6,280 research outputs found
An investigation of entorhinal spatial representations in self-localisation behaviours
Spatial-modulated cells of the medial entorhinal cortex (MEC) and neighbouring cortices are thought to provide the neural substrate for self-localisation behaviours. These cells include grid cells of the MEC which are thought to compute path integration operations to update self-location estimates. In order to read this grid code, downstream cells are thought to reconstruct a positional estimate as a simple rate-coded representation of space.
Here, I show the coding scheme of grid cell and putative readout cells recorded from mice performing a virtual reality (VR) linear location task which engaged mice in both beaconing and path integration behaviours. I found grid cells can encode two unique coding schemes on the linear track, namely a position code which reflects periodic grid fields anchored to salient features of the track and a distance code which reflects periodic grid fields without this anchoring. Grid cells were found to switch between these coding schemes within sessions. When grid cells were encoding position, mice performed better at trials that required path integration but not on trials that required beaconing. This result provides the first mechanistic evidence linking grid cell activity to path integration-dependent behaviour.
Putative readout cells were found in the form of ramp cells which fire proportionally as a function of location in defined regions of the linear track. This ramping activity was found to be primarily explained by track position rather than other kinematic variables like speed and acceleration. These representations were found to be maintained across both trial types and outcomes indicating they likely result from recall of the track structure.
Together, these results support the functional importance of grid and ramp cells for self-localisation behaviours. Future investigations will look into the coherence between these two neural populations, which may together form a complete neural system for coding and decoding self-location in the brain
Approximate Computing Survey, Part I: Terminology and Software & Hardware Approximation Techniques
The rapid growth of demanding applications in domains applying multimedia
processing and machine learning has marked a new era for edge and cloud
computing. These applications involve massive data and compute-intensive tasks,
and thus, typical computing paradigms in embedded systems and data centers are
stressed to meet the worldwide demand for high performance. Concurrently, the
landscape of the semiconductor field in the last 15 years has constituted power
as a first-class design concern. As a result, the community of computing
systems is forced to find alternative design approaches to facilitate
high-performance and/or power-efficient computing. Among the examined
solutions, Approximate Computing has attracted an ever-increasing interest,
with research works applying approximations across the entire traditional
computing stack, i.e., at software, hardware, and architectural levels. Over
the last decade, there is a plethora of approximation techniques in software
(programs, frameworks, compilers, runtimes, languages), hardware (circuits,
accelerators), and architectures (processors, memories). The current article is
Part I of our comprehensive survey on Approximate Computing, and it reviews its
motivation, terminology and principles, as well it classifies and presents the
technical details of the state-of-the-art software and hardware approximation
techniques.Comment: Under Review at ACM Computing Survey
Halogenation of polypnictogen ligand complexes
After that a previous investigation from our group demonstrated that the iodination and the āclassicalā oxidation of En ligand complexes can afford different results and are therefore being considered as complementary tools for the synthesis of new polypnictogen complexes, we were interested in extending the investigation to other complexes as well as to other halogens or halogen sources. Therefore, the first object of this work was the investigation of the reactivity of [{CpMo(CO)2}2(Ī¼,ɳ2:ɳ2-P2)] (A) towards halogens (I2, Br2) and halogen sources (PBr5, PCl5). Based on the obtained results, we were interested in expanding the investigation of the reactivity of halogens towards different Pn ligand complexes, whose redox properties have already been elucidated. Accordingly, the next object was the investigation of the reactivity of the triple-decker complex [(Cp*Mo)2(Ī¼,ɳ6:ɳ6-P6)] (B) towards halogens (I2, Br2) and halogen sources (PBr5, PCl5). Finally, we were interested in how the nature of the En ligand and of the pnictogen atom involved could affect the outcome of the reaction. Thus, we wanted to explore a possible alternative way to obtain E-X bonds without using the harsh conditions required for halogenation reactions. Therefore, the next objectives were the investigation of the halogenation of the triple decker complexes [(CpāāāCo)2(Ī¼,ɳ2:ɳ2-E2)2] (E = As (C), P (D)) bearing two independent E2 units and the exploration of the possibility of quenching the cations of [(CpāāāCo)2(Ī¼,ɳ4:ɳ4-E4)][TEF]2 (E = P, As) with nucleophilic halides. In conclusion, the investigation of the reactivity of the heterobimetallic triple-decker complexes [(Cp*Fe)(CpāāāCo)(Ī¼,ɳ5:ɳ4-E5)] (E = P (E), As (F)) towards halogens (I2, Br2) and halogen sources (PCl5) was exploited.
The results of these investigation show that the En ligand involved in the halogenation reactions was the variable with the highest influence on the different products obtained. It is not possible to find a general trend based on the halogen used because the outcome was always different from one polypnictogen complex to the other. While in some cases the reactivity of the respective En ligand compound was similar towards Br2 and Cl2 sources but completely different with I2 (e.g. with A and D), in other cases it was comparable to I2 and Br2 and different towards PCl5 (e.g. with E and F), or the same with all the halogens (e.g. with C). On the other hand, with B the reactivity was different towards all the halogen sources, with the formation of similar products among the iodinated or chlorinated derivatives or among the brominated and chlorinated ones. The halogenation of the tetrahedrane complex A, compared to B, has a higher chemoselectivity. The halogenation of the triple decker complexes led in
general to a large number of products, especially when PCl5 was involved. Specifically, for B, it was observed that the chlorination reaction requires lower temperatures to isolate some of the products. The investigation of this reactivity for compounds C-F showed that the nature of the pnictogen ligand affects the final products, contrarily to what was observed for the one- or two-electron oxidation of the same compounds.
In conclusion, the halogenation can be considered an additional tool for the synthesis of new functionalized En ligand complexes, whose related difficulties (high number of products, low yields) can be partly ābalancedā by the opportunity of further functionalization of the products obtained
Studies on genetic and epigenetic regulation of gene expression dynamics
The information required to build an organism is contained in its genome and the first
biochemical process that activates the genetic information stored in DNA is transcription.
Cell type specific gene expression shapes cellular functional diversity and dysregulation
of transcription is a central tenet of human disease. Therefore, understanding
transcriptional regulation is central to understanding biology in health and disease.
Transcription is a dynamic process, occurring in discrete bursts of activity that can be
characterized by two kinetic parameters; burst frequency describing how often genes
burst and burst size describing how many transcripts are generated in each burst. Genes
are under strict regulatory control by distinct sequences in the genome as well as
epigenetic modifications. To properly study how genetic and epigenetic factors affect
transcription, it needs to be treated as the dynamic cellular process it is. In this thesis, I
present the development of methods that allow identification of newly induced gene
expression over short timescales, as well as inference of kinetic parameters describing
how frequently genes burst and how many transcripts each burst give rise to. The work is
presented through four papers:
In paper I, I describe the development of a novel method for profiling newly transcribed
RNA molecules. We use this method to show that therapeutic compounds affecting
different epigenetic enzymes elicit distinct, compound specific responses mediated by
different sets of transcription factors already after one hour of treatment that can only
be detected when measuring newly transcribed RNA.
The goal of paper II is to determine how genetic variation shapes transcriptional bursting.
To this end, we infer transcriptome-wide burst kinetics parameters from genetically
distinct donors and find variation that selectively affects burst sizes and frequencies.
Paper III describes a method for inferring transcriptional kinetics transcriptome-wide
using single-cell RNA-sequencing. We use this method to describe how the regulation of
transcriptional bursting is encoded in the genome. Our findings show that gene specific
burst sizes are dependent on core promoter architecture and that enhancers affect burst
frequencies. Furthermore, cell type specific differential gene expression is regulated by
cell type specific burst frequencies.
Lastly, Paper IV shows how transcription shapes cell types. We collect data on cellular
morphologies, electrophysiological characteristics, and measure gene expression in the
same neurons collected from the mouse motor cortex. Our findings show that cells
belonging to the same, distinct transcriptomic families have distinct and non-overlapping
morpho-electric characteristics. Within families, there is continuous and correlated
variation in all modalities, challenging the notion of cell types as discrete entities
Modulation of the substrate specificity of the kinase PDK1 by distinct conformations of the full-length protein
The activation of at least 23 different mammalian kinases requires the phosphorylation of their hydrophobic motifs by the kinase PDK1. A linker connects the phosphoinositide-binding PH domain to the catalytic domain, which contains a docking site for substrates called the PIF pocket. Here, we used a chemical biology approach to show that PDK1 existed in equilibrium between at least three distinct conformations with differing substrate specificities. The inositol polyphosphate derivative HYG8 bound to the PH domain and disrupted PDK1 dimerization by stabilizing a monomeric conformation in which the PH domain associated with the catalytic domain and the PIF pocket was accessible. In the absence of lipids, HYG8 potently inhibited the phosphorylation of Akt (also termed PKB) but did not affect the intrinsic activity of PDK1 or the phosphorylation of SGK, which requires docking to the PIF pocket. In contrast, the small molecule valsartan bound to the PIF pocket and stabilized a second distinct monomeric conformation. Our study reveals dynamic conformations of full-length PDK1 in which the location of the linker and the PH domain relative to the catalytic domain determines the selective phosphorylation of PDK1 substrates. The study further suggests new approaches for the design of drugs to selectively modulate signaling downstream of PDK1
Modelling, Monitoring, Control and Optimization for Complex Industrial Processes
This reprint includes 22 research papers and an editorial, collected from the Special Issue "Modelling, Monitoring, Control and Optimization for Complex Industrial Processes", highlighting recent research advances and emerging research directions in complex industrial processes. This reprint aims to promote the research field and benefit the readers from both academic communities and industrial sectors
EXAMINING PROTEIN CONFORMATIONAL DYNAMICS USING COMPUTATIONAL TECHNIQUES: STUDIES ON PHOSPHATIDYLINOSITOL-3-KINASE AND THE SODIUM-IODIDE SYMPORTER
Experimental biophysics techniques used to study proteins, polymers of amino acids that comprise most therapeutic targets of human disease, face limitations in their ability to interrogate the continual structural fluctuations exhibited by these macromolecules in the context of their myriad cellular functions. This dissertation aims to illustrate case studies that demonstrate how protein conformational dynamics can be characterized using computational methods, yielding novel insights into their functional regulation and activity. Towards this end, the work presented here describes two specific membrane proteins of therapeutic relevance: Phosphoinositide 3-kinase (PI3KĪ±), and the Na+/I- symporter (NIS).
The PI3KCA gene, encoding the catalytic subunit of the PI3KĪ± protein that phosphorylates phosphatidylinositol-4,5-bisphosphate (PIP2) to generate phosphatidylinositol-3,4,5-triphosphate (PIP3), is highly mutated in human cancer. As such, a deeper mechanistic understanding of PI3KĪ± could facilitate the development of novel chemotherapeutic approaches. The second chapter of this dissertation describes molecular dynamics (MD) simulations that were conducted to determine how PI3KĪ± conformations are influenced by physiological effectors and the nSH2 domain of a regulatory subunit, p85. The results reported here suggest that dynamic allostery plays a role in populating the catalytically competent conformation of PI3KĪ±.
NIS, a thirteen-helix transmembrane protein found in the thyroid and other tissues, transports iodide, a required constituent of thyroid hormones T3 and T4. Despite extensive experimental information and clinical data, many mechanistic details about NIS remain unresolved. The third chapter of this dissertation describes the results of unbiased and enhanced-sampling MD simulations of inwardly and outwardly open models of bound NIS under an enforced ion gradient. Simulations of NIS in the absence or presence of perchlorate are also described. The work presented in this dissertation aims to add to our mechanistic understanding of NIS ion transport and elucidate conformational states that occur between the inward and outward transitions of NIS in the absence and presence of bound Na+ and I- ions, which can provide valuable insight into its physiological activity and inform therapeutic interventions.
Taken together, these case studies demonstrate the ability of computational techniques to provide novel insights into the impact of structural dynamics on the functional regulation of therapeutically important biological macromolecules
Metabolic impacts of weight loss intervention on morbid obesity
Morbid obesity can result in life-altering health issues, such as type 2 diabetes. Roux-en-Y gastric bypass (RYGB) surgery has been demonstrated to be one of the most effective treatments for morbid obesity and its co-morbidities in long-term. This aim of this thesis is to investigate the metabolic impact of weight loss intervention (RYGB, caloric restriction, and gut hormone treatment) on urine, plasma, and faecal profiles from morbidly obese patients, and to answer two hypotheses: 1) RYGB-induced metabolic changes are partially attributed to caloric restriction and increased gut hormones; 2) RYGB alters metabolic profile of faecal bacterial pellets separated using a newly developed method. Samples at pre-intervention time point were compared with post-intervention time point, and multivariate and univariate analysis were applied based on different types of datasets using different software to avoid missing potential biomarkers. Samples at post-intervention time point were compared across the intervention groups using the same strategy as above. At 1-month-post-intervention, RYGB-induced metabolic changes could be attributed by caloric restriction via increased metabolisms of ketone bodies, lactic acid, and tricarboxylic acid, and decreased concentrations of total apolipoprotein A1, high-density lipoprotein (HDL) subfraction 3&4, and very-low-density-lipoprotein (VLDL) subfraction 5. RYGB-induced distinct metabolic changes included metabolisms of amino acids, short chain fatty acids, creatine, increased concentration of low-density lipoprotein fraction of triglycerides, and decreased concentration of HDL subfraction 2 of phospholipids. Gut hormone treatment exerted limited metabolic effects on urine and plasma samples. A separation method was developed for faecal bacterial pellets profiling and applied on RYGB and caloric restriction cohorts. Propionate and butyrate productions via dicarboxylic acid pathway were increased significantly 2-5 years after RYGB and 3 months after caloric restriction, respectively. My study showed RYGB-induced metabolic changes could not be fully explained by caloric restriction nor increased gut hormone levels; Gut hormone treatment induced limited metabolic changes and could be an alternate therapy for morbid obesity followed by clinical trial with increased sample size and follow-up study in long term.Open Acces
Unsupervised inference methods for protein sequence data
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