Looking at Developmental Neurotoxicity Testing from the Perspective of an Invertebrate Embryo

Developmental neurotoxicity (DNT) of chemical compounds disrupts the formation of a normal brain. There is impressive progress in the development of alternative testing methods for DNT potential in chemicals, some of which also incorporate invertebrate animals. This review briefly touches upon studies on the genetically tractable model organisms of Caenorhabditis elegans and Drosophila melanogaster about the action of specific developmental neurotoxicants. The formation of a functional nervous system requires precisely timed axonal pathfinding to the correct cellular targets. To address this complex key event, our lab developed an alternative assay using a serum-free culture of intact locust embryos. The first neural pathways in the leg of embryonic locusts are established by a pair of afferent pioneer neurons which use guidance cues from membrane-bound and diffusible semaphorin proteins. In a systematic approach according to recommendations for alternative testing, the embryo assay quantifies defects in pioneer navigation after exposure to a panel of recognized test compounds for DNT. The outcome indicates a high predictability for test-compound classification. Since the pyramidal neurons of the mammalian cortex also use a semaphorin gradient for neurite guidance, the assay is based on evolutionary conserved cellular mechanisms, supporting its relevance for cortical development.     

Macroscopic modeling of slow axonal transport of rapidly diffusible soluble proteins

The purpose of this paper is to develop a macroscopic model of slow axonal transport of soluble proteins which may be transported in axons by both diffusion and active molecular-motor-assisted transport mechanisms. The model relies on the “stop-and-go” hypothesis put forward by Brown et al. [A. Brown, L. Wang, P. Jung, Stochastic simulation of neurofilament transport in axons: the “stop-and-go” hypothesis, Molecular Biology of the Cell 16 (2005) 4243–4255.] according to which the motion of neurofilaments in slow axonal transport does not occur at a constant velocity; instead, neurofilaments move along microtubules alternating between short periods of rapid movement, short on-track pauses, and prolonged off-track pauses, when they temporarily disengage from microtubules. For soluble proteins, diffusion may also play an important role in overall slow axonal transport; to account for this effect governing equations of the dynamic system model developed in Craciun et al. [G. Craciun, A. Brown, A. Friedman, A dynamical system model of neurofilament in axons, Journal of Theoretical Biology 237 (2005) 316–322.] are extended to incorporate diffusivity of off track proteins (proteins unbound to a stationary matrix). The model correctly predicts that the total concentration of organelles forms the bell-shaped wave that spreads out as it propagates toward the axon tip.     

Beating in Membrane Potential Mediated by Cortical γ-Oscillations for Reading Out Synchronous Neuronal Activities Over Distant Cortical Areas

I investigate whether cortical -oscillations are relevant to reading out synchronous neuronal firings that are distributed over the brain. A cortical neural network model is proposed and simulated. The model consists of two sensory networks (SI and SII) and one coincidence-sensitive network (CS). -oscillatory inputs and external stimuli are applied to interneurons and projection neurons of the sensory networks, respectively. The SI and SII networks project to the CS network in a divergent/convergent manner. Here I show that beating in membrane potential of CS neurons mediates the detection of synchronous neuronal firings between the SI and SII networks. A slight increase (a few Hz) in difference between frequencies of the -oscillations in the SI and SII networks generates the beating in the CS network. The synchronous neuronal firings are detected at each peak of the beating, regardless of difference in signal transmission time between SI-to-CS and SII-to-CS pathways.     

New Insights in the Pathogenesis of Multiple Sclerosis—Role of Acrolein in Neuronal and Myelin Damage

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by an inappropriate inflammatory reaction resulting in widespread myelin injury along white matter tracts. Neurological impairment as a result of the disease can be attributed to immune-mediated injury to myelin, axons and mitochondria, but the molecular mechanisms underlying the neuropathy remain incompletely understood. Incomplete mechanistic knowledge hinders the development of therapies capable of alleviating symptoms and slowing disease progression in the long-term. Recently, oxidative stress has been implicated as a key component of neural tissue damage prompting investigation of reactive oxygen species (ROS) scavengers as a potential therapeutic option. Despite the establishment of oxidative stress as a crucial process in MS development and progression, ROS scavengers have had limited success in animal studies which has prompted pursuit of an alternative target capable of curtailing oxidative stress. Acrolein, a toxic β-unsaturated aldehyde capable of initiating and perpetuating oxidative stress, has been suggested as a viable point of intervention to guide the development of new treatments. Sequestering acrolein using an FDA-approved compound, hydralazine, offers neuroprotection resulting in dampened symptom severity and slowed disease progression in experimental autoimmune encephalomyelitis (EAE) mice. These results provide promise for therapeutic development, indicating the possible utility of neutralizing acrolein to preserve and improve neurological function in MS patients.     

Pressing Processing Diminishes Outgrowth and Bridging for AgMg/Bi-2223 Tapes

Multifilamentary Bi-2223 tapes were fabricated by PIT, using a silver alloy sheath with 2.5% magnesium metal. Outgrowth and bridging are major disadvantages for some silver alloy sheathed Bi-2223 tapes. To solve the outgrowth problem, green tapes were pressed with different reduction rates and then sintered at high temperatures. Critical current I _c of the sintered tapes was measured at nitrogen temperature using the four-probe method. The morphology of the filament core was observed with scanning electron microscope (SEM) to investigate outgrowth of sintered tapes with different reduction rates. Outgrowth and bridging on cross and longitudinal sections of filaments were studied using TEM images. Experimental results suggest that pressing processing may diminish outgrowth and bridging. Number of outgrowths and cases of bridging are reduced when the reduction rate increases, but the slope of the reduction falls at large reduction rates. The I _c curve indicates that there is an optimum reduction rate at which I _c reaches a maximum. At the best reduction rate the amount of outgrowth and bridging is close to the lowest. Experimental results show that pressing processing can diminish outgrowth and bridging by as much as 50%. Therefore, proper pressing is an effective method for both diminishing outgrowth and bridging and enhancement of I _c.     

Novel Applications of NSAIDs: Insight and Future Perspectives in Cardiovascular,Neurodegenerative, Diabetes and Cancer Disease Therapy

Once it became clear that inflammation takes place in the modulation of different degenerative disease including neurodegenerative, cardiovascular, diabetes and cancer the researchers has started intensive programs evaluating potential role of non-steroidal anti-inflammatory drugs (NSAIDs) in the prevention or therapy of these diseases. This review discusses the novel mechanism of action of NSAIDs and its potential use in the pharmacotherapy of neurodegenerative, cardiovascular, diabetes and cancer diseases. Many different molecular and cellular factors which are not yet fully understood play an important role in the pathogenesis of inflammation, axonal damage, demyelination, atherosclerosis, carcinogenesis thus further NSAID studies for a new potential indications based on precise pharmacotherapy model are warranted since NSAIDs are a heterogeneous group of medicines with relative different pharmacokinetics and pharmacodynamics profiles. Hopefully the new data from studies will fill in the gap between experimental and clinical results and translate our knowledge into successful disease therapy.     

弥漫性轴索损伤实验装置的研制和应用

为研究弥漫性轴索损伤(DAI)问题,研制了一套稳定性高、重复性好且能比较真实地模拟DAI临床损伤机制的实验装置。详细阐述了实验装置的设计过程,包括驱动力的选择、联动结构设计、限位固定块的设计和传感器的选择等。最后通过大鼠实验验证了实验装置的可行性和优越性。     

In the Right Place at the Right Time: miRNAs as Key Regulators in Developing Axons

During neuronal circuit formation, axons progressively develop into a presynaptic compartment aided by extracellular signals. Axons display a remarkably high degree of autonomy supported in part by a local translation machinery that permits the subcellular production of proteins required for their development. Here, we review the latest findings showing that microRNAs (miRNAs) are critical regulators of this machinery, orchestrating the spatiotemporal regulation of local translation in response to cues. We first survey the current efforts toward unraveling the axonal miRNA repertoire through miRNA profiling, and we reveal the presence of a putative axonal miRNA signature. We also provide an overview of the molecular underpinnings of miRNA action. Our review of the available experimental evidence delineates two broad paradigms: cue-induced relief of miRNA-mediated inhibition, leading to bursts of protein translation, and cue-induced miRNA activation, which results in reduced protein production. Overall, this review highlights how a decade of intense investigation has led to a new appreciation of miRNAs as key elements of the local translation regulatory network controlling axon development.