In the process of pre-mRNA splicing introns are removed from pre-mRNA and exons are joined together. Current studies show, that about 95 % of genes, which contain more than two exons, can undergo alternative splicing. In this process some exons are included in or excluded from the final mRNA. Majority of pre-mRNA splicing take place co- transcriptionaly at this time RNA polymerase II is still attached to pre-mRNA. Alternative splicing is complex process that takes place in a close proximity of DNA and histones that might modulate alternative splicing decisions. Futher studies have validated fibronectin gene (FN1) and his alternative exons EDA and EDB (extra domain A and B) as suitably model for studying alternative splicing. Study using FN1 minigene reporter system, which is composed from EDA exon and two surrounding introns and exons, has proved that insertion of transcription enhancer SV40 infront of promotor, the level of EDA inclusion is decreased. So far, has not been prooved if this mechanism can function in real genome context and if distal transcription elements can influence alternative splicing. In this study, we have predicted transcription enhancer for FN1 gene by using The Ensemble Regulatory Build and FANTOM 5. The predicted transcription enhancer, is located 23,5 kbp upstream of TSS...

Cannabis is widely consumed by humans for pharmacological effects that are mediated by THC, though there is little evidence that THC is a primary reinforcer in non-human animal models. We hypothesized that THC may have potent reinforcement enhancing effects, comparable to other drugs (e.g., nicotine and caffeine) which are also widely consumed by humans, but difficult to establish as primary reinforcers in non-humans. In three experiments with male and female rats saccharin (SACC) or a visual stimulus (VS) served as reinforcers for operant behavior. We explored several pharmacological parameters of THC on responding for SACC or VS, including THC dose, intervals between THC injections and testing, and intervals between test sessions. THC acts as a reinforcement enhancer for both SACC and a VS across a range of doses and intervals. Daily THC injections systematically reduced behavior, possibly due to accumulation of THC bioavailability.

Basal breast cancer is a heterogeneous disease whose unfavourable outcome is determined by a high risk of tumour relapse and metastasis formation. The potential of a cancer cell to adapt to foreign environments is favoured by oncogenic cell plasticity, which is supported by epigenetic reprogramming. It was previously demonstrated that MYC acts as an oncogenic reprogramming factor by inducing epigenetic rewiring at enhancers (Poli et al., 2018). This causes the activation of oncogenic pathways and pro-metastatic transcription factors such as SOX9, but scant pieces of evidence support a causal link between epigenetic alteration of oncogenic enhancers and cell plasticity. In the present work, we investigated the establishment of an alternative epigenetic program during tumorigenesis in a basal breast cancer xenograft derived model. We found that tumorigenic cells, primary tumour derived cells and metastasis derived cells showed intrinsically different phenotypic and epigenetic signatures, and that metastatic derived cells were characterized by the acquisition of pro-metastatic features, such as migration and invasion, that may increase their metastatic potential. Specifically, we provided data supporting the notion that changes of the chromatin landscape during tumour progression increased the responsiveness of cancer cells to environmental cues that they may encounter during dissemination and colonization of distant organs. We focused on investigating the role played by putative regulatory elements localized around the SOX9 locus, whose chromatin accessibility and interaction with the SOX9 promoter were increased in metastatic cells. We observed that SOX9 expression was responsive to the activation of the retinoic acid (ATRA) pathway, and our data suggests that this response may be strengthened by transcriptional memory priming SOX9 regulatory elements after a first exposure, so that the response is faster and more robust after the second one. SOX9 transcription modulation and ATRA response were also shown to be linked to the activation of a quiescence program specific of metastatic cells, which we hypothesise may favour cells during the dissemination steps of the metastatic cascade.

Although the finite impulse response (FIR) Adaptive Line Enhancer (ALE) was developed in 1975 and has been used in a host of applications, no comprehensive performance analysis has been performed for this method, meaning no general equation exists for its signal-to-noise ratio (SNR) gain. Such an equation would provide practitioners an avenue for determining the amount of noise reduction the ALE provides for a particular application and would add to the general knowledge of adaptive filtering. Based on this motivation, this work derives the general equation for the FIR ALE SNR gain and verifies the equation through computer simulation, under the following assumptions: (1) A simplified Least Mean Squares (LMS) method is used for updating the embedded adaptive filter located within the ALE, (2) The received signal (i.e. the input signal to the ALE) is a summation of sinusoids buried in additive zero-mean white-Gaussian noise (AWGN), (3) The received signal is oversampled (i.e. the sampling rate is larger than the Nyquist rate), and (4) The ALE filter length is an integer multiple of the number of samples within one fundamental period of the original, noiseless signal.

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