Mapping the Nucleus

DNA is not just randomly “stuffed” inside the nucleus of cells. Instead, it is highly organized! Similar to how we map our earth, we want to construct a map of the nucleus. One mapping method is to find repeated segments within the genome and bind compatible fluorescent markers. This would be like finding all of the twins, triplets, and other multiplets on earth and having them wear special fluorescent hats (A). However, just like for humans, finding these repeats naturally within the cell is pretty rare. Instead, we use a technique that synthetically produces these multiplets and markers and we are not limited to just twins and triplets, but can create segments up to 96 repeats long- 96tuplet! Once introduced, we are able to visualize the location of specific segments of DNA within the cell (B). Shown is what the actual labeling looks like within the nucleus of a cell! Ultimately, our goal as humans is to understand the locations of countries and their relationships with each other over time. Similarly, this nuclear map will help us understand the interactions between different areas and how this may affect the cell’s processes in disease, under normal conditions, and more.Ope

The Synergy of Speculative Decoding and Batching in Serving Large Language Models

Large Language Models (LLMs) like GPT are state-of-the-art text generation models that provide significant assistance in daily routines. However, LLM execution is inherently sequential, since they only produce one token at a time, thus incurring low hardware utilization on modern GPUs. Batching and speculative decoding are two techniques to improve GPU hardware utilization in LLM inference. To study their synergy, we implement a prototype implementation and perform an extensive characterization analysis on various LLM models and GPU architectures. We observe that the optimal speculation length depends on the batch size used. We analyze the key observation and build a quantitative model to explain it. Based on our analysis, we propose a new adaptive speculative decoding strategy that chooses the optimal speculation length for different batch sizes. Our evaluations show that our proposed method can achieve equal or better performance than the state-of-the-art speculation decoding schemes with fixed speculation length

Dynamics and functional roles of splicing factor autoregulation

Non-spliceosomal splicing factors are essential, conserved regulators of alternative splicing. They provide concentration-dependent control of diverse pre-mRNAs. Many splicing factors direct unproductive splicing of their own pre-mRNAs through negative autoregulation. However, the impact of such feedback loops on splicing dynamics at the single cell level remains unclear. We developed a system to dynamically, quantitatively analyze negative autoregulatory splicing by the SF2 splicing factor in response to perturbations in single HEK293 cells. Here, we show that negative autoregulatory splicing provides critical functions for gene regulation, establishing a ceiling of SF2 protein concentration, reducing cell-cell heterogeneity in SF2 levels, and buffering variation in SF2 transcription. Most importantly, it adapts SF2 splicing activity to variations in demand from other pre-mRNA substrates. A minimal mathematical model of autoregulatory splicing explains these experimentally observed features, and provides values for effective biochemical parameters. These results reveal the unique functional roles that splicing negative autoregulation plays in homeostatically regulating transcriptional programs

Dynamics and functional roles of splicing factor autoregulation

Non-spliceosomal splicing factors are essential, conserved regulators of alternative splicing. They provide concentration-dependent control of diverse pre-mRNAs. Many splicing factors direct unproductive splicing of their own pre-mRNAs through negative autoregulation. However, the impact of such feedback loops on splicing dynamics at the single cell level remains unclear. We developed a system to dynamically, quantitatively analyze negative autoregulatory splicing by the SF2 splicing factor in response to perturbations in single HEK293 cells. Here, we show that negative autoregulatory splicing provides critical functions for gene regulation, establishing a ceiling of SF2 protein concentration, reducing cell-cell heterogeneity in SF2 levels, and buffering variation in SF2 transcription. Most importantly, it adapts SF2 splicing activity to variations in demand from other pre-mRNA substrates. A minimal mathematical model of autoregulatory splicing explains these experimentally observed features, and provides values for effective biochemical parameters. These results reveal the unique functional roles that splicing negative autoregulation plays in homeostatically regulating transcriptional programs

Awareness of consequences in agenesis of the corpus callosum: Semantic analysis of responses

Objective: Agenesis of the corpus callosum (AgCC) in individuals with general intelligence within the normal range results in a syndrome of mild to moderate deficiencies in cognitive, emotional, and social functioning that are still being explored. Anecdotal accounts from families suggest that these cognitive and psychosocial deficiencies affect the ability of these individuals to anticipate the consequences of their decisions and behaviors. This research was designed to clarify the nature of social and emotional cognition in AgCC with respect to imagination of the consequences of decisions by assessing responses from the Awareness of Consequences Scale (AOCS). Method: Verbal AOCS responses from persons with AgCC and age and IQ-matched neurotypical controls were scored in the normal manner, and also subjected to semantic analyses using both latent semantic analysis and Linguistic Inquiry and Word Count. Results: It was found that, relative to neurotypical controls, individuals with AgCC scored significantly lower on the typical scoring of the AOCS, had nontypical semantic content in their responses, and used fewer emotion and cognitive content (insight) words. These results were apparent in responses to the three most complex of the AOCS scenarios. Conclusions: Results were consistent with the hypothesis that persons with AgCC are deficient in the capacity to imagine the emotional and cognitive consequences of potential actions on others. particularly in the face of greater situational and social complexity

The context-dependent, combinatorial logic of BMP signaling

Cell-cell communication systems typically comprise families of ligand and receptor variants that function together in combinations. Pathway activation depends in a complex way on which ligands are present and what receptors are expressed by the signal-receiving cell. To understand the combinatorial logic of such a system, we systematically measured pairwise Bone Morphogenetic Protein (BMP) ligand interactions in cells with varying receptor expression. Ligands could be classified into equivalence groups based on their profile of positive and negative synergies with other ligands. These groups varied with receptor expression, explaining how ligands can functionally replace each other in one context but not another. Context-dependent combinatorial interactions could be explained by a biochemical model based on competitive formation of alternative signaling complexes with distinct activities. Together, these results provide insights into the roles of BMP combinations in developmental and therapeutic contexts and establish a framework for analyzing other combinatorial, context-dependent signaling systems

The context-dependent, combinatorial logic of BMP signaling

Cell-cell communication systems typically comprise families of ligand and receptor variants that function together in combinations. Pathway activation depends in a complex way on which ligands are present and what receptors are expressed by the signal-receiving cell. To understand the combinatorial logic of such a system, we systematically measured pairwise Bone Morphogenetic Protein (BMP) ligand interactions in cells with varying receptor expression. Ligands could be classified into equivalence groups based on their profile of positive and negative synergies with other ligands. These groups varied with receptor expression, explaining how ligands can functionally replace each other in one context but not another. Context-dependent combinatorial interactions could be explained by a biochemical model based on competitive formation of alternative signaling complexes with distinct activities. Together, these results provide insights into the roles of BMP combinations in developmental and therapeutic contexts and establish a framework for analyzing other combinatorial, context-dependent signaling systems

Ligand-receptor promiscuity enables cellular addressing

In multicellular organisms, secreted ligands selectively activate, or "address," specific target cell populations to control cell fate decision-making and other processes. Key cell-cell communication pathways use multiple promiscuously interacting ligands and receptors, provoking the question of how addressing specificity can emerge from molecular promiscuity. To investigate this issue, we developed a general mathematical modeling framework based on the bone morphogenetic protein (BMP) pathway architecture. We find that promiscuously interacting ligand-receptor systems allow a small number of ligands, acting in combinations, to address a larger number of individual cell types, each defined by its receptor expression profile. Promiscuous systems outperform seemingly more specific one-to-one signaling architectures in addressing capacity. Combinatorial addressing extends to groups of cell types, is robust to receptor expression noise, grows more powerful with increasing receptor multiplicity, and is maximized by specific biochemical parameter relationships. Together, these results identify fundamental design principles governing cell addressing by ligand combinations

Epistemic (in)justice and decolonisation in higher education : experiences of a cross-site teaching project

Higher education has been strongly contested in recent times, on the grounds of its role in reproducing epistemic injustice, leading to calls to ‘decolonise’ institutions, curricula and teaching practices. Meanwhile, the practice of epistemic critique also points to potentials for challenge, learning and change. This article offers critical reflections in two distinct moments of time: firstly, reflections on experiences of a cross-site teaching project (2016) involving three of the authors (Mucha, Pesch and Wielenga) from the Departments of Political Science at the Universities of Düsseldorf (Germany) and Pretoria (South Africa) in an academic virtual collaboration project using shared classes and video-conferencing tools to study peace-building, human mobility and mediation. Secondly, the writing process for this article has involved a further collaborative author (Khoo) to comment upon and theorise curriculum-making and teaching experiences. We look at the different contexts in each country and how far the curricula and syllabi at both universities can be supplemented by cross-site teaching elements to deal with epistemic asymmetries in higher education reflexively, while leaning towards a more just knowledge (re)production. Some key challenges and limitations of the cross-site project are also discussed.https://journals.ufs.ac.za/index.php/aa/indexpm2020Political Science