effectively into the brain. Therefore, there is a high demand for carriers delivering nucleic acid drugs to the brain. Ionizable nanocarriers (INs) have great advantages in gene therapy due to their pH-responsive properties, which facilitate the safe and efficient delivery of targets, responsive release in the disease microenvironment, and the protection of nucleic acids from degradation. To better understand INs and their potential as therapeutic vectors for brain diseases, the present review describes their biological properties, recent progress in the field, and promising applications. In particular, the related prospects and challenges are discussed to promote the further development of INs.</p>","PeriodicalId":94303,"journal":{"name":"Brain-X","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/brx2.7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50144491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systolic pressure target after endovascular thrombectomy in acute large-vessel occlusion ischemic stroke patients: Comment on ENCHANTED2/MT","authors":"Yunpeng Yuan,&nbsp;Baozhu Wei,&nbsp;Wenyun Zhu,&nbsp;Yang Liu,&nbsp;Yingfeng Wan","doi":"10.1002/brx2.4","DOIUrl":"https://doi.org/10.1002/brx2.4","url":null,"abstract":"<p>Patients with large-vessel occlusion ischemic stroke continue to have high mortality and disability rates after mechanical thrombectomy with or without intravenous alteplase treatment. Elevated blood pressure during the perioperative period is associated with higher mortality and disability prevalence rates.<span>¹</span> Thus, lowering post-procedure systolic pressure is a potential approach to improving patients' outcomes. The guideline<span>²</span> recommends a systolic pressure of &lt;180 mmHg before and after mechanical thrombectomy without randomized clinical trial evidence.</p><p>Recently, Yang et al.<span>³</span> reported the results of the multicenter, open-label, blinded-endpoint, and randomized controlled trial ENCHANTED2/MT, which aimed to determine if a more aggressive blood pressure goal is beneficial in patients with acute ischemic stroke. Patients were required to have a diagnosis of large-vessel occlusion acute ischemic stroke and a successful endovascular thrombectomy procedure followed by hypertension (defined as ≥2 successive measurements of systolic blood pressure ≥140 mmHg for &gt;10 min). The randomization arms were &lt;120 mmHg versus 140–180 mmHg for 72 h, and the primary outcome was assessed by a shift analysis of the modified Rankin Scale at 90 days. The 821 patients who were prospectively enrolled between 2020 and 2022 were randomized, and the source populations were derived from 44 hospitals in China. The trial was suspended in June 2022 due to safety concerns after an independent data and safety monitoring board reviewed the data. Unexpectedly, the primary results were that the more intensive treatment group was more likely to have worse outcomes and higher early neurological deterioration and disability rates than the less intensive treatment group.</p><p>This study again proved the complex relationship between blood pressure and functional outcomes after acute large-vessel occlusion ischemic stroke.<span>¹</span> This is an important trial that was built on accumulating observational data in the field and provided randomized trial evidence that more intensive blood pressure lowering (&lt;120 mmHg) is not only neutral but harmful. In this regard, this study is of broad general interest to emergency departments and stroke centers, as blood pressure is a parameter that must be managed in all stroke patients' post-procedures.</p><p>However, several points need to be noted and comprehensively discussed before interpreting the results and applying them clinically. First, fig. 2 from the ENCHANTED2/MT trial paper<span>³</span> suggested that a systolic pressure of &lt;120 mmHg was only narrowly achieved in the more intensive treatment group during the first 3 days. Although current guidelines<span>²</span> recommend a blood pressure of &lt;180 mmHg, no optimal blood pressure target for patients with ischemic stroke who undergo mechanical thrombectomy h","PeriodicalId":94303,"journal":{"name":"Brain-X","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/brx2.4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50117446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}