Characterising the RNA targets and position-dependent splicing regulation by TDP-43: implications for neurodegenerative diseases

L

Robust Motion Control of XYTable for Laser Cutting Machine

The position control algorithm for a beltdriven servomechanism of the laser cutting machine is described. High-accuracy position tracking control procedure for system with inherent elasticity due to the low-cost belt-driven servomechanism is derived based on continuos sliding mode technique. The proposed robust position tracking control algorithm was tested by simulations and used in the industrial application of a motion controller for the CNC machine. Simulation and experimental results are reported. I. INTRODUCTION Tool machines have several motion axes. In order to control all motion axes servo controls with motion controllers are indispensable in CNC controllers for machining centers. Motion controllers must be able to guarantee execution of demanded motion, which satisfies the desired tolerance of the finished workpiece. There are two fundamental motion tasks, which are used in modern mechanical systems: PTP (Point-To-Point) movement for moving from one position point to another ..

Robust Sliding Mode Based Impedance Control

The industrial robots are confronted with performing tasks where a contact with their environment occurs. Therefore, a need for control algorithms with position tracking performance and the force control ability appears. Up to date a lot of algorithms were proposed which deal with robot motion and force control. They could be mainly separated into two great classes, namely Hybrid control, where constrained and unconstrained DOFs of the robot are observed separately based on the principe of the ortoghonality, and Impedance control where the robot should adopt some physical properties such as mass, damping and stiffness in order to assure stable dynamic interaction with the environment. In this paper the robust impedance control law based on the attractive theory of sliding mode is proposed. The control law guarantees a robot predefined impedance and therefore force regulation based on possessed impedance properties is discussed. Experimental result on a simple 1 DOF mechanism is shown t..

Analysis of alternative splicing associated with aging and neurodegeneration in the human brain

Age is the most important risk factor for neurodegeneration; however, the effects of aging and neurodegeneration on gene expression in the human brain have most often been studied separately. Here, we analyzed changes in transcript levels and alternative splicing in the temporal cortex of individuals of different ages who were cognitively normal, affected by frontotemporal lobar degeneration (FTLD), or affected by Alzheimer's disease (AD). We identified age-related splicing changes in cognitively normal individuals and found that these were present also in 95% of individuals with FTLD or AD, independent of their age. These changes were consistent with increased polypyrimidine tract binding protein (PTB)–dependent splicing activity. We also identified disease-specific splicing changes that were present in individuals with FTLD or AD, but not in cognitively normal individuals. These changes were consistent with the decreased neuro-oncological ventral antigen (NOVA)–dependent splicing regulation, and the decreased nuclear abundance of NOVA proteins. As expected, a dramatic down-regulation of neuronal genes was associated with disease, whereas a modest down-regulation of glial and neuronal genes was associated with aging. Whereas our data indicated that the age-related splicing changes are regulated independently of transcript-level changes, these two regulatory mechanisms affected expression of genes with similar functions, including metabolism and DNA repair. In conclusion, the alternative splicing changes identified in this study provide a new link between aging and neurodegeneration

Widespread binding of FUS along nascent RNA regulates alternative splicing in the brain

Fused in sarcoma (FUS) and TAR DNA-binding protein 43 (TDP-43) are RNA-binding proteins pathogenetically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), but it is not known if they regulate the same transcripts. We addressed this question using crosslinking and immunoprecipitation (iCLIP) in mouse brain, which showed that FUS binds along the whole length of the nascent RNA with limited sequence specificity to GGU and related motifs. A saw-tooth binding pattern in long genes demonstrated that FUS remains bound to pre-mRNAs until splicing is completed. Analysis of FUS(−/−) brain demonstrated a role for FUS in alternative splicing, with increased crosslinking of FUS in introns around the repressed exons. We did not observe a significant overlap in the RNA binding sites or the exons regulated by FUS and TDP-43. Nevertheless, we found that both proteins regulate genes that function in neuronal development

Characterizing the RNA targets and position-dependent splicing regulation by TDP-43

TDP-43 is a predominantly nuclear RNA-binding protein that forms inclusion bodies in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). The mRNA targets of TDP-43 in the human brain and its role in RNA processing are largely unknown. Using individual nucleotide-resolution ultraviolet cross-linking and immunoprecipitation (iCLIP), we found that TDP-43 preferentially bound long clusters of UG-rich sequences in vivo. Analysis of RNA binding by TDP-43 in brains from subjects with FTLD revealed that the greatest increases in binding were to the MALAT1 and NEAT1 noncoding RNAs. We also found that binding of TDP-43 to pre-mRNAs influenced alternative splicing in a similar position-dependent manner to Nova proteins. In addition, we identified unusually long clusters of TDP-43 binding at deep intronic positions downstream of silenced exons. A substantial proportion of alternative mRNA isoforms regulated by TDP-43 encode proteins that regulate neuronal development or have been implicated in neurological diseases, highlighting the importance of TDP-43 for the regulation of splicing in the brain