DHODH modulates transcriptional elongation in the neural crest and melanoma

Melanoma is a tumour of transformed melanocytes, which are originally derived from the embryonic neural crest. It is unknown to what extent the programs that regulate neural crest development interact with mutations in the BRAF oncogene, which is the most commonly mutated gene in human melanoma1. We have used zebrafish embryos to identify the initiating transcriptional events that occur on activation of human BRAF(V600E) (which encodes an amino acid substitution mutant of BRAF) in the neural crest lineage. Zebrafish embryos that are transgenic for mitfa:BRAF(V600E) and lack p53 (also known as tp53) have a gene signature that is enriched for markers of multipotent neural crest cells, and neural crest progenitors from these embryos fail to terminally differentiate. To determine whether these early transcriptional events are important for melanoma pathogenesis, we performed a chemical genetic screen to identify small-molecule suppressors of the neural crest lineage, which were then tested for their effects on melanoma. One class of compound, inhibitors of dihydroorotate dehydrogenase (DHODH), for example leflunomide, led to an almost complete abrogation of neural crest development in zebrafish and to a reduction in the self-renewal of mammalian neural crest stem cells. Leflunomide exerts these effects by inhibiting the transcriptional elongation of genes that are required for neural crest development and melanoma growth. When used alone or in combination with a specific inhibitor of the BRAF(V600E) oncogene, DHODH inhibition led to a marked decrease in melanoma growth both in vitro and in mouse xenograft studies. Taken together, these studies highlight developmental pathways in neural crest cells that have a direct bearing on melanoma formation

Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stem cells

February 17, 2011The conversion of lineage-committed cells to induced pluripotent stem cells (iPSCs) by reprogramming is accompanied by a global remodeling of the epigenome[superscript 1, 2, 3, 4, 5], resulting in altered patterns of gene expression[superscript 2, 6, 7, 8, 9]. Here we characterize the transcriptional reorganization of large intergenic non-coding RNAs (lincRNAs)[superscript 10, 11] that occurs upon derivation of human iPSCs and identify numerous lincRNAs whose expression is linked to pluripotency. Among these, we defined ten lincRNAs whose expression was elevated in iPSCs compared with embryonic stem cells, suggesting that their activation may promote the emergence of iPSCs. Supporting this, our results indicate that these lincRNAs are direct targets of key pluripotency transcription factors. Using loss-of-function and gain-of-function approaches, we found that one such lincRNA (lincRNA-RoR) modulates reprogramming, thus providing a first demonstration for critical functions of lincRNAs in the derivation of pluripotent stem cells

Explainable NLQ-based Visual Interactive System: Challenges and Objectives

Nowadays, visual interactive systems (Vis) are attracting more attention in research and industries because of their effectiveness in conveying information. Additionally, to make rational decisions based on extracted data, Vis is critical for identifying and comprehending trends, outliers, and patterns in data. Existing research has employed a broad range of methodologies to yield visualization insights into certain decision-making systems, allowing participants to perceive a specific problem from a wide range of viewpoints. However, there are still enough scopes to design a new Vis where some systematic techniques are required to visualize the data with proper explanations. In this regard, we analyze several existing works and observe a surge of research interest in the new realm of explainable and NLQ-based Vis. In this paper, our main goal is to present a novel idea for designing an explainable NLQ-based Vis named-ExNLQVis. Therefore, (i) we aim to discuss a proposed NLQ-based Vis that will follow a deep learning-based NLP approach to extract necessary information from user inputs, make visual-respective decisions, and generate appropriate visualizations based on the preceding decisions. (ii) we extend our prior model to an explainable visualization model that not only accurately visualizes data but also explains why it appears depending on the natural language query (NLQ). To accomplish this system, we consider several challenges and objectives and briefly discuss our proposed method accordingly. We also provide the implementation and evaluation guidelines to establish our system

Comparative efficacy of powdered form of stevia (<i>Stevia rebaudiana</i> Bertoni) leaves and glimepiride in induced diabetic rats

Now a day, various medicinal plants are becoming popular for the treatment of different diseases. Some medicinal plants are being used for the treatment of diabetes all over the world. The study was conducted to investigate the effects of powdered form of Stevia (Stevia rebaudiana Bertoni) leaves on blood glucose concentration and body weight in Streptozotocin induced diabetic rats and for its efficacy study with a patent drug, Glimepiride. The effects of powdered form of Stevia leaves was evaluated in the Streptozotocin (STZ; 55 mg/kg body weight as single intraperitoneal injection) induced diabetic rats and for this, powdered form of Stevia leaves was orally administered at three different dose rates of 150 mg/kg, 200 mg/Kg and 250 mg/Kg body weight, respectively once a day for 3 weeks. Changes in the blood glucose levels and body weights were measured and the data obtained were compared with that of Glimepiride statistically by using Student's unpaired t-test. The powdered form of Stevia leaves produced significant (p &lt; 0.01 or p &lt; 0.05) hypoglycemic effects on Streptozotocin induced diabetic rats in comparison with that of the standard drug, Glimepiride. Powdered form of Stevia leaves at a dose rate of 250 mg/Kg decreased body weight significantly (p &lt; 0.01 or p &lt; 0.05) in STZ-induced diabetic rats. From this study, it was observed that powdered form of Stevia leaves possessed both hypoglycemic and body weight reducing effects. Key words: Stevia rebaudiana Bertoni, glimepiride, streptozotocin, diabetic rat doi: 10.3329/bjvm.v6i2.2338 Bangl. J. Vet. Med. (2008). 6 (2): 211-215</jats:p

Entomological Survey for New Vector Incrimination and Re-Confirmation of Established Malaria Vectors in Endemic Areas of Bangladesh (4 Sentinel Sites)

In Bangladesh malaria is one of the major public health problems and there are 3 malaria endemic hill tract districts which are the major areas among the red zones of malaria enedemicity. This study was aimed at assessment of the new vector incrimination as well as re-confirmation of the established vectors in Naikhangchari, Thanchi, Laxmichari and Baghachari. The anopheline population were collected and tested to incriminate the vector of malaria and their role in transmission, to find out the sporozoite rate, determination of oocyst rate of parasite and entomological innocultaion rate was diagnosed. Anopheline mosquito samples were directly collected from the sites using human bait, cattle landing and CDC light traps. The collected mosquitoes were dissected to find out the sporozoite in the salivary gland, oocyst in the midgut and to see the ovary for determination of the mosquito’s status of parous or nail-parous to determine the length of gonotropic cycle. The highest collection of a primary vector An. philippinensis was in Laxmichari (186 samples) and the highest collection of a secondary vector species An. vagus was in Thanchi (392). After the dissection no sporozoite or oocyst were detected among the collected anopheles’ samples. The vectoral capacity of An. philippinesis should be re-evaluated in the further studies. The pick biting hours of An. philippinensis and An. vagus varied in the 3 study sites which is an important finding of this study.</jats:p