Invertebrate genetic models of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a common adult-onset neurodegenerative disease characterized by the progressive death of motor neurons in the cerebral cortex, brain stem, and spinal cord. The exact mechanisms underlying the pathogenesis of ALS remain unclear. The current consensus regarding the pathogenesis of ALS suggests that the interaction between genetic susceptibility and harmful environmental factors is a promising cause of ALS onset. The investigation of putative harmful environmental factors has been the subject of several ongoing studies, but the use of transgenic animal models to study ALS has provided valuable information on the onset of ALS. Here, we review the current common invertebrate genetic models used to study the pathology, pathophysiology, and pathogenesis of ALS. The considerations of the usage, advantages, disadvantages, costs, and availability of each invertebrate model will also be discussed

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Soundfield control using loudspeaker array

Control of loudspeaker arrays have been studied in the past few years for a wide variety of applications. One of such application is to control a pre-defined listening environment to achieve audible and inaudible zones so as to gain a personalized and immersive sound experience. One existing feasible approach to achieve soundfield control is to compute time- or frequency-domain coefficients for each loudspeaker such that the generated sound signals at the pre-defined listening locations can achieve the desired sound energy level for the superimposed sound signals. Several methodologies have recently been proposed to achieve a desired soundfield within a listening zone of interest. These methods include maximizing the energy ratio between energies of audible and inaudible zones, maximizing energy difference between two zones and maximizing the energy ratio while maintaining a desired sound energy level in the zone of interest. Although the above methods provide directional sound to the zone of interest, they cannot guarantee precise control of the soundfield within the audible/inaudible regions. As a result, undesired fluctuations of the soundfield or even sound distortion may occur. To address the issue, least squares (LS) methods along with regularisation techniques such as ordinary cross validation (OCV), generalized cross validation (GCV), the L-curve and the truncation method have also been proposed to achieve a desired sound energy level in a pre-defined zone of interest. Although these LS methods can improve the performance of soundfield control system, direct application of these methods will however introduce regularisation error (RE). In this thesis an iterative LS based algorithm is proposed. This algorithm utilizes the round-off error (ROE) as a regularisation parameter for the ill-conditioned system matrix over the zone of interest. Unlike existing LS methods, the proposed approach estimates the system matrix inverse iteratively and identifies the best estimate of the matrix inverse. In addition, the proposed algorithm does not accumulate significant ROE when the system matrix is ill-conditioned. Instead, the accumulated ROE is taken as a regularisation parameter which is evaluated iteratively to achieve a good trade-off between matrix inverse accuracy and the amount of RE. To achieve the above, a matrix sparseness criterion is proposed to evaluate the accuracy of the inverse estimate. This measure is subsequently used to terminate the iteration process. Furthermore, incorporating this criterion to the proposed method of estimating the loudspeaker coefficients, one can take into account the trade-off between the estimation error (during the convergence of the matrix inverse estimate) and the ROE (caused by mathematical computation when the system is ill-conditioned). The proposed algorithm is further extended to the scenario when the misplacement error (MPE) is present in the sound control system. It is found that the proposed algorithm can compensate and minimize the effect of MPE on the generated soundfield by exploiting the characteristics of the MPE when computing the regularisation parameter. Simulation results show that the proposed algorithm can outperform other LS-based regularisation methods in terms of normalized output error (NOE) in the presence or absence of MPE.Master of Engineerin

Iridium-Catalyzed Asymmetric Ring-Opening of Oxabenzonorbornadienes with N-Substituted Piperazine Nucleophiles

Iridium-catalyzed asymmetric ring-opening of oxabenzonorbornadienes with N-substituted piperazines was described. The reaction afforded the corresponding ring-opening products in high yields and moderate enantioselectivities in the presence of 2.5 mol % [Ir(COD)Cl]2 and 5.0 mol % (S)-p-Tol-BINAP. The effects of various chiral bidentate ligands, catalyst loading, solvent, and temperature on the yield and enantioselectivity were also investigated. A plausible mechanism was proposed to account for the formation of the corresponding trans-ring opened products based on the X-ray structure of product 2i

Grasping Force Control for a Robotic Hand by Slip Detection Using Developed Micro Laser Doppler Velocimeter

The purpose of this paper is to show the feasibility of grasping force control by feeding back signals of the developed micro-laser Doppler velocimeter (μ-LDV) and by discriminating whether a grasped object is slipping or not. LDV is well known as a high response surface velocity sensor which can measure various surfaces—such as metal, paper, film, and so on—thus suggesting the potential application of LDV as a slip sensor for grasping various objects. However, the use of LDV as a slip sensor has not yet been reported because the size of LDVs is too large to be installed on a robotic fingertip. We have solved the size problem and enabled the performance of a feasibility test with a few-millimeter-scale LDV referred to as micro-LDV (μ-LDV) by modifying the design which was adopted from MEMS (microelectromechanical systems) fabrication process. In this paper, by applying our developed μ-LDV as a slip sensor, we have successfully demonstrated grasping force control with three target objects—aluminum block, wood block, and white acrylic block—considering that various objects made of these materials can be found in homes and factories, without grasping force feedback. We provide proofs that LDV is a new promising candidate slip sensor for grasping force control to execute target grasping

Ru-Catalyzed Asymmetric Addition of Arylboronic Acids to Aliphatic Aldehydes via P-Chiral Monophosphorous Ligands

Chiral alcohols are among the most widely applied in fine chemicals, pharmaceuticals and agrochemicals. Herein, the Ru-monophosphine catalyst formed in situ was found to promote an enantioselective addition of aliphatic aldehydes with arylboronic acids, delivering the chiral alcohols in excellent yields and enantioselectivities and exhibiting a broad scope of aliphatic aldehydes and arylboronic acids. The enantioselectivities are highly dependent on the monophosphorous ligands. The utility of this asymmetric synthetic method was showcased by a large-scale transformation

Venetoclax efficacy on acute myeloid leukemia is enhanced by the combination with butyrate

Abstract Venetoclax has been approved recently for treatment of Acute myeloid leukemia (AML). Venetoclax is a BH3-mimetic and induces apoptosis via Bcl-2 inhibition. However, venetoclax’s effect is still restrictive and a novel strategy is needed. In the present study, we demonstrate that sodium butyrate (NaB) facilitates the venetoclax’s efficacy of cell death in AML cells. As a single agent, NaB or venetoclax exerted just a weak effect on cell death induction for AML cell line KG-1. The combination with NaB and venetoclax drastically induced cell death. NaB upregulated pro-apoptotic factors, Bax and Bak, indicating the synergistic effect by the collaboration with Bcl-2 inhibition by venetoclax. The combined treatment with NaB and venetoclax strongly cleaved a caspase substrate poly (ADP-ribose) polymerase (PARP) and a potent pan-caspase inhibitor Q-VD-OPh almost completely blocked the cell death induced by the combination, meaning that the combination mainly induced apoptosis. The combination with NaB and venetoclax also strongly induced cell death in another AML cell line SKNO-1 but did not affect chronic myeloid leukemia (CML) cell line K562, indicating that the effect was specific for AML cells. Our results provide a novel strategy to strengthen the effect of venetoclax for AML treatment