关键词： Experimental models of disease   Neurological disorders  

摘要： The search for effective therapies for neurological disease has been impeded by our limited understanding of the causative molecular and cellular mechanisms. Kampmann describes how new CRISPR-based functional genomics approaches can uncover disease mechanisms and therapeutic targets in neurological diseases. Neurodegenerative, neurodevelopmental and neuropsychiatric disorders are among the greatest public health challenges, as many lack disease-modifying treatments. A major reason for the absence of effective therapies is our limited understanding of the causative molecular and cellular mechanisms. Genome-wide association studies are providing a growing catalogue of disease-associated genetic variants, and the next challenge is to elucidate how these variants cause disease and to translate this understanding into therapies. This Review describes how new CRISPR-based functional genomics approaches can uncover disease mechanisms and therapeutic targets in neurological diseases. The bacterial CRISPR system can be used in experimental disease models to edit genomes and to control gene expression levels through CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa). These genetic perturbations can be implemented in massively parallel genetic screens to evaluate the functional consequences for human cells. CRISPR screens are particularly powerful in combination with induced pluripotent stem cell technology, which enables the derivation of differentiated cell types, such as neurons and glia, and brain organoids from cells obtained from patients. Modelling of disease-associated changes in gene expression via CRISPRi and CRISPRa can pinpoint causal changes. In addition, genetic modifier screens can be used to elucidate disease mechanisms and causal determinants of cell type-selective vulnerability and to identify therapeutic targets.

关键词： TRPV4   Intracerebral hemorrhage   Neurological deficits   Motor paralysis   c-Fos  

摘要： Intracerebral hemorrhage (ICH) is one of the most severe subtypes of stroke with high morbidity and mortality. Although a lot of drug discovery studies have been conducted, the drugs with satisfactory therapeutic effects for motor paralysis after ICH have yet to reach clinical application. Transient receptor potential vanilloid 4 (TRPV4), a Ca2+-permeable cation channel and activated by hypoosmolarity and warm temperature, is expressed in various cell types. The present study investigated whether TRPV4 would participate in the brain damage in a mouse model of ICH. ICH was induced by intrastriatal treatment of collagenase. Administration of GSK1016790A, a selective TRPV4 agonist, attenuated neurological and motor deficits. The inhibitory effects of the TRPV4 agonist in collagenase-injected WT mice were completely disappeared in TRPV4-KO mice. The TRPV4 agonist did not alter brain injury volume and brain edema at 1 and 3 days after ICH induction. The TRPV4 agonist did not show any differences with respect to the increased number of Iba1-positive microglia/macrophages, GFAP-positive astrocytes, and Gr1-positive neutrophils at 1 and 3 days after ICH induction. Quantitative RT-PCR experiments revealed that the TRPV4 agonist significantly upregulated the expression level of c-fos, a marker of neuronal activity, while the agonist gave no effects on the expression level of cytokines/chemokines at 1 day after ICH induction, These results suggest that stimulation of TRPV4 would ameliorate ICH-induced brain injury, presumably by increased neuronal activity and TRPV4 provides a novel therapeutic target for the treatment for ICH. (C) 2020 Elsevier Inc. All rights reserved.

关键词： high pressure   liquid-liquid phase separation   protein condensates   SynGAP   PSD-95  

摘要： Biomolecular condensates consisting of proteins and nucleic acids can serve critical biological functions, so that some condensates are referred as membraneless organelles. They can also be disease-causing, if their assembly is misregulated. A major physicochemical basis of the formation of biomolecular condensates is liquid-liquid phase separation (LLPS). In general, LLPS depends on environmental variables, such as temperature and hydrostatic pressure. The effects of pressure on the LLPS of a binary SynGAP/PSD-95 protein system mimicking postsynaptic densities, which are protein assemblies underneath the plasma membrane of excitatory synapses, were investigated. Quite unexpectedly, the model system LLPS is much more sensitive to pressure than the folded states of typical globular proteins. Phase-separated droplets of SynGAP/PSD-95 were found to dissolve into a homogeneous solution already at ten-to-hundred bar levels. The pressure sensitivity of SynGAP/PSD-95 is seen here as a consequence of both pressure-dependent multivalent interaction strength and void volume effects. Considering that organisms in the deep sea are under pressures up to about 1 kbar, this implies that deep-sea organisms have to devise means to counteract this high pressure sensitivity of biomolecular condensates to avoid harm. Intriguingly, these findings may shed light on the biophysical underpinning of pressure-related neurological disorders in terrestrial vertebrates.

关键词： electronic skin   carbon nanotube   flexible electronics   synaptic transistor   ferroelectret nanogenerator  

摘要： There is an increasing interest in the development of memristive or artificial synaptic devices that emulate the neuronal activities for neuromorphic computing applications. While there have already been many reports on artificial synaptic transistors implemented on rigid substrates, the use of flexible devices could potentially enable an even broader range of applications. In this paper, we report artificial synaptic thin-film transistors built on an ultrathin flexible substrate using high carrier mobility semiconducting single-wall carbon nanotubes. The synaptic characteristics of the flexible synaptic transistor including long-term/short-term plasticity, spike-amplitude-dependent plasticity, spike-width-dependent plasticity, paired-pulse facilitation, and spike-time-dependent plasticity have all been systematically characterized. Furthermore, we have demonstrated a flexible neurological electronic skin and its peripheral nerve with a flexible ferroelectret nanogenerator (FENG) serving as the sensory mechanoreceptor that generates action potentials to be processed and transmitted by the artificial synapse. In such neurological electronic skin, the flexible FENG sensor converts the tactile input (magnitude and frequency of force) into presynaptic action potential pulses, which are then passed to the gate of the synaptic transistor to induce change in its postsynaptic current, mimicking the modulation of synaptic weight in a biological synapse. Our neurological electronic skin closely imitates the behavior of actual human skin, and it allows for instantaneous detection of force stimuli and offers biological synapse-like behavior to relay the stimulus signals to the next stage. The flexible sensory skin could potentially be used to interface with skeletal muscle fibers for applications in neuroprosthetic devices.

关键词： molecular diagnostics   stroke   multiple sclerosis   traumatic brain injury   Alzheimer's disease  

摘要： The identification of precision blood biomarkers which can accurately indicate damage to brain tissue could yield molecular diagnostics with the potential to improve how we detect and treat neurological pathologies. However, a majority of candidate blood biomarkers for neurological damage that are studied today are proteins which were arbitrarily proposed several decades before the advent of high-throughput omic techniques, and it is unclear whether they represent the best possible targets relative to the remainder of the human proteome. Here, we leveraged mRNA expression data generated from nearly 12,000 human specimens to algorithmically evaluate over 17,000 protein-coding genes in terms of their potential to produce blood biomarkers for neurological damage based on their expression profiles both across the body and within the brain. The circulating levels of proteins associated with the top-ranked genes were then measured in blood sampled from a diverse cohort of patients diagnosed with a variety of acute and chronic neurological disorders, including ischemic stroke, hemorrhagic stroke, traumatic brain injury, Alzheimer's disease, and multiple sclerosis, and evaluated for their diagnostic performance. Our analysis identifies several previously unexplored candidate blood biomarkers of neurological damage with possible clinical utility, many of which whose presence in blood is likely linked to specific cell-level pathologic processes. Furthermore, our findings also suggest that many frequently cited previously proposed blood biomarkers exhibit expression profiles which could limit their diagnostic efficacy.

关键词： Apicomplexa   behavioral disorder   mental health   personality changes   Toxoplasma gondii   toxoplasmosis   transcripts change  

摘要： Toxoplasmosis, a disease that disrupts fetal brain development and severely affects the host's brain, has been linked to many behavioral and neurological disorders. There is growing interest in how a single-celled neurotropic parasite, Toxoplasma gondii, can control or change the behavior of the host as well as how it dominates the host's neurons. Secrets beyond these could be answered by decoding the Toxoplasma gondii genome, unravelling the function of genomic sequences, and exploring epigenetics and mRNAs alterations, as well as the postulated mechanisms contributing to various neurological and psychiatric symptoms caused by this parasite. Substantial efforts have been made to elucidate the action of T. gondii on host immunity and the biology of its infection. However, the available studies on the molecular aspects of toxoplasmosis that affect central nervous system (CNS) circuits remain limited, and much research is still needed on this interesting topic. In my opinion, this parasite is a gift for studying the biology of the nervous system and related diseases. We should utilize the unique features of Toxoplasma, such as its abilities to modulate brain physiology, for neurological studies or as a possible tool or approach to cure neurological disease.

关键词： driving simulation   driving assessment   driving fitness evaluation   neurological deficit   brain injury   neurodegenerative disease  

摘要： Objective: To identify driving characteristics of fit-, unfit-, and conditionally fit-to-drive neurological patient populations using a driving simulator with three high-risk scenarios comprising rural, highway, and urban environments. Methods: The study included 91 neurological patients undergoing a multidisciplinary assessment for driver's license revalidation, consisting of a clinical, neuropsychological, functional, and on-road evaluation. The groups drove through three independent driving scenarios, during which a variety of measures describing reaction time, vehicular control, and traffic rule compliance were performed. One-way analysis of variance (ANOVA) with Bonferroni correction was used for group comparison, independently for each driving scenario, and Pearson correlations were calculated between simulator variables and neuropsychological test scores. Results: The fit- and unfit-to-drive population significantly differed (p < .05) in reaction times, regardless of the scenario. No significant differences in traffic rule compliance or vehicular control parameters were observed in the rural environment (p > .05). On the highway, the unfit group exhibited greater variability of steering wheel angle, higher steering reversal rate, and a higher rate of turn signal errors. In the urban environment, the unfit group oversped more, had more collisions, and exhibited greater lane position variability. The latter, along with reaction times in the rural and highway scenarios, was also shown to significantly differ between the conditional and unfit group (p < .05). No significant differences were observed between the fit and the conditional group (p > .05). Weak to moderate associations (range: -0.5 to 0.29) between neuropsychological tests and various simulator variables were also observed. Conclusions: Our results show that driving simulators are able to capture differences between (fit- and unfit-to-drive) neurological patient populations and therefore bear the pote

关键词： 临床见习   教学方法   神经病学   PBL教学   Language of Keywords: Chinese  

摘要： Objective: To report neurological manifestations seen in patients hospitalized with Coronavirus disease 2019 (COVID-19) from a large academic medical center in Chicago, Illinois. Methods: We retrospectively reviewed data records of 50 patients with COVID-19 who were evaluated by the neurology services from March 1, 2020 - April 30, 2020. Patients were categorized into 2 groups based on timing of developing neurological manifestations: the "Neuro first" group had neurological manifestations upon initial assessment, and the "COVID first" group developed neurological symptoms greater than 24 h after hospitalization. The demographics, comorbidities, disease severity and neurological symptoms and diagnoses of both groups were analyzed. Statistical analysis was performed to compare the two groups. Results: A total of 50 patients (48% African American and 24% Latino) were included in the analysis. Most common neurological manifestations observed were encephalopathy (n = 30), cerebrovascular disease (n = 20), cognitive impairment (n = 13), seizures (n = 13), hypoxic brain injury (n = 7), dysgeusia (n = 5), and extraocular movement abnormalities (n = 5). The "COVID-19 first" group had more evidence of physiologic disturbances on arrival with a more severe/critical disease course (83.3% vs 53.8%, p 0.025). Conclusion: Neurologic manifestations of COVID-19 are highly variable and can occur prior to the diagnosis of or as a complication of the viral infection. Despite similar baseline comorbidities and demographics, the COVID-19 patients who developed neurologic symptoms later in hospitalization had more severe disease courses. Differently from previous studies, we noted a high percentage of African American and Latino individuals in both groups.

关键词： GAD65   Autoimmune epilepsy   Limbic encephalitis   Cerebellar ataxia   Stiff-person syndrome   Immunotherapy  

摘要： We described the clinical and neuroimaging characteristics of seven Chinese patients with anti-GAD65 antibody-associated neurological disorders of whom epileptic seizures were the initial and main symptoms. All patients were given immunotherapy and followed up monthly. The outcome demonstrates that immunotherapy is helpful for non-seizure manifestations of anti-GAD65-associated neurological autoimmunity and is less effective in the treatment of seizures, yet partial responses can still occur in the early stage. Taken together we suggest a trial with immunotherapy in all patients in the early stage of the disease, and in patients with non-epilepsy symptoms in the later stage.