scholarly journals Loss of one Engrailed1 allele enhances induced α-synucleinopathy

2019 ◽  
Author(s):  
Diptaman Chatterjee ◽  
Daniel Saiz Sanchez ◽  
Emmanuel Quansah ◽  
Nolwen L Rey ◽  
Sonia George ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Wild Type ◽  
Dopamine System ◽  
Unbiased Stereology ◽  
Nigrostriatal Dopamine ◽  
System Degeneration ◽  
Cortical Regions ◽  
And Control ◽  
Further Development ◽  
Intrastriatal Injection

AbstractBackground:Parkinson’s disease (PD) is a synucleinopathy that has multiple neuropathological characteristics, with nigrostriatal dopamine system degeneration being a core feature. Current models of PD pathology typically fail to recapitulate several attributes of the pathogenic process and neuropathology. We aimed to define the effects of combining a mouse model exhibiting multiple PD-like changes with intrastriatal injections of α-synuclein (α-syn) pre-formed fibrils (PFFs) aggregates. We employed the heterozygous Engrailed 1 (En1+/-) mouse that features several pathophysiological hallmarks of clinical PD. Objective: To test the hypothesis that the neuropathological changes in the En1+/- mice will promote formation of α-syn aggregates following intrastriatal injections of pathogenic human α-syn PFFs. Methods: We unilaterally injected PFFs into the striata of 1 month-old En1+/- and control wild-type mice and euthanized animals at 3 months for post-mortem analysis. Results: Using immunohistochemistry and unbiased stereology, we established that PFF-injected En1+/- mice exhibited a near-threefold increase in pS129-α-syn-positive neurons in the substantia nigra compared to PFF-injected wild-type mice. The PFF-injected En1+/- mice also displayed significant increases in pS129-α-syn-positive neurons in the amygdala and ventral tegmental area; regions of known PD pathology with projections to the striatum. Additionally, we observed amplified pS129-α-syn-positive aggregation in En1+/- mice in multiple cortical regions. Conclusions: Following intrastriatal injection of PFFs, absence of an En1 allele leads to additional aggregation of pathological α-syn, potentially due to En1-loss mediated nigrostriatal impairment. We propose that further development of this double-hit model could be predictive of pre-clinical therapeutic potential and success for PD than existing mouse models.

Portable Life Support System: Current Status and Future Perspectives

2020 ◽  
Vol 14 (1) ◽  
pp. 12-28
Author(s):  
Jingang Jiang ◽  
Yihao Chen ◽  
Xuefeng Ma ◽  
Yongde Zhang ◽  
Zhiyuan Huang ◽  
...  
Keyword(s):  
Support System ◽  
Life Support ◽  
Support Systems ◽  
Vital Signs ◽  
Current Status ◽  
Life Support System ◽  
Life Support Systems ◽  
Special Circumstances ◽  
And Control ◽  
Further Development

Background: Portable life support system is used in the battlefield, disaster and in other special circumstances such as in space exploration, and underground survey to give the wounded a life support. The most dangerous period for the injured is the first hour after an injury, which is a crucial time for treatment. If the patient's vital signs were stabilized, more than 40% of the injured could be saved. The staff can efficiently complete the task if they get effective and stable vital signs during the operation. Therefore, in order to reduce the risk of disaster and battlefield mortality to improve operational safety and efficiency, it is necessary to study the portable life support system. Objective: The study aimed to provide an overview of recent portable life support system and its characteristics and design. Methods: This paper introduces the patents and products related to a portable life support system, and its characteristics and application. Results: This paper summarizes five kinds of portable life support systems which are box type, stretcher type, bed type, backpack type and mobile type. Moreover, the characteristics of different portable life support systems are analyzed. The paper expounds the problems of different types of portable life support systems and puts forward improvement methods to solve the problems. Finally, the paper points out the future development of the system. Conclusion: Portable life support system plays an increasingly important role in health care. In terms of the structure, function and control, further development and improvements are needed, along with the research on portable life support system.

scholarly journals In vivo electrophysiology of nigral and thalamic neurons in alpha-synuclein-overexpressing mice highlights differences from toxin-based models of parkinsonism

2013 ◽  
Vol 110 (12) ◽  
pp. 2792-2805 ◽  
Author(s):  
C. J. Lobb ◽  
A. K. Zaheer ◽  
Y. Smith ◽  
D. Jaeger
Keyword(s):  
Primary Motor Cortex ◽  
Alpha Synuclein ◽  
Motor Dysfunction ◽  
Motor Deficits ◽  
Dopamine Depletion ◽  
Wild Type ◽  
Beta Oscillations ◽  
Nigrostriatal Dopamine ◽  
6 Hydroxydopamine

Numerous studies have suggested that alpha-synuclein plays a prominent role in both familial and idiopathic Parkinson's disease (PD). Mice in which human alpha-synuclein is overexpressed (ASO) display progressive motor deficits and many nonmotor features of PD. However, it is unclear what in vivo pathophysiological mechanisms drive these motor deficits. It is also unknown whether previously proposed pathophysiological features (i.e., increased beta oscillations, bursting, and synchronization) described in toxin-based, nigrostriatal dopamine-depletion models are also present in ASO mice. To address these issues, we first confirmed that 5- to 6-mo-old ASO mice have robust motor dysfunction, despite the absence of significant nigrostriatal dopamine degeneration. In the same animals, we then recorded simultaneous single units and local field potentials (LFPs) in the substantia nigra pars reticulata (SNpr), the main basal ganglia output nucleus, and one of its main thalamic targets, the ventromedial nucleus, as well as LFPs in the primary motor cortex in anesthetized ASO mice and their age-matched, wild-type littermates. Neural activity was examined during slow wave activity and desynchronized cortical states, as previously described in 6-hydroxydopamine-lesioned rats. In contrast to toxin-based models, we found a small decrease, rather than an increase, in beta oscillations in the desynchronized state. Similarly, synchronized burst firing of nigral neurons observed in toxin-based models was not observed in ASO mice. Instead, we found more subtle changes in pauses of SNpr firing compared with wild-type control mice. Our results suggest that the pathophysiology underlying motor dysfunction in ASO mice is distinctly different from striatal dopamine-depletion models of parkinsonism.

scholarly journals Randomized, Blinded, Dose-Ranging Trial of an Ebola Virus Glycoprotein Nanoparticle Vaccine With Matrix-M Adjuvant in Healthy Adults

2019 ◽  
Vol 222 (4) ◽  
pp. 572-582 ◽  
Author(s):  
Louis Fries ◽  
Iksung Cho ◽  
Verena Krähling ◽  
Sarah K Fehling ◽  
Thomas Strecker ◽  
...  
Keyword(s):  
Public Health ◽  
Immune Response ◽  
Ebola Virus ◽  
Vaccine Development ◽  
Phase 1 ◽  
Healthy Adults ◽  
Wild Type ◽  
Dose Ranging ◽  
Further Development ◽  
Human Vaccine

Abstract Background Ebola virus (EBOV) epidemics pose a major public health risk. There currently is no licensed human vaccine against EBOV. The safety and immunogenicity of a recombinant EBOV glycoprotein (GP) nanoparticle vaccine formulated with or without Matrix-M adjuvant were evaluated to support vaccine development. Methods A phase 1, placebo-controlled, dose-escalation trial was conducted in 230 healthy adults to evaluate 4 EBOV GP antigen doses as single- or 2-dose regimens with or without adjuvant. Safety and immunogenicity were assessed through 1-year postdosing. Results All EBOV GP vaccine formulations were well tolerated. Receipt of 2 doses of EBOV GP with adjuvant showed a rapid increase in anti-EBOV GP immunoglobulin G titers with peak titers observed on Day 35 representing 498- to 754-fold increases from baseline; no evidence of an antigen dose response was observed. Serum EBOV-neutralizing and binding antibodies using wild-type Zaire EBOV (ZEBOV) or pseudovirion assays were 3- to 9-fold higher among recipients of 2-dose EBOV GP with adjuvant, compared with placebo on Day 35, which persisted through 1 year. Conclusions Ebola virus GP vaccine with Matrix-M adjuvant is well tolerated and elicits a robust and persistent immune response. These data suggest that further development of this candidate vaccine for prevention of EBOV disease is warranted.

Overview of Path-Planning and Obstacle Avoidance Algorithms for UAVs: A Comparative Study

2018 ◽  
Vol 06 (02) ◽  
pp. 95-118 ◽  
Author(s):  
Mohammadreza Radmanesh ◽  
Manish Kumar ◽  
Paul H. Guentert ◽  
Mohammad Sarim
Keyword(s):  
Path Planning ◽  
Comparative Study ◽  
Operating Conditions ◽  
Computational Time ◽  
Safe Operation ◽  
Sense And Avoid ◽  
Planning Algorithms ◽  
And Control ◽  
Global And Local ◽  
Further Development

Unmanned aerial vehicles (UAVs) have recently attracted the attention of researchers due to their numerous potential civilian applications. However, current robot navigation technologies need further development for efficient application to various scenarios. One key issue is the “Sense and Avoid” capability, currently of immense interest to researchers. Such a capability is required for safe operation of UAVs in civilian domain. For autonomous decision making and control of UAVs, several path-planning and navigation algorithms have been proposed. This is a challenging task to be carried out in a 3D environment, especially while accounting for sensor noise, uncertainties in operating conditions, and real-time applicability. Heuristic and non-heuristic or exact techniques are the two solution methodologies that categorize path-planning algorithms. The aim of this paper is to carry out a comprehensive and comparative study of existing UAV path-planning algorithms for both methods. Three different obstacle scenarios test the performance of each algorithm. We have compared the computational time and solution optimality, and tested each algorithm with variations in the availability of global and local obstacle information.

Selected Contribution: Differential role of nitric oxide synthase isoforms in fever of different etiologies: studies using Nosgene-deficient mice

2003 ◽  
Vol 94 (6) ◽  
pp. 2534-2544 ◽  
Author(s):  
Wieslaw Kozak ◽  
Anna Kozak
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Corn Oil ◽  
Normal Male ◽  
Wild Type ◽  
Oxide Synthase ◽  
And Control ◽  
Nos Isoforms ◽  
Deficient Mice

Male C57BL/6J mice deficient in nitric oxide synthase (NOS) genes (knockout) and control (wild-type) mice were implanted intra-abdominally with battery-operated miniature biotelemeters (model VMFH MiniMitter, Sunriver, OR) to monitor changes in body temperature. Intravenous injection of lipopolysaccharide (LPS; 50 μg/kg) was used to trigger fever in response to systemic inflammation in mice. To induce a febrile response to localized inflammation, the mice were injected subcutaneously with pure turpentine oil (30 μl/animal) into the left hindlimb. Oral administration (gavage) of N G-monomethyl-l-arginine (l-NMMA) for 3 days (80 mg · kg−1 · day−1in corn oil) before injection of pyrogens was used to inhibit all three NOSs ( N G-monomethyl-d-arginine acetate salt and corn oil were used as control). In normal male C57BL/6J mice, l-NMMA inhibited the LPS-induced fever by ∼60%, whereas it augmented fever by ∼65% in mice injected with turpentine. Challenging the respective NOS knockout mice with LPS and with l-NMMA revealed that inducible NOS and neuronal NOS isoforms are responsible for the induction of fever to LPS, whereas endothelial NOS (eNOS) is not involved. In contrast, none of the NOS isoforms appeared to trigger fever to turpentine. Inhibition of eNOS, however, exacerbates fever in mice treated with l-NMMA and turpentine, indicating that eNOS participates in the antipyretic mechanism. These data support the hypothesis that nitric oxide is a regulator of fever. Its action differs, however, depending on the pyrogen used and the NOS isoform.

scholarly journals The kfrA gene is the first in a tricistronic operon required for survival of IncP-1 plasmid R751

Microbiology ◽  
2006 ◽  
Vol 152 (6) ◽  
pp. 1621-1637 ◽  
Author(s):  
Malgorzata Adamczyk ◽  
Patrycja Dolowy ◽  
Michal Jonczyk ◽  
Christopher M. Thomas ◽  
Grazyna Jagura-Burdzy
Keyword(s):  
Coiled Coil ◽  
Broad Host Range ◽  
Gram Negative Bacteria ◽  
Bacterial Cells ◽  
Wild Type ◽  
C Terminus ◽  
Low Copy Number ◽  
And Control ◽  
Broad Host Range Plasmids

The kfrA gene of the IncP-1 broad-host-range plasmids is the best-studied member of a growing gene family that shows strong linkage to the minimal replicon of many low-copy-number plasmids. KfrA is a DNA binding protein with a long, alpha-helical, coiled-coil tail. Studying IncP-1β plasmid R751, evidence is presented that kfrA and its downstream genes upf54.8 and upf54.4 were organized in a tricistronic operon (renamed here kfrA kfrB kfrC), expressed from autoregulated kfrAp, that was also repressed by KorA and KorB. KfrA, KfrB and KfrC interacted and may have formed a multi-protein complex. Inactivation of either kfrA or kfrB in R751 resulted in long-term accumulation of plasmid-negative bacteria, whereas wild-type R751 itself persisted without selection. Immunofluorescence studies showed that KfrAR751 formed plasmid-associated foci, and deletion of the C terminus of KfrA caused plasmid R751ΔC 2 kfrA foci to disperse and mislocalize. Thus, the KfrABC complex may be an important component in the organization and control of the plasmid clusters that seem to form the segregating unit in bacterial cells. The studied operon is therefore part of the set of functions needed for R751 to function as an efficient vehicle for maintenance and spread of genes in Gram-negative bacteria.

Stimulation of the nigrostriatal dopamine system produces hypertension and tachycardia in rats

1994 ◽  
Vol 266 (6) ◽  
pp. H2489-H2496 ◽  
Author(s):  
M. T. Lin ◽  
J. J. Yang
Keyword(s):  
Corpus Striatum ◽  
Substantia Nigra Pars Compacta ◽  
Dopamine System ◽  
Arterial Blood ◽  
Nigrostriatal Dopamine ◽  
Induced Hypertension ◽  
Bilateral Vagotomy ◽  
6 Hydroxydopamine ◽  
Da Release ◽  
Stimulation Of

To test for the ability of the nigrostriatal dopamine (DA) system to influence cardiovascular function, experiments were carried out to assess the effects of electrical or chemical stimulation of the nigrostriatal DA system on arterial blood pressure, heart rate, and striatal DA release in anesthetized rats. Electrical stimulation of the substantia nigra pars compacta (SNC), in addition to enhancing the DA release in the corpus striatum (CS), elicited proportional hypertension and tachycardia. This could be mimicked by microinjection of two excitatory amino acids, kainic acid and glutamate, into the SNC area of rat brain. The SNC stimulation-induced hypertension, tachycardia, and increased striatal DA release were attenuated by prior destruction of the nigrostriatal DA system produced by intramedial forebrain bundle injection of 6-hydroxydopamine and by prior blockade of postsynaptic DA receptors produced by intra-CS injection of DA receptor antagonists, haloperidol or pimozide. The SNC stimulation-induced hypertension was attenuated by spinal transection, whereas the SNC stimulation-induced tachycardia was attenuated by bilateral vagotomy. The data suggest that stimulation of the nigrostriatal DA system produces both hypertension and tachycardia in rats.

scholarly journals Downregulation of CD40L–CD40 attenuates seizure susceptibility and severity of seizures

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Esther Pototskiy ◽  
Katherine Vinokuroff ◽  
Andrew Ojeda ◽  
C. Kendall Major ◽  
Deepak Sharma ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Molecular Techniques ◽  
Seizure Susceptibility ◽  
Wild Type ◽  
Upward Trend ◽  
Seizure Severity ◽  
Cd40 Expression ◽  
Neuro Inflammation ◽  
And Control ◽  
Deficient Mice

AbstractUnregulated neuro-inflammation mediates seizures in temporal lobe epilepsy (TLE). Our aim was to determine the effect of CD40–CD40L activation in experimental seizures. CD40 deficient mice (CD40KO) and control mice (wild type, WT) received pentenyltetrazole (PTZ) or pilocarpine to evaluate seizures and status epilepticus (SE) respectively. In mice, anti-CD40L antibody was administered intranasally before PTZ. Brain samples from human TLE and post-seizure mice were processed to determine CD40–CD40L expression using histological and molecular techniques. CD40 expression was higher in hippocampus from human TLE and in cortical neurons and hippocampal neural terminals after experimental seizures. CD40–CD40L levels increased after seizures in the hippocampus and in the cortex. After SE, CD40L/CD40 levels increased in cortex and showed an upward trend in the hippocampus. CD40KO mice demonstrated reduction in seizure severity and in latency compared to WT mice. Anti-CD40L antibody limited seizure susceptibility and seizure severity. CD40L–CD40 interaction can serve as a target for an immuno-therapy for TLE.

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