RRM adjacent TARDBP mutations disrupt RNA binding and enhance TDP-43 proteinopathy

Amyotrophic lateral sclerosis (ALS) presents with focal muscle weakness due to motor neuron degeneration that becomes generalized,leading to death from respiratory failure within 3–5 years from symptom onset. Despite the heterogeneity of aetiology, TDP- 43 proteinopathy is a common pathological feature that is observed in 495% of ALS and tau-negative frontotemporal dementia(FTD) cases. TDP-43 is a DNA/RNA-binding protein that in ALS and FTD translocates from being predominantly nuclear to formdetergent-resistant, hyperphosphorylated aggregates in the cytoplasm of affected neurons and glia. Mutations in TARDBP accountfor 1–4% of all ALS cases and almost all arise in the low complexity C-terminal domain that does not affect RNA binding andprocessing. Here we report an ALS/FTD kindred with a novel K181E TDP-43 mutation that is located in close proximity to the RRM1 domain. To offer predictive gene testing to at-risk family members, we undertook a series of functional studies to characterizethe properties of the mutation. Spectroscopy studies of the K181E protein revealed no evidence of significant misfolding.Although it is unable to bind to or splice RNA, it forms abundant aggregates in transfected cells. We extended our study to includeother ALS-linked mutations adjacent to the RRM domains that also disrupt RNA binding and greatly enhance TDP-43 aggregation,forming detergent-resistant and hyperphosphorylated inclusions. Lastly, we demonstrate that K181E binds to, and sequesters, wild-type TDP-43 within nuclear and cytoplasmic inclusions. Thus, we demonstrate that TDP-43 mutations that disrupt RNAbinding greatly enhance aggregation and are likely to be pathogenic as they promote wild-type TDP-43 to mislocalize andaggregate acting in a dominant-negative manner. This study highlights the importance of RNA binding to maintain TDP-43solubility and the role of TDP-43 aggregation in disease pathogenesis

HMGA2 protects induced pluripotent stem cell chromosomes against hydroxyurea-induced DNA damage.

High Motility Group A-T hook 2 (HMGA2) is a transcriptional regulator that binds to short AT rich sequences and is involved in global chromatin reorganization. HMGA2 is normally expressed during early development and is involved in specification of mesoderm-derived tissue. However, HMGA2 is re-expressed in many aggressive neoplasias and correlated with poor patient outcomes. Our previous research has shown an involvement of HMGA2 in Base Excision Repair (BER) and in stabilizing stalled replication forks. Cancer cells could hijack these properties of HMGA2 to suppress chromosomal instabilities. In this study, we use murine induced Pluripotent Stem Cells (iPSC) to investigate whether overexpression of HMGA2 provides protection against DNA damage. The chemotherapeutic Hydroxyurea (HU) was used to disrupt DNA synthesis, create stalled forks and induce DNA damage. Chromosomal instabilities were investigated via Giemsa staining of metaphase spreads. Our results clearly show fewer chromosomal aberrations for cells that express exogenous HMGA2 in comparison to the control. We also found overexpression of HMGA2 could increase cell survival at a high HU concentration, and that it reduces the rate of cell proliferation. These results are in excellent agreement with our previous findings and demonstrate a key role for HMGA2 in the cell cycle.Bachelor of Science in Biological Science

An effective collaborative movie recommender system with cuckoo search

Recommender systems are information filtering tools that aspire to predict the rating for users and items, predominantly from big data to recommend their likes. Movie recommendation systems provide a mechanism to assist users in classifying users with similar interests. This makes recommender systems essentially a central part of websites and e-commerce applications. This article focuses on the movie recommendation systems whose primary objective is to suggest a recommender system through data clustering and computational intelligence. In this research article, a novel recommender system has been discussed which makes use of k-means clustering by adopting cuckoo search optimization algorithm applied on the Movielens dataset. Our approach has been explained systematically, and the subsequent results have been discussed. It is also compared with existing approaches, and the results have been analyzed and interpreted. Evaluation metrics such as mean absolute error (MAE), standard deviation (SD), root mean square error (RMSE) and t-value for the movie recommender system delivers better results as our approach offers lesser value of the mean absolute error, standard deviation, and root mean square error. The experiment results obtained on Movielens dataset stipulate that the proposed approach may provide high performance regarding reliability, efficiency and delivers accurate personalized movie recommendations when compared with existing methods. Our proposed system (K-mean Cuckoo) has 0.68 MAE, which is superior to existing work (0.78 MAE) [1] and also has improvement of our previous work (0.75 MAE) [2]

Project Management Tools Employed in Various Industries

A project is a specific venture that has a clear start and a finish in order to accomplish a set of predefined goals through a sequence of predetermined processes. Project management is the art or the discipline to ensure that the project can be successful, through a seamless performance of orderly arranged activities and phases resulting in project deliverables [1]. This paper is based on a case study of what are the tools or methodologies are available for the different stages in the project life cycle, what are the different project management methodologies and tools employed in the different stages of the project life-cycle. These tools are considered to be very useful in guiding the whole organization into the same direction. Despite the acknowledged fact that projects in any organization should support the overall strategy of the organization, it was noticed that the usage of the tools in the project life cycle was rare projects rarely use these tools. The paper also seeks to see if the size of the organization was representative of the level of project management maturity in the use of processes and tools during the project life cycle. The paper also looks at the nature of the industry to see if that has a bearing on the processes or tools in use in the organizations that fall under each industrial category analyzed. The paper also tries to compare project management processes in those projects that are mainline to the business and those that are ancillary to the business. Lastly, the paper also touches upon what are the trends in methodologies that project managers have to be aware of when embarking on the utilization of processes or tools for a project