Huntington's disease (HD) is caused by a polyglutamine expansion mutation in the huntingtin protein that confers a toxic gain-of-function and causes the protein to become aggregate-prone. ...Aggregate-prone proteins are cleared by macroautophagy, and upregulating this process by rapamycin, which inhibits the mammalian target of rapamycin (mTOR), attenuates their toxicity in various HD models. Recently, we demonstrated that lithium induces mTOR-independent autophagy by inhibiting inositol monophosphatase (IMPase) and reducing inositol and IP3 levels. Here we show that glycogen synthase kinase-3β (GSK-3β), another enzyme inhibited by lithium, has opposite effects. In contrast to IMPase inhibition that enhances autophagy, GSK3β inhibition attenuates autophagy and mutant huntingtin clearance by activating mTOR. In order to counteract the autophagy inhibitory effects of mTOR activation resulting from lithium treatment, we have used the mTOR inhibitor rapamycin in combination with lithium. This combination enhances macroautophagy by mTOR-independent (IMPase inhibition by lithium) and mTOR-dependent (mTOR inhibition by rapamycin) pathways. We provide proof-of-principle for this rational combination treatment approach in vivo by showing greater protection against neurodegeneration in an HD fly model with TOR inhibition and lithium, or in HD flies treated with rapamycin and lithium, compared with either pathway alone.
Huntington's disease (HD) is a devastating autosomal dominant neurodegenerative disease caused by a CAG trinucleotide repeat expansion encoding an abnormally long polyglutamine tract in the ...huntingtin protein. Much has been learnt since the mutation was identified in 1993. We review the functions of wild-type huntingtin. Mutant huntingtin may cause toxicity via a range of different mechanisms. The primary consequence of the mutation is to confer a toxic gain of function on the mutant protein and this may be modified by certain normal activities that are impaired by the mutation. It is likely that the toxicity of mutant huntingtin is revealed after a series of cleavage events leading to the production of N-terminal huntingtin fragment(s) containing the expanded polyglutamine tract. Although aggregation of the mutant protein is a hallmark of the disease, the role of aggregation is complex and the arguments for protective roles of inclusions are discussed. Mutant huntingtin may mediate some of its toxicity in the nucleus by perturbing specific transcriptional pathways. HD may also inhibit mitochondrial function and proteasome activity. Importantly, not all of the effects of mutant huntingtin may be cell-autonomous, and it is possible that abnormalities in neighbouring neurons and glia may also have an impact on connected cells. It is likely that there is still much to learn about mutant huntingtin toxicity, and important insights have already come and may still come from chemical and genetic screens. Importantly, basic biological studies in HD have led to numerous potential therapeutic strategies.
A robust assessment of tunnels due to uncertainties present in soil and ground motion properties can affect the dynamic response of these structures. In this paper, a stochastic analysis considering ...an aleatory variability in shear velocity Vs by performing Monte Carlo simulations and assessing its influence on underground tunnels. To numerically assess the response of the soil‐tunnel system to near‐fault earthquake ground motion, the required computational domain usually spans multiple kilometers including both earthquake fault and the structure. Thus, these simulations are computationally expensive. An efficient alternative method, that is, the Domain Reduction Method (DRM), in which a modular two‐step methodology for reducing the computational costs in the large domain analysis is employed. A 3‐D soil‐tunnel structure interaction is modeled to simulate the response of tunnel subjected to an inclined earthquake fault. The numerical simulation of the soil‐tunnel‐fault system is conducted in an open‐source FE package called Multi‐hazard Analysis for STOchastic time DOmaiN phenomena (MASTODON) based on MOOSE framework. The interactive analyses are carried out for three distinct types of soils based on National Earthquake Hazards Reduction Program (NEHRP) provision, that is, soft, medium, and hard, by generating 130 realizations. The results provide many insights into the influence of local site effects, that is, frequency shift for the peak response and the importance of input ground motion characteristics that govern the response of underground structures. The dynamic response of the structure is very sensitive to the uncertainty in rock material properties, especially, the stiffness of the rock sample and the shear wave velocity.
Previous studies have suggested that cognitive and psychosocial underfunctioning in early‐treated adults with phenylketonuria (PKU) may be explained by suboptimal adherence to dietary treatments, ...however, these studies often employ small samples, with different outcome measures, definitions and cut‐offs. Samples have also tended to comprise participants with a limited range of blood phenylalanine concentrations, and often individuals who may not have been treated early enough to avoid neurological damage. In this study, we explore the impact of lifetime dietary control, as indicated by blood phenylalanine concentrations in childhood, adolescence and adulthood, on long‐term cognitive and psychosocial outcomes in a large sample of adults with PKU who were diagnosed by neonatal screening and commenced on dietary treatment within the first month of life. One hundred and fifty‐four participants underwent cognitive testing, assessing attention, learning, working memory, language, executive functioning and processing speed. One hundred and forty‐nine completed measures of psychosocial functioning, documenting educational, occupational, quality of life, emotional and social outcomes which were compared with a group of healthy controls. Many adults with PKU demonstrated cognitive impairments, most frequently affecting processing speed (23%), executive function (20%) and learning (12%). Cognitive outcomes were related to measures of historic metabolic control, but only processing speed was significantly related to phenylalanine concentration at the time of testing after controlling for historic levels. Adults with PKU did not, however, differ from controls in educational, occupational, quality of life or emotional outcomes, or on a measure of family functioning, and showed only minor differences in relationship style. These findings have implications for patient counselling and decisions regarding the management of PKU in adulthood.
Many neurodegenerative diseases exhibit protein accumulation and increased oxidative stress. Therapeutic strategies include clearing aggregate-prone proteins by enhancing autophagy or decreasing ...oxidative stress with antioxidants. Many autophagy-inducing stimuli increase reactive oxygen species (ROS), raising concerns that the benefits of autophagy up-regulation may be counterbalanced by ROS toxicity. Here we show that not all autophagy inducers significantly increase ROS. However, many antioxidants inhibit both basal and induced autophagy. By blocking autophagy, antioxidant drugs can increase the levels of aggregate-prone proteins associated with neurodegenerative disease. In fly and zebrafish models of Huntington's disease, antioxidants exacerbate the disease phenotype and abrogate the rescue seen with autophagy-inducing agents. Thus, the potential benefits in neurodegenerative diseases of some classes of antioxidants may be compromised by their autophagy-blocking properties.
This paper presents a review of investigations that recognised the effect of vehicle-pavement interaction (VPI) mechanism in estimating flexible pavement performance criteria. This state-of-the-art ...review highlights the importance of dynamic traffic loads illustrated through vehicular models that have potential in simulating realistic field conditions in the mechanistic pavement design process. Furthermore, this article documents the advanced pavement models along with uncoupled and coupled VPI methods of analyses to predict structural and functional performance characteristics. Based on extensive search, there seems to be an expansive scope to better the current pavement design procedures through the integration of VPI for evaluation of performance criteria. Overall, it is envisioned that the prospects underscored in this detailed note will help advance the design procedures and certainly create a mechanistic-based design template for flexible pavements that exemplifies practical roadway scenarios.
Structured beams carrying topological defects, namely phase and Stokes singularities, have gained extensive interest in numerous areas of optics. The non-separable spin and orbital angular momentum ...states of hybridly polarized Stokes singular beams provide additional freedom for manipulating optical fields. However, the characterization of hybridly polarized Stokes vortex beams remains challenging owing to the degeneracy associated with the complex polarization structures of these beams. In addition, experimental noise factors such as relative phase, amplitude, and polarization difference together with beam fluctuations add to the perplexity in the identification process. Here, we present a generalized diffraction-based Stokes polarimetry approach assisted with deep learning for efficient identification of Stokes singular beams. A total of 15 classes of beams are considered based on the type of Stokes singularity and their associated mode indices. The resultant total and polarization component intensities of Stokes singular beams after diffraction through a triangular aperture are exploited by the deep neural network to recognize these beams. Our approach presents a classification accuracy of 98.67% for 15 types of Stokes singular beams that comprise several degenerate cases. The present study illustrates the potential of diffraction of the Stokes singular beam with polarization transformation, modeling of experimental noise factors, and a deep learning framework for characterizing hybridly polarized beams.
•An expansin gene (EaEXPA1) from high biomass accumulating drought tolerant E. arundinaceus was overexpressed in commercial sugarcane variety.•Transgenic sugarcane lines showed improved physiological ...parameters than untransformed control under the drought stress.•Overexpression of EaEXPA1 gene also confer enhanced drought tolerance.
Sugarcane (Saccharum spp. hybrid) contributes to 80% of world sugar production and is a valuable source of biomass for the production of lignocellulosic ethanol making it an important commercial crop. Drought stress is one of the major abiotic stress factors which reduces the productivity and quality of sugarcane. Increase in the intensity and duration of drought coupled with the rising demand of sugar warrants the development of drought-tolerant sugarcane. Genetic engineering offers potential strategies to develop superior sugarcane varieties that improve crop productivity in drought-prone environments. Thus, with a view to develop drought-tolerant sugarcane, in the present study, an expansin gene which confers drought tolerance, was transformed into sugarcane. An expansin gene (EaEXPA1) from Erianthus arundinaceus, a wild relative of sugarcane, was overexpressed in the commercial sugarcane variety Co 86032 through Agrobacterium-mediated transformation. Transgenic lines exhibited significantly higher level of EaEXPA1 expression over the control plants. The performance evaluation of V1 transgenics under the drought stress revealed significantly higher relative water content, cell membrane thermostability, chlorophyll content, photosynthetic efficiency (Fv/Fm) and gas-exchange parameters than untransformed control plants. Here, it is reported for the first time that the overexpression of EaEXPA1 in sugarcane enhances drought tolerance. Thus, EaEXPA1 can be a potential target gene for improving drought tolerance in sugarcane.
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