Destruction of Dopaminergic Neurons in the Midbrain by 6-Hydroxydopamine Decreases Hippocampal Cell Proliferation in Rats: Reversal by Fluoxetine

Background Non-motor symptoms (e.g., depression, anxiety, and cognitive deficits) in patients with Parkinson disease (PD) precede the onset of the motor symptoms. Although these symptoms do not respond to pharmacological dopamine replacement therapy, their precise pathological mechanisms are currently unclear. The present study was undertaken to examine whether the unilateral 6-hydroxydopamine (6-OHDA) lesion to the substantia nigra pars compacta (SNc), which represents a model of long-term dopaminergic neurotoxicity, could affect cell proliferation in the adult rat brain. Furthermore, we examined the effects of the selective serotonin reuptake inhibitor (SSRI) fluoxetine and the selective noradrenaline reuptake inhibitor maprotiline on the reduction in cell proliferation in the subgranular zone (SGZ) by the unilateral 6-OHDA lesion. Methodology/Principal Findings A single unilateral injection of 6-OHDA into the rat SNc resulted in an almost complete loss of tyrosine hydroxylase (TH) immunoreactivity in the striatum and SNc, as well as in reductions of TH-positive cells and fibers in the ventral tegmental area (VTA). On the other hand, an injection of vehicle alone showed no overt change in TH immunoreactivity. A unilateral 6-OHDA lesion to SNc significantly decreased cell proliferation in the SGZ ipsilateral to the 6-OHDA lesion, but not in the contralateral SGZ or the subventricular zone (SVZ), of rats. Furthermore, subchronic (14 days) administration of fluoxetine (5 mg/kg/day), but not maprotiline significantly attenuated the reduction in cell proliferation in the SGZ by unilateral 6-OHDA lesion. Conclusions/Significance The present study suggests that cell proliferation in the SGZ of the dentate gyrus might be, in part, under dopaminergic control by SNc and VTA, and that subchronic administration of fluoxetine reversed the reduction in cell proliferation in the SGZ by 6-OHDA. Therefore, SSRIs such as fluoxetine might be potential therapeutic drugs for non-motor symptoms as well as motor symptoms in patients with PD, which might be associated with the reduction in cell proliferation in the SGZ

Characterization of Rhodamine-123 as a Tracer Dye for Use In In vitro Drug Transport Assays

Fluorescent tracer dyes represent an important class of sub-cellular probes and allow the examination of cellular processes in real-time with minimal impact upon these processes. Such tracer dyes are becoming increasingly used for the examination of membrane transport processes, as they are easy-to-use, cost effective probe substrates for a number of membrane protein transporters. Rhodamine 123, a member of the rhodamine family of flurone dyes, has been used to examine membrane transport by the ABCB1 gene product, MDR1. MDR1 is viewed as the archetypal drug transport protein, and is able to efflux a large number of clinically relevant drugs. In addition, ectopic activity of MDR1 has been associated with the development of multiple drug resistance phenotype, which results in a poor patient response to therapeutic intervention. It is thus important to be able to examine the potential for novel compounds to be MDR1 substrates. Given the increasing use rhodamine 123 as a tracer dye for MDR1, a full characterisation of its spectral properties in a range of in vitro assay-relevant media is warranted. Herein, we determine λmax for excitation and emission or rhodamine 123 and its metabolite rhodamine 110 in commonly used solvents and extraction buffers, demonstrating that fluorescence is highly dependent on the chemical environment: Optimal parameters are 1% (v/v) methanol in HBSS, with λex = 505 nm, λem = 525 nm. We characterise the uptake of rhodamine 123 into cells, via both passive and active processes, and demonstrate that this occurs primarily through OATP1A2-mediated facilitated transport at concentrations below 2 µM, and via micelle-mediated passive diffusion above this. Finally, we quantify the intracellular sequestration and metabolism of rhodamine 123, demonstrating that these are both cell line-dependent factors that may influence the interpretation of transport assays

Early Developing Pig Embryos Mediate Their Own Environment in the Maternal Tract

The maternal tract plays a critical role in the success of early embryonic development providing an optimal environment for establishment and maintenance of pregnancy. Preparation of this environment requires an intimate dialogue between the embryo and her mother. However, many intriguing aspects remain unknown in this unique communication system. To advance our understanding of the process by which a blastocyst is accepted by the endometrium and better address the clinical challenges of infertility and pregnancy failure, it is imperative to decipher this complex molecular dialogue. The objective of the present work is to define the local response of the maternal tract towards the embryo during the earliest stages of pregnancy. We used a novel in vivo experimental model that eliminated genetic variability and individual differences, followed by Affymetrix microarray to identify the signals involved in this embryo-maternal dialogue. Using laparoscopic insemination one oviduct of a sow was inseminated with spermatozoa and the contralateral oviduct was injected with diluent. This model allowed us to obtain samples from the oviduct and the tip of the uterine horn containing either embryos or oocytes from the same sow. Microarray analysis showed that most of the transcripts differentially expressed were down-regulated in the uterine horn in response to blastocysts when compared to oocytes. Many of the transcripts altered in response to the embryo in the uterine horn were related to the immune system. We used an in silico mathematical model to demonstrate the role of the embryo as a modulator of the immune system. This model revealed that relatively modest changes induced by the presence of the embryo could modulate the maternal immune response. These findings suggested that the presence of the embryo might regulate the immune system in the maternal tract to allow the refractory uterus to tolerate the embryo and support its development

A review of friction models in interacting joints for durability design.

This paper presents a comprehensive review of friction modelling to provide an understanding of design for durability within interacting systems. Friction is a complex phenomenon and occurs at the interface of two components in relative motion. Over the last several decades, the effects of friction and its modelling techniques have been of significant interests in terms of industrial applications. There is however a need to develop a unified mathematical model for friction to inform design for durability within the context of varying operational conditions. Classical dynamic mechanisms model for the design of control systems has not incorporated friction phenomena due to non-linearity behaviour. Therefore, the tribological performance concurrently with the joint dynamics of a manipulator joint applied in hazardous environments needs to be fully analysed. Previously the dynamics and impact models used in mechanical joints with clearance have also been examined. The inclusion of reliability and durability during the design phase is very important for manipulators which are deployed in harsh environmental and operational conditions. The revolute joint is susceptible to failures such as in heavy manipulators these revolute joints can be represented by lubricated conformal sliding surfaces. The presence of pollutants such as debris and corrosive constituents has the potential to alter the contacting surfaces, would in turn affect the performance of revolute joints, and puts both reliability and durability of the systems at greater risks of failure. Key literature is identified and a review on the latest developments of the science of friction modelling is presented here. This review is based on a large volume of knowledge. Gaps in the relevant field have been identified to capitalise on for future developments. Therefore, this review will bring significant benefits to researchers, academics and industrial professionals

Development of rapid mask fabrication technology for micro-abrasive jet machining

Micro-machining of a brittle material such as glass or silicon is important in micro fabrication. Particularly, micro-abrasive jet machining (??-AJM) has become a useful technique for micro-machining of such materials. The ??-AJM process is mainly based on the erosion of a mask which protects brittle substrate against high velocity of micro-particles. Therefore, fabrication of an adequate mask is very important. Generally, for the fabrication of a mask in the ??-AJM process, a photomask based on the semi-conductor fabrication process was used. In this research a rapid mask fabrication technology has been developed for the ??-AJM. By scanning the focused UV laser beam, a micro-mask pattern was fabricated directly without photolithography process and photomask. Therefore, rapid and economic mask fabrication can be possible for the micro-abrasive jet machining. Two kinds of mask patterns were fabricated by using SU-8 and photopolymer (Watershed 11110). Using fabricated mask patterns, abrasive-jet machining of Si wafer was conducted successfully.ope