Biology subjects
Publications and source records attributed to Awada, A..
High-frequency stimulation of the subthalamic nucleus (STN) has shown therapeutic potential in preclinical models of addiction. However, its rewarding properties remain unclear. Here, we show that cocaine withdrawal enhances STN intracranial self-stimulation, revealing a reward-based mechanism that may contribute to the beneficial effects of STN deep brain stimulation in addiction and related neuropsychiatric disorders.
We have previously demonstrated that the transcription-dependent interaction of the promoter and terminator ends of a gene, which results in the formation of a gene loop, is facilitated by the interaction of the general transcription factor TFIIB with the CF1, CPF and Rat1 termination complexes. To further elucidate the protein-protein interactions that stabilize gene loop, we performed mass spectrometry of affinity purified termination complexes from chromatin fraction. Quantitative proteomic analysis revealed additional interactions of termination factors with TFIID and SAGA complex. Since gene looping of intron-containing genes involves additional contacts of the promoter and terminator with the intron, we examined if termination factors interact with the splicing factors as well. All three termination complexes displayed statistically significant interactions with Prp19, Prp43, Sub2, Snu114, Brr2 and Smb1 splicing factors. Since Prp43 and Prp19 consistently emerged as the interactor of both initiation and termination factors, we affinity-purified both and performed mass spectrometry. Prp19 exhibited interactions with subunits of TFIID, CPF complex, and the RSC chromatin remodeling complex. These interactions were observed exclusively in the chromatin context, thereby implicating the factor in transcription of protein coding genes. Since fewer than 4% of yeast genes contain introns, we hypothesized that Prp19 might have a broader role in RNAPII transcription cycle. Auxin-mediated depletion of Prp19 resulted in about two-fold decrease in transcription of a subset of both intron-containing and intron-lacking genes. Specifically, the promoter recruitment of TBP registered a significant decline in the absence of Prp19. Chromatin immunoprecipitation (ChIP) analysis revealed crosslinking of Prp19 to the promoter proximal as well as downstream regions of both intronic and non-intronic genes. These findings demonstrate that Prp19 has a novel role in the initiation step of transcription in yeast.
The primate visual cortex contains various regions that exhibit specialization for different stimulus properties, such as motion, shape, and color. Within each region there is often further specialization, such that particular stimulus features, such as horizontal and vertical orientations, are overrepresented. These asymmetries are associated with well-known perceptual biases, but little is known about how they influence visual learning. Most theories would predict that learning is optimal, in the sense that it is unaffected by these asymmetries. But other approaches to learning would result in specific patterns of perceptual biases. To distinguish between these possibilities, we trained human observers to discriminate between expanding and contracting motion patterns, which have a highly asymmetrical representation in visual cortex. Observers exhibited biased percepts of these stimuli, and these biases were affected by training in ways that were often suboptimal. We simulated different neural network models and found that a learning rule that involved only adjustments to decision criteria, rather than connection weights, could account for our data. These results suggest that cortical asymmetries influence visual perception and that human observers often rely on suboptimal strategies for learning.
Visual perceptual learning (VPL) is an improvement in visual function following training. Although the practical utility of VPL was once thought to be limited by its specificity to the precise stimuli used during training, more recent work has shown that such specificity can be overcome with appropriate training protocols. In contrast, relatively little is known about the extent to which VPL exhibits motor specificity. Indeed, previous studies have shown that training paradigms that require one type of response (e.g., a button press) do not necessarily transfer to those that require a different response (e.g., a mouse movement). In this work, we have examined the effector specificity of VPL by training observers on tasks that maintain the same visual stimuli and task structure, but that require different effectors to indicate the response. We find that, in these conditions, VPL transfers fully between manual and oculomotor responses. These results are consistent with the idea that VPL entails the learning of a decision rule that can generalize across effectors.
Septin expressions are altered in cancer cells and exhibit poor prognoses in malignancies. As the first approach to develop a septin filament targeting agent, we optimized the structure of Forchlorfenuron (FCF), a known plant cytokinin to generate UR214-9, which contrary to FCF, causes septin-2/9 filamental structural catastrophe in cancer cells without altering cellular septin protein levels. In-silico docking using septin-2/septin-2 dimer complex showed that UR214-9 displaced the guanine carbonyl oxygen from the GDP binding domain and showed increased binding energy than FCF(-8.59vs-7.21). UR214-9 reduced cancer cell growth, downregulated HER2/STAT-3 axis and controlled growth of HER2+ pancreatic, breast and ovarian cancer xenografts in NSG mice and enhanced response of Herceptin against HER2+breast cancer xenograft. Transcriptome analysis of UR214-9 exposed cells demonstrated significant perturbation of <20 genes compared to afatinib which impacted >1200 genes in JIMT-1 breast cancer cells indicating target specificity and non-transcriptional functions of UR214-9. In summary, disrupting septins via UR214-9 is a new approach to control the growth of HER2+ malignancies.
Although the structure and function of the human visual system are determined in large part during early development, there is ample evidence for adult plasticity as well. Such plasticity has important consequences for restoring vision after cortical damage and for improving function in healthy people. Although these applications have shown promising results, they are often limited by pathological specificity: Improvements obtained through perceptual training fail to generalize beyond the trained stimulus feature or location. Efforts to reduce specificity have focused on the design of training tasks, but less is known about the effects of stimulus structure on the specificity of perceptual learning. Here, we leverage physiological findings from the dorsal visual pathway of the primate brain to explore the hypothesis that learning specificity is related to the complexity of the training stimulus. Specifically, because neurons in higher-level structures of the dorsal visual pathway exhibit little stimulus specificity, we reasoned that training with more complex stimuli would reduce the specificity of learning. We trained human observers on stimuli of varying complexity, ranging from simple sinewave gratings to complex optic flow fields. Our results show that training with more complex stimuli reduces specificity for spatial position and stimulus features. Such changes are associated with increased spatial integration. These findings were captured by a computational \"reweighting\" model that decoded the outputs of simulated neurons in areas MT and MST of the primate visual cortex. Our results suggest that the addition of more complex stimuli into perceptual learning paradigms provides a simple and effective way to minimize specificity in learning.