Parkinson's disease (PD) is the most common movement disorder with motor and nonmotor signs. The current therapeutic regimen for PD is mainly symptomatic as the etio-pathophysiology has not been ...fully elucidated. A variety of animal models has been generated to study different aspects of the disease for understanding the pathogenesis and therapeutic development. The disease model can be generated through neurotoxin-based or genetic-based approaches in a wide range of animals such as non-human primates (NHP), rodents, zebrafish,
(
)
, and drosophila. Cellular-based disease model is frequently used because of the ease of manipulation and suitability for large-screen assays. In neurotoxin-induced models, chemicals such as 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, and paraquat are used to recapitulate the disease. Genetic manipulation of PD-related genes, such as α-Synuclein(SNCA), Leucine-rich repeat kinase 2 (LRRK2), Pten-Induced Kinase 1 (PINK1), Parkin(PRKN), and Protein deglycase (DJ-1) Are used in the transgenic models. An emerging model that combines both genetic- and neurotoxin-based methods has been generated to study the role of the immune system in the pathogenesis of PD. Here, we discuss the advantages and limitations of the different PD models and their utility for different research purposes.
Although various lightning protection methods have been used in the industry, many outdoor high-voltage (HV) substations are still experiencing high failure rates due to lightning strikes. The ...applications of these rule-of-thumb-based methods generally lack coherence among the practitioners. IEC 62305-2 provides a systematic way for practitioners to assess the lightning risk for buildings or structures in a probabilistic way. However, this standard has not explicitly covered the application of HV substations. Moreover, IEC 62305-2 involves a tedious set of risk factors which may hinder many practitioners from applying the aforementioned standards while other preferred rule-of-thumb methods are available. As IEC 62305-2 does not specify the applicability to lightning risk assessment in HV substations, this paper proposes a novel approach to complement the standard-based risk assessment process. During this integrated risk assessment process, significant risks are identified, followed by ambiguous risks that will be adjusted in subsequent phases. The significant ambiguous risk factors such as fire load function (rf), environmental factor (CE), LPL class, and other governing factors have been analyzed and discussed. By adjusting these significant risk factors, the practitioners will understand the adjusted risk factors in relation to the practical implementation of lightning protection system (LPS). Therefore, integrating the substation characteristics, assumptions, and findings of ambiguous risk factors can result in a successful integrated lightning risk assessment process.
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•Synthetic microbial communities can be engineered for targeted functions.•Artificial selection has been employed to improve existing communities.•Several methods have been used to ...identify new compositions with desired functions.•Recent progress in computational model-based design has enabled novel design tools.•Computational and integrative approaches are promising avenues for advancement.
Microbial communities can perform a variety of behaviors that are useful in both therapeutic and industrial settings. Engineered communities that differ in composition from naturally occurring communities offer a unique opportunity for improving upon existing community functions and expanding the range of microbial community applications. This has prompted recent advances in various community design approaches including artificial selection procedures, reduction from existing communities, combinatorial evaluation of potential microbial combinations, and model-based in silico community optimization. Computational methods in particular offer a likely avenue toward improved synthetic community development going forward. This review introduces each class of design approach and surveys their recent applications and notable innovations, closing with a discussion of existing design challenges and potential opportunities for advancement.
Pandemic (H1N1) 2009 virus causes severe illness, including pneumonia, which leads to hospitalization and even death. To characterize the kinetic changes in viral load and identify factors of ...influence, we analyzed variables that could potentially influence the viral shedding time in a hospital-based cohort of 1,052 patients. Viral load was inversely correlated with number of days after the onset of fever and was maintained at a high level over the first 3 days. Patients with pneumonia had higher viral loads than those with bronchitis or upper respiratory tract infection. Median viral shedding time after the onset of symptoms was 9 days. Patients <13 years of age had a longer median viral shedding time than those >or=13 years of age (11 days vs. 7 days). These results suggest that younger children may require a longer isolation period and that patients with pneumonia may require treatment that is more aggressive than standard therapy for pandemic (H1N1) 2009 virus.
There is a current healthcare need for improved prosthetic socket fit provision for the masses using low-cost and simple to manufacture sensors that can measure pressure, shear, and friction. There ...is also a need to address society’s increasing concerns regarding the environmental impact of electronics and IoT devices. Prototype thin, low-cost, and low-weight pressure, shear, and loss of friction sensors have been developed and assembled for trans-femoral amputees. These flexible and conformable sensors are simple to manufacture and utilize more enviro-friendly novel magnetite-based QTSS™ (Quantum Technology Supersensor™) quantum materials. They have undergone some initial tests on flat and curved surfaces in a pilot amputee trial, which are presented in this paper. These initial findings indicate that the prototype pressure sensor strip is capable of measuring pressure both on flat and curved socket surfaces in a pilot amputee trial. They have also demonstrated that the prototype shear sensor can indicate increasing shear forces, the resultant direction of the shear forces, and loss of friction/slippage events. Further testing, amputee trials, and ongoing optimization is continuing as part of the SocketSense project to assist prosthetic comfort and fit.
Neuroprotectant strategies that have worked in rodent models of stroke have failed to provide protection in clinical trials. Here we show that the opposite circadian cycles in nocturnal rodents ...versus diurnal humans
may contribute to this failure in translation. We tested three independent neuroprotective approaches-normobaric hyperoxia, the free radical scavenger α-phenyl-butyl-tert-nitrone (αPBN), and the N-methyl-D-aspartic acid (NMDA) antagonist MK801-in mouse and rat models of focal cerebral ischaemia. All three treatments reduced infarction in day-time (inactive phase) rodent models of stroke, but not in night-time (active phase) rodent models of stroke, which match the phase (active, day-time) during which most strokes occur in clinical trials. Laser-speckle imaging showed that the penumbra of cerebral ischaemia was narrower in the active-phase mouse model than in the inactive-phase model. The smaller penumbra was associated with a lower density of terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL)-positive dying cells and reduced infarct growth from 12 to 72 h. When we induced circadian-like cycles in primary mouse neurons, deprivation of oxygen and glucose triggered a smaller release of glutamate and reactive oxygen species, as well as lower activation of apoptotic and necroptotic mediators, in 'active-phase' than in 'inactive-phase' rodent neurons. αPBN and MK801 reduced neuronal death only in 'inactive-phase' neurons. These findings suggest that the influence of circadian rhythm on neuroprotection must be considered for translational studies in stroke and central nervous system diseases.
Abstract
Background
Aberrant aggregation of α-synuclein (α-syn) is a key pathological feature of Parkinson’s disease (PD), but the precise role of intestinal α-syn in the progression of PD is ...unclear. In a number of genetic
Drosophila
models of PD, α-syn was frequently ectopically expressed in the neural system to investigate the pathobiology.
Method
We investigated the potential role of intestinal α-syn in PD pathogenesis using a
Drosophila
model. Human α-syn was overexpressed in
Drosophila
guts, and life span, survival, immunofluorescence and climbing were evaluated. Immunofluorescence, Western blotting and reactive oxygen species (ROS) staining were performed to assess the effects of intestinal α-syn on intestinal dysplasia. High‐throughput RNA and 16S rRNA gene sequencing, quantitative RT‐PCR, immunofluorescence, and ROS staining were performed to determine the underlying molecular mechanism.
Results
We found that the intestinal α-syn alone recapitulated many phenotypic and pathological features of PD, including impaired life span, loss of dopaminergic neurons, and progressive motor defects. The intestine-derived α-syn disrupted intestinal homeostasis and accelerated the onset of intestinal ageing. Moreover, intestinal expression of α-syn induced dysbiosis, while microbiome depletion was efficient to restore intestinal homeostasis and ameliorate the progression of PD. Intestinal α-syn triggered ROS, and eventually led to the activation of the dual oxidase (DUOX)–ROS–Jun N-terminal Kinase (JNK) pathway. In addition, α-syn from both the gut and the brain synergized to accelerate the progression of PD.
Conclusions
The intestinal expression of α-syn recapitulates many phenotypic and pathologic features of PD, and induces dysbiosis that aggravates the pathology through the DUOX–ROS–JNK pathway in
Drosophila
. Our findings provide new insights into the role of intestinal α-syn in PD pathophysiology.
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