Weiping Wang, Haiyan Zhao, Chang He, Yuanbo Cui, Zhen Wang, Alexander Hramov, Ping Luan, Xiong Luo, Jipeng Ouyang, Kurths Jürgen
Currently, no specific treatments are available for Alzheimer's disease (AD). Mild cognitive impairment (MCI), the preclinical stage of AD, has a high possibility of reversing symptoms through neural regulation. A state dynamics model for single brain regions was developed to simulate blood oxygen level-dependent signals in a patient with early mild cognitive impairment. Subsequently, the analysis of functional connections was used to comprehensively consider multiple complex network centralities to locate the intervention targets, and a multiple brain region collaborative control scheme was designed. Finally, the reliability and effectiveness of the intervention were verified at the brain region and subnetwork levels. This technique provides a basis for future clinical diagnosis and treatment of AD and MCI.
{"title":"Target localization intervention and prognosis evaluation for an individual with mild cognitive impairment","authors":"Weiping Wang, Haiyan Zhao, Chang He, Yuanbo Cui, Zhen Wang, Alexander Hramov, Ping Luan, Xiong Luo, Jipeng Ouyang, Kurths Jürgen","doi":"10.1002/brx2.25","DOIUrl":"https://doi.org/10.1002/brx2.25","url":null,"abstract":"<p>Currently, no specific treatments are available for Alzheimer's disease (AD). Mild cognitive impairment (MCI), the preclinical stage of AD, has a high possibility of reversing symptoms through neural regulation. A state dynamics model for single brain regions was developed to simulate blood oxygen level-dependent signals in a patient with early mild cognitive impairment. Subsequently, the analysis of functional connections was used to comprehensively consider multiple complex network centralities to locate the intervention targets, and a multiple brain region collaborative control scheme was designed. Finally, the reliability and effectiveness of the intervention were verified at the brain region and subnetwork levels. This technique provides a basis for future clinical diagnosis and treatment of AD and MCI.</p>","PeriodicalId":94303,"journal":{"name":"Brain-X","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/brx2.25","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50140498","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}
Acute myocardial infarction (AMI) occurs in 1.6%–2.1% of patients with acute stroke.1 Primary percutaneous coronary intervention (PCI) and antithrombotic therapy, which improve cardiovascular outcomes in patients with AMI, may elevate the risks of hemorrhagic stroke in the acute phase of stroke.2 How to manage the ischemic and bleeding risks in patients with AMI complicating acute stroke (AMI-CAS) is challenging in clinics. Therapeutics for AMI-CAS should be well-balanced by collaborating with cardiologists and neurologists. The institute in the present study has a structure to provide a heart–brain team approach,3 which was defined as cardiac catheterization and antithrombotic therapies, according to the status and severity of an acute stroke and the patient's condition.
In this issue of the Journal of the American Heart Association, Suzuki et al.4 described different clinical characteristics, coronary revascularization and antithrombotic therapies and cardiovascular and major bleeding outcomes of patients with AMI-CAS. These findings were based on a retrospective cohort study using data from the National Cerebral and Cardiovascular Center (Suita, Japan) between 1 January 2007, and 30 September 2020 and included 2393 consecutive patients with AMI. Of these patients, those with takotsubo cardiomyopathy (n = 3) were excluded. The primary outcome was defined as a composite of major adverse cerebral/cardiovascular events (MACCEs), which included cardiac-cause death, nonfatal myocardial infarction, and nonfatal stroke. The authors reported a few attractive findings. Firstly, AMI-CAS was identified in 1.6% (39/2390) of study participants in the current study. The characteristics of AMI-CAS tend to be women (46.2% vs. 26.2%; P = 0.005), chronic kidney disease (71.8% vs. 47.0%; P = 0.002), atrial fibrillation (38.5% vs. 9.8%; P < 0.001) and stroke (33.3% vs. 11.1%; P < 0.001). In 39 patients with AMI-CAS, 37 patients (37/39 = 94.9%) and 2 patients (2/39 = 5.1%) were diagnosed as having an ischemic stroke or hemorrhagic stroke, respectively. 69.2% and 10.3% of them were attributable to cardioembolic and atherosclerotic causes, respectively. AMI occurred within 3 days from the onset of acute stroke in 59.0% of patients with AMI-CAS, and the median duration of AMI from the onset of acute stroke was 2 days (interquartile range, 0–8 days). Secondly, medical procedures were conducted with a diverse frequency between AMI-CAS patients and AMI patients without acute stroke. Primary PCI (43.6% vs. 84.7%; p < 0.001), stent implantation (30.8% vs. 77.9%; p < 0.001) and dual-antithrombotic therapy (38.5% vs. 85.7%) were less frequently received in AMI-CAS, whereas thrombectomy (7.7% vs. 1.4%; p = 0.02) was higher than AMI patients without acute stroke. Additionally, angiotensin-converting
{"title":"Heart–brain team approach of acute myocardial infarction complicating acute stroke: Evidencing the knowledge gap","authors":"Na Li, Xin Tian, Yongzheng Guo","doi":"10.1002/brx2.28","DOIUrl":"https://doi.org/10.1002/brx2.28","url":null,"abstract":"<p>Acute myocardial infarction (AMI) occurs in 1.6%–2.1% of patients with acute stroke.<span><sup>1</sup></span> Primary percutaneous coronary intervention (PCI) and antithrombotic therapy, which improve cardiovascular outcomes in patients with AMI, may elevate the risks of hemorrhagic stroke in the acute phase of stroke.<span><sup>2</sup></span> How to manage the ischemic and bleeding risks in patients with AMI complicating acute stroke (AMI-CAS) is challenging in clinics. Therapeutics for AMI-CAS should be well-balanced by collaborating with cardiologists and neurologists. The institute in the present study has a structure to provide a heart–brain team approach,<span><sup>3</sup></span> which was defined as cardiac catheterization and antithrombotic therapies, according to the status and severity of an acute stroke and the patient's condition.</p><p>In this issue of the <i>Journal of the American Heart Association</i>, Suzuki et al.<span><sup>4</sup></span> described different clinical characteristics, coronary revascularization and antithrombotic therapies and cardiovascular and major bleeding outcomes of patients with AMI-CAS. These findings were based on a retrospective cohort study using data from the National Cerebral and Cardiovascular Center (Suita, Japan) between 1 January 2007, and 30 September 2020 and included 2393 consecutive patients with AMI. Of these patients, those with takotsubo cardiomyopathy (<i>n</i> = 3) were excluded. The primary outcome was defined as a composite of major adverse cerebral/cardiovascular events (MACCEs), which included cardiac-cause death, nonfatal myocardial infarction, and nonfatal stroke. The authors reported a few attractive findings. Firstly, AMI-CAS was identified in 1.6% (39/2390) of study participants in the current study. The characteristics of AMI-CAS tend to be women (46.2% vs. 26.2%; <i>P</i> = 0.005), chronic kidney disease (71.8% vs. 47.0%; <i>P</i> = 0.002), atrial fibrillation (38.5% vs. 9.8%; <i>P</i> < 0.001) and stroke (33.3% vs. 11.1%; <i>P</i> < 0.001). In 39 patients with AMI-CAS, 37 patients (37/39 = 94.9%) and 2 patients (2/39 = 5.1%) were diagnosed as having an ischemic stroke or hemorrhagic stroke, respectively. 69.2% and 10.3% of them were attributable to cardioembolic and atherosclerotic causes, respectively. AMI occurred within 3 days from the onset of acute stroke in 59.0% of patients with AMI-CAS, and the median duration of AMI from the onset of acute stroke was 2 days (interquartile range, 0–8 days). Secondly, medical procedures were conducted with a diverse frequency between AMI-CAS patients and AMI patients without acute stroke. Primary PCI (43.6% vs. 84.7%; <i>p</i> < 0.001), stent implantation (30.8% vs. 77.9%; <i>p</i> < 0.001) and dual-antithrombotic therapy (38.5% vs. 85.7%) were less frequently received in AMI-CAS, whereas thrombectomy (7.7% vs. 1.4%; <i>p</i> = 0.02) was higher than AMI patients without acute stroke. Additionally, angiotensin-converting ","PeriodicalId":94303,"journal":{"name":"Brain-X","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/brx2.28","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50150912","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}
Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide. Because of the complex pathogenesis of AD and the unique location of AD lesions, effective clinical treatment strategies for this disease remain elusive. However, the development of nanotechnology has allowed a new era of AD treatment to emerge. AD nanomedicines are products of interdisciplinary research that enable high precision and targeted delivery. Additionally, they can specifically regulate various pathogenic factors. This review focuses on nanomedicines based on the pathological mechanisms of AD that can target AD lesions. We also discuss the precise regulatory effects of nanomedicines (including the nanomaterials themselves) on pathogenic proteins, neuroinflammatory molecules, and other pathogenic factors. We summarize the clinical trials that have examined new AD drugs, highlighting the development of new nanomedicines and the progress in their clinical translation. Nanotechnology-based AD treatment is a nascent field, and a complete cure is distant at present; therefore, we also elaborate on the shortcomings of current AD nanomedicines. Finally, we discuss the prospects to guide the future development of AD nanomedicines.
{"title":"Nanomedicines for Alzheimer's disease: Therapies based on pathological mechanisms","authors":"Guowang Cheng, Aihua Xie, Zhao Yan, Xiaozhen Zhu, Yafang Song, Tongkai Chen","doi":"10.1002/brx2.27","DOIUrl":"https://doi.org/10.1002/brx2.27","url":null,"abstract":"<p>Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide. Because of the complex pathogenesis of AD and the unique location of AD lesions, effective clinical treatment strategies for this disease remain elusive. However, the development of nanotechnology has allowed a new era of AD treatment to emerge. AD nanomedicines are products of interdisciplinary research that enable high precision and targeted delivery. Additionally, they can specifically regulate various pathogenic factors. This review focuses on nanomedicines based on the pathological mechanisms of AD that can target AD lesions. We also discuss the precise regulatory effects of nanomedicines (including the nanomaterials themselves) on pathogenic proteins, neuroinflammatory molecules, and other pathogenic factors. We summarize the clinical trials that have examined new AD drugs, highlighting the development of new nanomedicines and the progress in their clinical translation. Nanotechnology-based AD treatment is a nascent field, and a complete cure is distant at present; therefore, we also elaborate on the shortcomings of current AD nanomedicines. Finally, we discuss the prospects to guide the future development of AD nanomedicines.</p>","PeriodicalId":94303,"journal":{"name":"Brain-X","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/brx2.27","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50146362","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}
Zhenyu Feng, Jinran Yu, Yichen Wei, Yifei Wang, Bobo Tian, Yonghai Li, Liuqi Cheng, Zhong Lin Wang, Qijun Sun
Inspired by biological neural networks, the fabrication of artificial neuromorphic systems with multimodal perception capacity shows promises in overcoming the “von Neumann bottleneck” and takes advantage of the efficient perception and computation of diverse types of signals. Here, we combine a triboelectric nanogenerator with an α-phase indium selenide (α-In2Se3) optoelectronic synaptic transistor to construct a tribo-ferro-optoelectronic artificial neuromorphic device with multimodal plasticity. Based on the excellent ferroelectric and optoelectronic characteristics of the α-In2Se3 channel, typical synaptic behaviors (e.g., pair-pulse facilitation and short-term/long-term plasticity) are successfully simulated in response to the synergistic effect of mechanical and optical stimuli. The interaction of mechanical displacement and light illumination enables heterosynaptic plasticity and spatiotemporal dynamic logic. Furthermore, multiple Boolean logical functions and associative learning behaviors are successfully implemented using the paired stimuli of displacement pulses and light pulses. The proposed tribo-ferro-optoelectronic artificial neuromorphic devices have great potential for application in interactive neural networks and next-generation artificial intelligence.
{"title":"Tribo-ferro-optoelectronic neuromorphic transistor of α-In2Se3","authors":"Zhenyu Feng, Jinran Yu, Yichen Wei, Yifei Wang, Bobo Tian, Yonghai Li, Liuqi Cheng, Zhong Lin Wang, Qijun Sun","doi":"10.1002/brx2.24","DOIUrl":"https://doi.org/10.1002/brx2.24","url":null,"abstract":"<p>Inspired by biological neural networks, the fabrication of artificial neuromorphic systems with multimodal perception capacity shows promises in overcoming the “von Neumann bottleneck” and takes advantage of the efficient perception and computation of diverse types of signals. Here, we combine a triboelectric nanogenerator with an <i>α</i>-phase indium selenide (<i>α</i>-In<sub>2</sub>Se<sub>3</sub>) optoelectronic synaptic transistor to construct a tribo-ferro-optoelectronic artificial neuromorphic device with multimodal plasticity. Based on the excellent ferroelectric and optoelectronic characteristics of the <i>α</i>-In<sub>2</sub>Se<sub>3</sub> channel, typical synaptic behaviors (e.g., pair-pulse facilitation and short-term/long-term plasticity) are successfully simulated in response to the synergistic effect of mechanical and optical stimuli. The interaction of mechanical displacement and light illumination enables heterosynaptic plasticity and spatiotemporal dynamic logic. Furthermore, multiple Boolean logical functions and associative learning behaviors are successfully implemented using the paired stimuli of displacement pulses and light pulses. The proposed tribo-ferro-optoelectronic artificial neuromorphic devices have great potential for application in interactive neural networks and next-generation artificial intelligence.</p>","PeriodicalId":94303,"journal":{"name":"Brain-X","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/brx2.24","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50145781","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}
Brain tumor (BT) is one of many malignancies that have substantially enhanced global human morbidity and mortality rates. Early detection and characterization of glioma are essential for effective preventive strategies. Currently, the use of Transformers, a deep learning model for BT diagnosis and treatment, is attracting significant attention. The transformer self-attention mechanism automatically learns the associations between input data for efficient processing and analysis. Research indicates that Transformers could play an essential role in the BT segmentation of magnetic resonance imaging (MRI) images, the MRI and histopathology-based grading of brain cancer, BT molecular expression prediction, the classification of primary brain metastasis sites, voxel-level dose and BT radiotherapy outcome prediction, synergistic prediction, and the pathway deconvolution of drug combinations. In this review, the feasibility, accuracy, and applicability of various algorithms are systematically analyzed and their prospects are discussed. Overall, this review aimed to discuss and provide an overview of the increasing applications of Transformers in real-time BT detection and therapy, indicating their broad prospects and potential. In the future, Transformers are expected to be increasingly used for the diagnosis and subsequent treatment of BT because of the continuous development and improvement of Transformer-based deep learning technology. However, more work is required to investigate their properties for anomaly detection, medical image classification, network design development, and application to other medical data.
{"title":"Potential roles of transformers in brain tumor diagnosis and treatment","authors":"Yu-Long Lan, Shuang Zou, Bing Qin, Xiangdong Zhu","doi":"10.1002/brx2.23","DOIUrl":"https://doi.org/10.1002/brx2.23","url":null,"abstract":"<p>Brain tumor (BT) is one of many malignancies that have substantially enhanced global human morbidity and mortality rates. Early detection and characterization of glioma are essential for effective preventive strategies. Currently, the use of Transformers, a deep learning model for BT diagnosis and treatment, is attracting significant attention. The transformer self-attention mechanism automatically learns the associations between input data for efficient processing and analysis. Research indicates that Transformers could play an essential role in the BT segmentation of magnetic resonance imaging (MRI) images, the MRI and histopathology-based grading of brain cancer, BT molecular expression prediction, the classification of primary brain metastasis sites, voxel-level dose and BT radiotherapy outcome prediction, synergistic prediction, and the pathway deconvolution of drug combinations. In this review, the feasibility, accuracy, and applicability of various algorithms are systematically analyzed and their prospects are discussed. Overall, this review aimed to discuss and provide an overview of the increasing applications of Transformers in real-time BT detection and therapy, indicating their broad prospects and potential. In the future, Transformers are expected to be increasingly used for the diagnosis and subsequent treatment of BT because of the continuous development and improvement of Transformer-based deep learning technology. However, more work is required to investigate their properties for anomaly detection, medical image classification, network design development, and application to other medical data.</p>","PeriodicalId":94303,"journal":{"name":"Brain-X","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/brx2.23","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50150382","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}
The brain structure and language skills of children are understood to be in a phase of rapid development and are especially represented by key phonological-semantic expressions that actively develop with age. In the present study, resting-state functional magnetic resonance imaging data from 85 healthy children were retrospectively analyzed. Correlations of the phonological processing and speeded naming of specific brain regions of interest with age were assessed using the fractional amplitude of low-frequency fluctuations (fALFF), degree centrality (DC), regional homogeneity (ReHo), and chain mediation effect analysis. Our results suggest that the developmental stages of children's posterior cingulate gyrus (PCC) and right inferior frontal gyrus (IFG) mediate language development in children. Additionally, the functional similarity of the bilateral IFG triangular part was noted during development as was the stronger activation and higher local and whole-brain connectivity of the left IFG triangular part. Moreover, the PCC displayed stronger activation and higher local connectivity in the same period. Our data suggest that the development of the PCC and right IFG and the similarity of bilateral IFG function are important imaging markers of phonological processing and speeded naming in children and that the PCC and IFG show a more comprehensive development with age.
{"title":"Functional magnetic resonance imaging study of children's brain development in phonological processing and speeded naming","authors":"Zeyu Song, Zhenqi Jiang, Yingwei Fan, Liang Lu, Zhao Zhang, Yifei Wang, Yu Chen, Lifei Liu, Xiaoying Tang, Hanjun Li","doi":"10.1002/brx2.20","DOIUrl":"https://doi.org/10.1002/brx2.20","url":null,"abstract":"<p>The brain structure and language skills of children are understood to be in a phase of rapid development and are especially represented by key phonological-semantic expressions that actively develop with age. In the present study, resting-state functional magnetic resonance imaging data from 85 healthy children were retrospectively analyzed. Correlations of the phonological processing and speeded naming of specific brain regions of interest with age were assessed using the fractional amplitude of low-frequency fluctuations (fALFF), degree centrality (DC), regional homogeneity (ReHo), and chain mediation effect analysis. Our results suggest that the developmental stages of children's posterior cingulate gyrus (PCC) and right inferior frontal gyrus (IFG) mediate language development in children. Additionally, the functional similarity of the bilateral IFG triangular part was noted during development as was the stronger activation and higher local and whole-brain connectivity of the left IFG triangular part. Moreover, the PCC displayed stronger activation and higher local connectivity in the same period. Our data suggest that the development of the PCC and right IFG and the similarity of bilateral IFG function are important imaging markers of phonological processing and speeded naming in children and that the PCC and IFG show a more comprehensive development with age.</p>","PeriodicalId":94303,"journal":{"name":"Brain-X","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/brx2.20","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50128033","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}
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.1. 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,2 wherein secreted contractile injection systems (CISs), which are analogous to bacteriophage tails, can be harnessed as nanodevices.3. 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.4
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 Nature.5 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 Photorhabdus 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.
The most promising application of the precise delivery based on such PVC-derived eCISs is the specific targetin
{"title":"Revolutionary delivery system enables precise protein transportation","authors":"Qian Zhang, 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><sup>1</sup></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><sup>2</sup></span> wherein secreted contractile injection systems (CISs), which are analogous to bacteriophage tails, can be harnessed as nanodevices.<span><sup>3</sup></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><sup>4</sup></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><sup>5</sup></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":null,"pages":null},"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}
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).1 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.2 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.3 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).4
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
{"title":"SPEAC-seq: A new method to investigate astrocyte-microglia crosstalk","authors":"Yao Tang, 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><sup>1</sup></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><sup>2</sup></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><sup>3</sup></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><sup>4</sup></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":null,"pages":null},"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}
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,1 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.,2 research had not yet examined the core of consciousness recovery.
Hu et al. presented findings indicating that consciousness recovery is an active, not passive, process.3 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−]