Concepts and analogies in cybernetics: Mathematical investigations of the role of analogy in concept formation and problem solving; with emphasis for conflict resolution via object and morphism eliminations

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.We address two problematic areas of cybernetics; nam. Analogical Problem Solving (APS) and Analogical Learning (AL). Both these human faculties do unquestionably require Intelligence. In addition, we point out that shifting of representations is the main unified theme underlying these two intellectual tasks. We focus our attention on the formulation and clarification of the notion of analogy, which has been loosely treated and used in the literature; and also on its role in shifting of representations. We describe analogizing situations in a new representational scheme, borrowed from mathematics and modified and extended to cater for our targets. We call it k-structure, closely resembling semantic networks and directed graphs; the main components of it are the so-called objects and morphisms. We argue and substantiate the need for such a representation scheme, by analysing what its constituents stand for and by cataloguing its virtues, the main one being its visual appeal and its mathematical clarity, and by listing its disadvantages when it is compared to other representation systems. Emphasis is also given to its descriptive power and usefulness by implementing it in a number of APS and AL situations. Besides representation issues, attention is paid to intelligence mechanisms which are involved in APS and AL. A cornerstone in APS and a fundamental theme in AL is the 'skeletization of k-structures'. APS is conceived as 'harmonization of skeletons'. The methodology we develop involves techniques which are computer implemented and extensively studied in theoretic terms via a proposed theory for extended k-structures. To name but a few: 1. 'the separation of the context of a concept from the concept itself', based on the ideas of k-opens and k-spaces; 2, 'object and morphism elimination' of a controversial nature; and 3. 'conflict or deadlock or dilemma resolution' which naturally arises in a k-structure interaction. The overall system, is then applied to capture the essence of EVANS' (1963) analogy-type problems and WINSTOM (1970) learning-type situations. In our attempt not to be too informal, we use basic notions and terminology from abstract Algebra, Topology and Category theory. We rather tend to be "non-logical" (analogical) in EVANS' and WINSTON's sense; "non-numeric", in MESAROVIC (1970) terms (we rather deal with abstract conceptual entities); "non-linguistic" (we do not touch natural language); and "non-resolution" oriented, in the sense of BLEDSOE (1977). However, we give hints sometimes about logical deductive axiomatic systems, employing First Order Predicate Calculus (FOPC); and about semiotics, by which we denote syntactic-semantic-pragmatic features of our system and issues of the problem domains it is acting upon. We believe in what we call: shift from the traditional 'Heuristic search paradigm' era to the 'Analogy-paradigm' era underlying Artificial Intelligence and Cybernetics. We justify this merely by listing a number of A. I. works, which employ, in some way or another, the concept of analogy, over the last fifteen years or so, where a noticeable peak is obvious during the last years and especially in 1977. Finally, we hope that if the proposed conceptual framework and techniques developed do not straightforwardly constitute some kind of platform for Artificial Intelligence, at least it would give some insights into and illuminate our understanding of the two most fundamental faculties the human brain is occupied with; namely problem solving and learning

Extreme High-Field Superconductivity in Thin Re Films

We report the high-field superconducting properties of thin, disordered Re films via magneto-transport and tunneling density of states measurements. Films with thicknesses in the range of 9 nm to 3 nm had normal state sheet resistances of $\sim$0.2 k$\Omega$ to $\sim$1 k$\Omega$ and corresponding transition temperatures in the range of 6 K to 3 K. Tunneling spectra were consistent with those of a moderate coupling BCS superconductor. Notwithstanding these unremarkable superconducting properties, the films exhibited an extraordinarily high upper critical field. We estimate their zero-temperature $H_{c2}$ to be more than twice the Pauli limit. Indeed, in 6 nm samples the estimated reduced critical field $H_{c2}/T_c\sim$ 5.6 T/K is among the highest reported for any elemental superconductor. Although the sheet resistances of the films were well below the quantum resistance $R_Q=h/4e^2$, their $H_{c2}$'s approached the theoretical upper limit of a strongly disordered superconductor for which $k_F\ell\sim1$.Comment: 12 pages, 10 figure

Locomotor recovery following contusive spinal cord injury does not require oligodendrocyte remyelination

The contribution of oligodendrocytes to remyelination in functional recovery after spinal cord injury is not fully understood. Here, the authors show that oligodendrocyte progenitor cell differentiation is not required for functional recovery after spinal cord injury in mice

p53 Regulates Cell Cycle and MicroRNAs to Promote Differentiation of Human Embryonic Stem Cells

Multiple studies show that tumor suppressor p53 is a barrier to dedifferentiation; whether this is strictly due to repression of proliferation remains a subject of debate. Here, we show that p53 plays an active role in promoting differentiation of human embryonic stem cells (hESCs) and opposing self-renewal by regulation of specific target genes and microRNAs. In contrast to mouse embryonic stem cells, p53 in hESCs is maintained at low levels in the nucleus, albeit in a deacetylated, inactive state. In response to retinoic acid, CBP/p300 acetylates p53 at lysine 373, which leads to dissociation from E3-ubiquitin ligases HDM2 and TRIM24. Stabilized p53 binds CDKN1A to establish a G1 phase of cell cycle without activation of cell death pathways. In parallel, p53 activates expression of miR-34a and miR-145, which in turn repress stem cell factors OCT4, KLF4, LIN28A, and SOX2 and prevent backsliding to pluripotency. Induction of p53 levels is a key step: RNA-interference-mediated knockdown of p53 delays differentiation, whereas depletion of negative regulators of p53 or ectopic expression of p53 yields spontaneous differentiation of hESCs, independently of retinoic acid. Ectopic expression of p53R175H, a mutated form of p53 that does not bind DNA or regulate transcription, failed to induce differentiation. These studies underscore the importance of a p53-regulated network in determining the human stem cell state

Chondroitinase and Growth Factors Enhance Activation and Oligodendrocyte Differentiation of Endogenous Neural Precursor Cells after Spinal Cord Injury

The adult spinal cord harbours a population of multipotent neural precursor cells (NPCs) with the ability to replace oligodendrocytes. However, despite this capacity, proliferation and endogenous remyelination is severely limited after spinal cord injury (SCI). In the post-traumatic microenvironment following SCI, endogenous spinal NPCs mainly differentiate into astrocytes which could contribute to astrogliosis that exacerbate the outcomes of SCI. These findings emphasize a key role for the post-SCI niche in modulating the behaviour of spinal NPCs after SCI. We recently reported that chondroitin sulphate proteoglycans (CSPGs) in the glial scar restrict the outcomes of NPC transplantation in SCI by reducing the survival, migration and integration of engrafted NPCs within the injured spinal cord. These inhibitory effects were attenuated by administration of chondroitinase (ChABC) prior to NPC transplantation. Here, in a rat model of compressive SCI, we show that perturbing CSPGs by ChABC in combination with sustained infusion of growth factors (EGF, bFGF and PDGF-AA) optimize the activation and oligodendroglial differentiation of spinal NPCs after injury. Four days following SCI, we intrathecally delivered ChABC and/or GFs for seven days. We performed BrdU incorporation to label proliferating cells during the treatment period after SCI. This strategy increased the proliferation of spinal NPCs, reduced the generation of new astrocytes and promoted their differentiation along an oligodendroglial lineage, a prerequisite for remyelination. Furthermore, ChABC and GF treatments enhanced the response of non-neural cells by increasing the generation of new vascular endothelial cells and decreasing the number of proliferating macrophages/microglia after SCI. In conclusions, our data strongly suggest that optimization of the behaviour of endogenous spinal NPCs after SCI is critical not only to promote endogenous oligodendrocyte replacement, but also to reverse the otherwise detrimental effects of their activation into astrocytes which could negatively influence the repair process after SCI

Antimicrobial stewardship effectiveness on rationalizing the use of last line of antibiotics in a short period with limited human resources: A single centre cohort study

Objective: Antibiotics reserve (ARs) are given as a last line of treatment when other antibiotics are no longer effective. Rising threat of antimicrobial resistance makes growing use of ARs a real problem to patient safety. A single centre interventional cohort study was conducted in order to measure impact on clinical outcomes of A-team programme with limited human resources in a short period. A-team programme started on 01. September 2017. Results: In 3 months preintervention and 3 months intervention period, from 3038 and 3156 hospitalized adult patients, 249 (59% of them were male, median age = 69 years) and 96 (51% of them were male, median age = 70 years) received parenteral ARs. Total duration of hospitalization of patients on AR was reduced from 28 to 17 days of hospitalization on 100 patient-days (OR = 1.92; 95% CI 1.83-2.01; p < 0.001) with no statistical significant difference in rehospitalisation due to infection of patients that were treated with ARs within 2 months after discharge. Despite short period of time and limited human resources, A-team restrictive interventions rationalised parenteral AR use and led to positive impact on clinical outcomes. These results could help our and other A-teams in similar situation in continuing with the programme to bring more evidence

dp53 Restrains Ectopic Neural Stem Cell Formation in the Drosophila Brain in a Non-Apoptotic Mechanism Involving Archipelago and Cyclin E

Accumulating evidence suggests that tumor-initiating stem cells or cancer stem cells (CSCs) possibly originating from normal stem cells may be the root cause of certain malignancies. How stem cell homeostasis is impaired in tumor tissues is not well understood, although certain tumor suppressors have been implicated. In this study, we use the Drosophila neural stem cells (NSCs) called neuroblasts as a model to study this process. Loss-of-function of Numb, a key cell fate determinant with well-conserved mammalian counterparts, leads to the formation of ectopic neuroblasts and a tumor phenotype in the larval brain. Overexpression of the Drosophila tumor suppressor p53 (dp53) was able to suppress ectopic neuroblast formation caused by numb loss-of-function. This occurred in a non-apoptotic manner and was independent of Dacapo, the fly counterpart of the well-characterized mammalian p53 target p21 involved in cellular senescence. The observation that dp53 affected Edu incorporation into neuroblasts led us to test the hypothesis that dp53 acts through regulation of factors involved in cell cycle progression. Our results show that the inhibitory effect of dp53 on ectopic neuroblast formation was mediated largely through its regulation of Cyclin E (Cyc E). Overexpression of Cyc E was able to abrogate dp53′s ability to rescue numb loss-of-function phenotypes. Increasing Cyc E levels by attenuating Archipelago (Ago), a recently identified transcriptional target of dp53 and a negative regulator of Cyc E, had similar effects. Conversely, reducing Cyc E activity by overexpressing Ago blocked ectopic neuroblast formation in numb mutant. Our results reveal an intimate connection between cell cycle progression and NSC self-renewal vs. differentiation control, and indicate that p53-mediated regulation of ectopic NSC self-renewal through the Ago/Cyc E axis becomes particularly important when NSC homeostasis is perturbed as in numb loss-of-function condition. This has important clinical implications

Astrocytes: biology and pathology

Astrocytes are specialized glial cells that outnumber neurons by over fivefold. They contiguously tile the entire central nervous system (CNS) and exert many essential complex functions in the healthy CNS. Astrocytes respond to all forms of CNS insults through a process referred to as reactive astrogliosis, which has become a pathological hallmark of CNS structural lesions. Substantial progress has been made recently in determining functions and mechanisms of reactive astrogliosis and in identifying roles of astrocytes in CNS disorders and pathologies. A vast molecular arsenal at the disposal of reactive astrocytes is being defined. Transgenic mouse models are dissecting specific aspects of reactive astrocytosis and glial scar formation in vivo. Astrocyte involvement in specific clinicopathological entities is being defined. It is now clear that reactive astrogliosis is not a simple all-or-none phenomenon but is a finely gradated continuum of changes that occur in context-dependent manners regulated by specific signaling events. These changes range from reversible alterations in gene expression and cell hypertrophy with preservation of cellular domains and tissue structure, to long-lasting scar formation with rearrangement of tissue structure. Increasing evidence points towards the potential of reactive astrogliosis to play either primary or contributing roles in CNS disorders via loss of normal astrocyte functions or gain of abnormal effects. This article reviews (1) astrocyte functions in healthy CNS, (2) mechanisms and functions of reactive astrogliosis and glial scar formation, and (3) ways in which reactive astrocytes may cause or contribute to specific CNS disorders and lesions