Dyskinesias after neural transplantation in Parkinson's disease: what do we know and what is next?

Since the 1980 s, when cell transplantation into the brain as a cure for Parkinson's disease hit the headlines, several patients with Parkinson's disease have received transplantation of cells from aborted fetuses with the aim of replacing the dopamine cells destroyed by the disease. The results in human studies were unpredictable and raised controversy. Some patients showed remarkable improvement, but many of the patients who underwent transplantation experienced serious disabling adverse reactions, putting an end to human trials since the late 1990 s. These side effects consisted of patients' developing troublesome involuntary, uncontrolled movements in the absence of dopaminergic medication, so-called off-phase, graft-induced dyskinesias. Notwithstanding the several mechanisms having been proposed, the pathogenesis of this type of dyskinesias remained unclear and there was no effective treatment. It has been suggested that graft-induced dyskinesias could be related to fiber outgrowth from the graft causing increased dopamine release, that could be related to the failure of grafts to restore a precise distribution of dopaminergic synaptic contacts on host neurons or may also be induced by inflammatory and immune responses around the graft. A recent study, however, hypothesized that an important factor for the development of graft-induced dyskinesias could include the composition of the cell suspension and specifically that a high proportion of serotonergic neurons cografted in these transplants engage in nonphysiological properties such as false transmitter release. The findings from this study showed serotonergic hyperinnervation in the grafted striatum of two patients with Parkinson's disease who exhibited major motor recovery after transplantation with fetal mesencephalic tissue but later developed graft-induced dyskinesias. Moreover, the dyskinesias were significantly attenuated by administration of a serotonin agonist, which activates the inhibitory serotonin autoreceptors and attenuates transmitter release from serotonergic neurons, indicating that graft-induced dyskinesias were caused by the dense serotonergic innervation engaging in false transmitter release. Here the implications of the recent findings for the development of new human trials testing the safety and efficacy of cell transplantation in patients with Parkinson's disease are discussed

A novel test method for continuous nonlinear biaxial tensile deformation of sheet metals by bulging with stepped-dies

In this paper, a novel test method named bulging with stepped-dies is proposed to overcome the difficulty of traditional test methods in realizing continuous nonlinear loading paths from initial yield up to fracture on a sheet metal. To achieve this aim, the section shape of a stepped-die cavity is varied with increasing depth. During bulging with a stepped-die, the stress state at the pole of bulging area of the sheet changes continuously with the increase in bulging height, which results in a specific nonlinear loading path. A theoretical model is established to calculate the stress components at the pole based on the assumption that the bulged surface near the pole was approximated by a rotational ellipsoid. Bulging experiments with three different stepped-dies are performed by using ST16 steel sheet. Stress and strain paths up to fracture and equivalent stress-strain curves at the pole are analyzed and compared with the results of bulging with elliptical dies. It is shown that continuous nonlinear loading paths can be effectively realized through bulging with stepped-dies and the stress ratio at the pole changes from 0.5 up to 2.0 at most in one bulging experiment. The feasibility of the novel test method is validated successfully. And the experimental data obtained are useful to determine constitutive and forming limit models suitable for complex loading conditions

Experimental and modelling study of interaction between friction and galling under contact load change conditions

The galling process remains one of the least understood phenomena in metal forming. The transfer of material from a work-piece onto the tool surface can cause an evolutionary increase in COF and thus the use of a constant COF in FE simulations leads to progressively inaccurate results. For an aluminium work-piece, material transfer, which has history and pressure dependency, is determined by a dynamic balance between the generation and ejection of wear particles acting as a 'third body' abrasive element at the contact interface. To address this dynamic interactive phenomenon, pin-on-disc tests between AA6082 and G3500 were performed under step load change conditions. The COF evolutions, morphologies of the transfer layer and its cross-section were studied. It has been found that contact load change will disequilibrate and rebuild the dynamic balance and high load will increase the generation and ejection rate of third body and vice versa. Moreover, based on the experimental results, an interactive model was developed and presented to simulate the dynamic formation process of the aluminium third body layer under load change conditions, enabling multi-cycle simulations to model the galling distribution and friction variation

Investigation of the friction coefficient evolution and lubricant breakdown behaviour of AA7075 aluminium alloy forming processes at elevated temperatures

The lubricant behaviour at elevated temperatures was investigated by conducting pin-on-disc tests between P20 tool steel and AA7075 aluminium alloy. The effects of temperature, initial lubricant volume, contact pressure and sliding speed on the lubricant behaviour (i.e. evolutions of the coefficient of friction (COF) and the breakdown phenomenon) were experimentally studied. The evolutions of COF at elevated temperatures consisted of three distinct stages with different friction mechanisms. The first stage (stage I) occurred with low friction when the boundary lubrication was present. The second stage (stage II) was the transition process in which the COF rapidly increased as the lubricant film thickness decreased to a critical value. In the final plateau stage (stage III), lubricant breakdown occurred and intimate contact at the interface led to high friction values. At the low friction stage (stage I), the value of COF increased with increasing temperature. The increase in temperature, contact pressure and sliding speed as well as the decrease in initial lubricant volume accelerated the lubricant breakdown

Corticotropin-releasing hormone exerts direct effects on neuronal progenitor cells: implications for neuroprotection

Neurogenesis during embryonic and adult life is tightly regulated by a network of transcriptional, growth and hormonal factors. Emerging evidence indicates that activation of the stress response, via the associated glucocorticoid increase, reduces neurogenesis and contributes to the development of adult diseases.As corticotrophin-releasing hormone (CRH) or factor is the major mediator of adaptive response to stressors, we sought to investigate its involvement in this process. Accordingly, we found that CRH could reverse the damaging effects of glucocorticoid on neural stem/progenitor cells (NS/PCs), while its genetic deficiency results in compromised proliferation and enhanced apoptosis during neurogenesis. Analyses in fetal and adult mouse brain revealed significant expression of CRH receptors in proliferating neuronal progenitors. Furthermore, by using primary cultures of NS/PCs, we characterized the molecular mechanisms and identified CRH receptor-1 as the receptor mediating the neuroprotective effects of CRH. Finally, we demonstrate the expression of CRH receptors in human fetal brain from early gestational age, in areas of active neuronal proliferation. These observations raise the intriguing possibility for CRH-mediated pharmacological applications in diseases characterized by altered neuronal homeostasis, including depression, dementia, neurodegenerative diseases, brain traumas and obesity

Clinical application of stem cell therapy in Parkinson's disease

Cell replacement therapies in Parkinson's disease (PD) aim to provide long-lasting relief of patients' symptoms. Previous clinical trials using transplantation of human fetal ventral mesencephalic (hfVM) tissue in the striata of PD patients have provided proof-of-principle that such grafts can restore striatal dopaminergic (DA-ergic) function. The transplants survive, reinnervate the striatum, and generate adequate symptomatic relief in some patients for more than a decade following operation. However, the initial clinical trials lacked homogeneity of outcomes and were hindered by the development of troublesome graft-induced dyskinesias in a subgroup of patients. Although recent knowledge has provided insights for overcoming these obstacles, it is unlikely that transplantation of hfVM tissue will become routine treatment for PD owing to problems with tissue availability and standardization of the grafts. The main focus now is on producing DA-ergic neuroblasts for transplantation from stem cells (SCs). There is a range of emerging sources of SCs for generating a DA-ergic fate in vitro. However, the translation of these efforts in vivo currently lacks efficacy and sustainability. A successful, clinically competitive SC therapy in PD needs to produce long-lasting symptomatic relief without side effects while counteracting PD progression

VerdictDB: Universalizing Approximate Query Processing

Despite 25 years of research in academia, approximate query processing (AQP) has had little industrial adoption. One of the major causes of this slow adoption is the reluctance of traditional vendors to make radical changes to their legacy codebases, and the preoccupation of newer vendors (e.g., SQL-on-Hadoop products) with implementing standard features. Additionally, the few AQP engines that are available are each tied to a specific platform and require users to completely abandon their existing databases---an unrealistic expectation given the infancy of the AQP technology. Therefore, we argue that a universal solution is needed: a database-agnostic approximation engine that will widen the reach of this emerging technology across various platforms. Our proposal, called VerdictDB, uses a middleware architecture that requires no changes to the backend database, and thus, can work with all off-the-shelf engines. Operating at the driver-level, VerdictDB intercepts analytical queries issued to the database and rewrites them into another query that, if executed by any standard relational engine, will yield sufficient information for computing an approximate answer. VerdictDB uses the returned result set to compute an approximate answer and error estimates, which are then passed on to the user or application. However, lack of access to the query execution layer introduces significant challenges in terms of generality, correctness, and efficiency. This paper shows how VerdictDB overcomes these challenges and delivers up to 171$\times$ speedup (18.45$\times$ on average) for a variety of existing engines, such as Impala, Spark SQL, and Amazon Redshift, while incurring less than 2.6% relative error. VerdictDB is open-sourced under Apache License.Comment: Extended technical report of the paper that appeared in Proceedings of the 2018 International Conference on Management of Data, pp. 1461-1476. ACM, 201

Solid-state hot forge bonding of aluminium-steel bimetallic gears: Deformation mechanisms, microstructure and mechanical properties

Solid-state dissimilar bi- or multi-metallic bonding is promising for achieving lightweight or multifunctional components in automotive, nuclear power and aerospace industries. To understand how to achieve a high-quality bonding interface between dissimilar materials, aluminium alloy (Al)–steel (Fe) bimetal gears manufactured under hot forge bonding were systematically investigated. In this work, comprehensive analyses of forge bonding mechanics, microstructure features, bonding interface behaviours and resulting mechanical properties were undertaken using ex/in-situ experiments and finite element modelling. The results revealed that the bonding behaviour and microstructure evolution were significantly affected by the mechanical property mismatch between the two dissimilar workpieces (AA6082 and E355). This mismatch could be effectively adjusted by setting different forging temperatures. The interfacial bonding strengths of AA6082 and E355, manufactured at low and high temperatures, were observed to be governed by interdiffusion and oxide particles, respectively. Balancing interdiffusion and oxide breaking appears to be key to achieving optimized interface strength for dissimilar bimetallic forge bonding technology

Interactive mechanism and friction modelling of transient tribological phenomena in metal forming processes: A review

The accurate representation of tribological boundary conditions at the tool-workpiece interface is crucial for analysis and optimization of formability, material flow, and surface quality of components during metal forming processes. It has been found that these tribological conditions vary spatially and historically with process parameters and contact conditions. These time-dependent tribological behaviours are also known as transient tribological phenomena, which are widely observed during forming processes and many other manufacturing application scenarios. However, constant friction values are usually assigned to represent complex and dynamic interfacial conditions, which would introduce deviations in the relevant predictions. In this paper, transient tribological phenomena and the contemporary understanding of the interaction between friction and wear are reviewed, and it has been found that these phenomena are induced by the transitions of friction mechanisms and highly dependent on complex loading conditions at the interface. Friction modelling techniques for transient behaviours for metal forming applications are also reviewed. To accurately describe the evolutionary friction values and corresponding wear during forming, the advanced interactive friction modelling has been established for different application scenarios, including lubricated condition, dry sliding condition (metal-on-metal contact), and coated system