Based on Logic Time Petri nets (LTPNs) models, this paper focuses on improving the efficiency of Petri Net intelligent search method execution. With an analysis of the E-Commerce Logistics (ECL) ...system, the method of system scheduling using LTPNs is studied, and the Ant Colony algorithm is proposed based on it. By introducing the concept of pheromones to system transition, using the Ant Colony algorithm (ACA) in the processing of the network, and setting the heuristic factor in combination with the time boundary, the non-deterministic behavior can be automatically analyzed and selected in the LTPNs so that the efficiency of control and scheduling during the system dynamics operation is improved. The result of the analysis of the ECL system serves as evidence of the superiority of ACA.
Dgcr8 is involved in the biogenesis of canonical miRNAs to process pri-miRNA into pre-miRNA. Previous studies have provided evidence that Dgcr8 plays an essential role in different biological ...processes. However, the function of maternal and zygotic Dgcr8 in early embryonic development remains largely unknown. Recently, we have reported a novel approach for generating germline-specific deletions in zebrafish. This germline knockout model offers an opportunity to investigate into the differential roles of maternal or zygotic Dgcr8. Although germline specific dgcr8 deletion has no influence on gonad development, maternal or zygotic dgcr8 is essential for embryonic development in the offspring. Both maternal
(M
) and maternal zygotic
(MZ
) mutants display multiple developmental defects and die within 1 week. Moreover, MZ
mutant displays more severe morphogenesis defects. However, when a miR-430 duplex (the most abundantly expressed miRNA in early embryonic stage) is used to rescue the maternal mutant phenotype, the Mdgcr8 embryos could be rescued successfully and grow into adulthood and achieve sexual maturation, whereas the MZ
embryos are only partially rescued and they all die within 1 week. The differential phenotypes between the Mdgcr8 and MZ
embryos provide us with an opportunity to study the roles of individual miRNAs during early development.
This paper proposes VDStream, a new effective method, to discover arbitrary shape clusters over variable density data streams. The algorithm can reduce the influence of history data and effectively ...eliminate the interference of noise data. When the density of data streams changes, VDStream can dynamically adjust the parameters of density to find precise clusters. Experiments demonstrate the effectiveness and efficiency of VDStream.
A central objective in deciphering the nervous system in health and disease is to define the connections of neurons. The propensity of neurotropic viruses to spread among synaptically-linked neurons ...makes them ideal for mapping neural circuits. So far, several classes of viral neuronal tracers have become available and provide a powerful toolbox for delineating neural networks. In this paper, we review the recent developments of neurotropic viral tracers and highlight their unique properties in revealing patterns of neuronal connections.
•The role of mutations enabling AAV2 to undergo retrograde transport is individually analyzed.•Decapeptide insertion is pivotal for the retrograde functionality.•V708I could be dispensable and even ...deleterious depending on the projection neurons.
Recombinant adeno-associated viruses (rAAVs) are widespread vectors in neuroscience research. However, the nearly absent retrograde access to projection neurons hampers their application in functional dissection of neural circuits and in therapeutic intervention. Recently, engineering of the AAV2 capsid has generated an AAV variant, called rAAV2-retro, with exceptional retrograde functionality. This variant comprises a 10-mer peptide insertion at residue 587 and two point mutations (LADQDYTKTA + V708I + N382D). Here, we evaluated the contribution of each mutation to retrograde transport in prefrontal cortex -striatum and amygdala-striatum pathways, respectively. Results showed that disruption of the inserted decapeptide almost completely abolishes the retrograde access to neurons projecting to striatum. Eliminating N382D has little effect on the retrograde functionality. Restoring another mutation V708I, however, even improves its performance in amygdala-striatum pathway. Parallel comparison within same animal further confirms this conflicting effect of V708I. These results demonstrate a pivotal role of decapeptide insertion in gaining the capacity of retrograde transport and highlight a neural circuit-dependent contribution of V708I. It suggests constant and custom engineering of rAAV2-retro might be required to tackle the challenge of tremendous neuronal heterogeneity.
Parkinson's disease (PD) is a debilitating neurodegenerative disorder. Its symptoms are typically treated with levodopa or dopamine receptor agonists, but its action lacks specificity due to the wide ...distribution of dopamine receptors in the central nervous system and periphery. Here, we report the development of a gene therapy strategy to selectively manipulate PD-affected circuitry. Targeting striatal D1 medium spiny neurons (MSNs), whose activity is chronically suppressed in PD, we engineered a therapeutic strategy comprised of a highly efficient retrograde adeno-associated virus (AAV), promoter elements with strong D1-MSN activity, and a chemogenetic effector to enable precise D1-MSN activation after systemic ligand administration. Application of this therapeutic approach rescues locomotion, tremor, and motor skill defects in both mouse and primate models of PD, supporting the feasibility of targeted circuit modulation tools for the treatment of PD in humans.
Abstract
Background
Both the clinical and preclinical studies have suggested embryonic or infant exposure to ketamine, a general anesthetic, pose a great threat to the developing brain. However, it ...remains unclear how ketamine may contribute to the brain dysfunctions.
Methods
A mouse model of prenatal exposure to ketamine was generated by i.m. injection and continuous i.p. infusion of pregnant mice. Open field test and elevated plus maze test were used to analyze the behavioral alterations induced by ketamine. Immunostaining by c-Fos was used to map the neuron activity. Chemogenetic modulation of the neurons was used to rescue the abnormal neuron activity and behaviors.
Results
Here we show that mice prenatally exposed to ketamine displayed anxiety-like behaviors during adulthood, but not during puberty. C-Fos immunostaining identified abnormal neuronal activity in Bed Nucleus of the Stria Terminalis, the silencing of which by chemogenetics restores the anxiety-like behaviors.
Conclusions
Taken together, these results demonstrate a circuitry mechanism of ketamine-induced anxiety-like behaviors.
The baseline of glucose level is one of the most fundamental metrics of glucose metabolism assessments and diabetes diagnosis. Under the demands of maintaining physical activity levels and ...stimulation from various external factors, blood glucose levels are in a fractal fluctuation state and maintain a day-night rhythm in physical condition. Although several stressors stimulation has been considered to increase glucose levels, how stress affects the glucose oscillation is unknown. Methods: In the study, we measure the glucose levels of mice by glucometer for exploring how the blood collection affect the fractal fluctuation of glucose. Furthermore, we monitor the glucose levels of rats by the continuous glucose monitoring system to study the change of glucose day-night rhythm underlying external stress. Results: We found that stressors (i.e., blood collection) expand the fractal fluctuation of blood glucose. Strikingly, external stress stimulation irreversibly erases the circadian rhythm of glucose levels. The cycle of activity and body temperature, which are tested simultaneously, are also disturbed by stress stimulation. Conclusions: These results reveal a novel insight that stress stimulation leads to an irreversible disruption of the glucose cycle and provides vital implications for the pathogenesis and treatment of long-term stress-induced glucose metabolic disorders.
Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders with varying degrees of social, communicative and behavioral problems. ASD is diagnosed by impairment in two core behavioral ...domains: (1) social interaction and communication, and (2) repetitive, restrictive behaviors. Other neurological abnormalities are also frequently observed in ASD. The etiology of ASD is now poorly understood. A growing body of evidence suggests a complex interaction between genes, epigenetics and environment in ASD development. Of note, protein kinase C (PKC), an important cluster of protein kinases in the cell, has been implicated in ASD by multiple lines of evidence coming from both human genetic association and transcriptome analysis. The susceptible genetic polymorphisms and altered expression levels of PKC-encoding genes implicate over-activation of PKC in ASD development. To delineate the pathological role of PKC, we pharmacologically stimulated its activity during the early development of zebrafish by Phorbol 12-myristate 13-acetate (PMA). Results demonstrated that early PKC hyper-activation led to developmental delay and microcephaly in zebrafish. In line with the phenotypes, neuroanatomical and cellular analysis revealed decreased cell proliferation and neurogenesis. Strikingly, Wnt/β- catenin, an important pathway in regulating brain growth was identified to be disrupted. Expression of the transcriptional target of β-catenin was also significantly reduced. Furthermore, we found behavioral problems in zebrafish with developmental PKC hyper-activation like motor abnormalities, heightened stress reactivity and impaired habituation learning. Altogether, these results demonstrate a casualty between developmental PKC hyper-activation and the neuropathological traits and the impairment of β-catenin-regulated neurogenesis. In addition, the descents of PMA-exposed fish also display neuro-developmental defects characterized by premature GABAergic neuron differentiation, brain overgrowth and increased anxiety-like behaviors. The molecular studies revealed a heightened beta-catenin signaling in offspring of PMA-exposed fish, indicated by its nuclear accumulation and increased transcription of its downstream targets. Concordantly, increased cell proliferation was observed, which is just contrary to their parents. Moreover, the transcriptome analysis identified the oxidative phosphorylation pathway enriched of dysregulated genes, implying mitochondrial dysfunction and oxidative stress in the offspring of PMA-exposed fish. Both features are strongly associated with brain disorders. Therefore, these data suggest that earlylife PKC over-stimulation could further contribute to the neurodevelopmental defects in the subsequent generation through modulating β-catenin signaling and the mitochondrial respiratory chain. In conclusion, the present thesis suggests that PKC could be a critical pathway in ASD pathogenesis. It also highlights a novel molecular risk factor for ASD that might function across generations, which may help to deepen the understanding about how some environmental factors exert their pathogenic actions and impact the offspring’s resilience and susceptibility to neuropsychiatric disorders.
Brain-derived neurotrophic factor (BDNF) is a key mediator in the development of chronic pain. Sortilin is known to interact with proBDNF and regulate its activity-dependent secretion in cortical ...neurons. In a rat model of inflammatory pain with intraplantar injection of complete Freund's adjuvant (CFA), we examined the functional role of proBDNF-sortilin interaction in dorsal root ganglia (DRG).
Expression and co-localization of BDNF and sortilin were determined by immunofluorescence. ProBDNF-sortilin interaction interface was mapped using co-immunoprecipitation and bimolecular fluorescence complementation assay. The analgesic effect of intrathecal injection of a synthetic peptide interfering with proBDNF-sortilin interaction was measured in the CFA model.
BDNF and sortilin were co-localized and their expression was significantly increased in ipsilateral L4/5 DRG upon hind paw CFA injection.
adeno-associated virus-mediated knockdown of sortilin-1 in L5 DRG alleviated pain-like responses. Mapping by serial deletions in the BDNF prodomain indicated that amino acid residues 71-100 supported the proBDNF-sortilin interaction. A synthetic peptide identical to amino acid residues 89-98 of proBDNF, as compared with scrambled peptide, was found to interfere with proBDNF-sortilin interaction, inhibit activity-dependent release of BDNF
and reduce CFA-induced mechanical allodynia and heat hyperalgesia
. The synthetic peptide also interfered with capsaicin-induced phosphorylation of extracellular signal-regulated kinases in ipsilateral spinal cord of CFA-injected rats.
Sortilin-mediated secretion of BDNF from DRG neurons contributes to CFA-induced inflammatory pain. Interfering with proBDNF-sortilin interaction reduced activity-dependent release of BDNF and might serve as a therapeutic approach for chronic inflammatory pain.
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