Improving Table Compression with Combinatorial Optimization

We study the problem of compressing massive tables within the partition-training paradigm introduced by Buchsbaum et al. [SODA'00], in which a table is partitioned by an off-line training procedure into disjoint intervals of columns, each of which is compressed separately by a standard, on-line compressor like gzip. We provide a new theory that unifies previous experimental observations on partitioning and heuristic observations on column permutation, all of which are used to improve compression rates. Based on the theory, we devise the first on-line training algorithms for table compression, which can be applied to individual files, not just continuously operating sources; and also a new, off-line training algorithm, based on a link to the asymmetric traveling salesman problem, which improves on prior work by rearranging columns prior to partitioning. We demonstrate these results experimentally. On various test files, the on-line algorithms provide 35-55% improvement over gzip with negligible slowdown; the off-line reordering provides up to 20% further improvement over partitioning alone. We also show that a variation of the table compression problem is MAX-SNP hard.Comment: 22 pages, 2 figures, 5 tables, 23 references. Extended abstract appears in Proc. 13th ACM-SIAM SODA, pp. 213-222, 200

Discovering novel mechanisms of human cortical development disease using in vivo mouse model and in vitro human-derived cerebral organoids.

This thesis combines three research studies with the common interest of identifying novel mechanisms underlying human cortical development. This aim is pursued from different angles, always basing the investigations on human induced pluripotent stem cell-derived 2D and 3D in vitro model systems that are partly combined with in vivo studies in the developing mouse cortex. Namely, in the pieces of work combined here, we 1) bring to light a neurodevelopmental role of a gene already implicated in adult nervous system function, 2) discover a novel mechanism that fine-tunes human neurogenesis, and 3) identify a novel gene whose mutations lead to a malformation of cortical development. The entirety of this work thus adds several aspects to the existing knowledge. In the first study, we identified a neurodevelopmental function of a gene mutated in patients with the progressive gait disorder hereditary spastic paraplegia (HSP). In this group of inherited neurodegenerative diseases, mutations in lipid, mitochondrial, cytoskeletal or transport proteins lead to degeneration of primary motor neurons, which, due to the length of their axons, are particularly sensitive to disruption of these processes. Here, were generated cerebral organoids (COs) derived from HSP patients with mutations in SPG11 coding for spatacsin. Previous work had shown impaired proliferation of SPG11 patient-derived neural progenitor cells (NPCs). We found a proliferation defect also in CO NPCs, leading to a thinner progenitor zone and premature neurogenesis due to increased asymmetric progenitor divisions, along with smaller size of patient-derived COs. Molecularly, we found a decrease in deactivated GSK3β and increase in P-βcatenin at the basis of the observed proliferation/neurogenesis imbalance. We thus confirmed the neurodevelopmental role of SPG11 that had previously been suggested from 2D human in vitro findings. Both the observed reduction in proliferating progenitors and in organoid size were rescued through inhibition of GSK3β, with the Food and Drug Administration (FDA) approved compound tideglusib only affecting patient COs. These rescue experiments thus stressed the opportunity that COs represent for drug testing and translation of findings to precision medicine. In the second study, we investigated the role of a novel posttranslational modification (PTM) termed AMPylation in neurogenesis. Using a novel probe for the detection of AMPylated proteins and a combination of mass spectrometry-based proteomics, immunohistochemistry, and acute interference with the expression of the AMPylating enzyme, we made several interesting findings: AMPylation takes place on a cell type-specific set of proteins, is responsive to the predominant environmental condition, and both AMPylator and targets localize to cell type-specific intracellular localizations. During the process of neuronal differentiation, the set of AMPylated proteins is completely remodeled, with a very high number of unique targets in neurons. These include metabolic enzymes as in all analyzed cell types and, additionally and specifically, cytoskeletal and motor proteins. Cytoskeletal and motor proteins in neural progenitors and neurons are known to be differentially modified by several PTMs whose correct establishment is highly important during neurodevelopment; AMPylation may thus be an additional one. To assess the role of AMPylation in neurodevelopment, we manipulated the expression of the AMPylating enzyme FICD in COs. Downregulation kept cells in a proliferating progenitor state, whereas overexpression increased neurogenesis. We thus suggest AMPylation as a novel PTM fine-tuning neurogenesis. The third study focused on the identification of new mechanisms underlying cortical malformations, aiming at a better understanding of how the human brain develops. In patients with periventricular heterotopia (PH), a neuronal migration disorder in which a subset of neurons fail to migrate to the developing cortical plate and instead form nodules of grey matter lining the lateral ventricles as their site of production, biallelic mutations in endothelin converting enzyme 2 (ECE2) were identified as candidate causative. Combining in vitro and in vivo models, we found a role for ECE2 in neuronal migration and cortical development. In the absence of ECE2, several processes of general importance to proper neuronal migration were disrupted. Namely, changes in progenitor cell polarity and morphology and in apical adherens junctions led to their delamination, restricting their use as a scaffold for neuronal migration. This resulted in ectopic neurons reminiscent of nodules in PH. Besides a deregulation of cytoskeletal, polarity, and apical adhesion proteins, extracellular matrix (ECM) proteins were reduced in absence of ECE2, suggesting its role in ECM production and underlining the necessity of ECM components for proper neuronal migration during cortical development. Moreover, we detected differential phosphorylation of several cytoskeletal, motor and adhesion proteins in the absence of ECE2, which is functionally in line with the former findings and suggests an additional involvement of ECE2 in the regulation of PTMs. Altogether, the studies presented here underline the heterogeneity and complexity of pathways and mechanisms that contribute to human cortical development and its disorders, converging on the regulation of cytoskeleton and transport within the involved cells and of the ECM on their outside. <br

Abjection and the Melancholic Imagination: Towards a Poststructuralist Psychoanalytic Reading of Blake’s The Book of Urizen

Julia Kristeva’s work on the semiotic and the symbolic seem particularly relevant to Blake’s poem The Book of Urizen insofar as she is concerned with how we develop as speaking beings and how language both disguises and reveals evidence of a previous state of union with what she calls the maternal chora. These ideas allow for an interesting reading of Blake’s concern with the splitting off of Urizen from the Eternals and how this splitting off enables him to emerge as a signifying subject who bears traces of traumatic loss and upheaval, or of what Kristeva would term “the abject.” Abjection is a key concept for Kristeva and plays an essential role in what she describes as the “melancholic imagination.” Abjection in Urizen manifests as a sort of paranoid repression and repudiation of the drives, of mutability, multiplicity, the body, and the Other. Urizen, throughout the poem, becomes overtly identified with the Symbolic Father and becomes himself the bearer of symbolic codes, legislator of rational discourse and semantic meaning

A Logic for Ambiguous Description

AbstractA logic formalizing ambiguity, which appears both in natural language and in mathematical discourse, is presented, through a sequent calculus and a semantics, together with some elementary results