Computing, Modelling, and Scientific Practice: Foundational Analyses and Limitations

This dissertation examines aspects of the interplay between computing and scientific practice. The appropriate foundational framework for such an endeavour is rather real computability than the classical computability theory. This is so because physical sciences, engineering, and applied mathematics mostly employ functions defined in continuous domains. But, contrary to the case of computation over natural numbers, there is no universally accepted framework for real computation; rather, there are two incompatible approaches --computable analysis and BSS model--, both claiming to formalise algorithmic computation and to offer foundations for scientific computing. The dissertation consists of three parts. In the first part, we examine what notion of 'algorithmic computation' underlies each approach and how it is respectively formalised. It is argued that the very existence of the two rival frameworks indicates that 'algorithm' is not one unique concept in mathematics, but it is used in more than one way. We test this hypothesis for consistency with mathematical practice as well as with key foundational works that aim to define the term. As a result, new connections between certain subfields of mathematics and computer science are drawn, and a distinction between 'algorithms' and 'effective procedures' is proposed. In the second part, we focus on the second goal of the two rival approaches to real computation; namely, to provide foundations for scientific computing. We examine both frameworks in detail, what idealisations they employ, and how they relate to floating-point arithmetic systems used in real computers. We explore limitations and advantages of both frameworks, and answer questions about which one is preferable for computational modelling and which one for addressing general computability issues. In the third part, analog computing and its relation to analogue (physical) modelling in science are investigated. Based on some paradigmatic cases of the former, a certain view about the nature of computation is defended, and the indispensable role of representation in it is emphasized and accounted for. We also propose a novel account of the distinction between analog and digital computation and, based on it, we compare analog computational modelling to physical modelling. It is concluded that the two practices, despite their apparent similarities, are orthogonal

What About Them? The Health and Well-being of Those Who Care for Others

Employee Health and Wellness Programs are increasingly more prevalent in different work environments and industries. Studies have shown that these programs can potentially increase employee productivity and reduce absenteeism, in addition to emphasizing a priority on mental and physical wellness. Healthcare workers already have a stressful job, but since the breakout of COVID-19, they have been overwhelmed with this pandemic to an even higher degree. It is important that healthcare workers take care of their own health and wellness and that it is prioritized at their place of work. Through surveying various healthcare workers, this study investigates if healthcare professionals are provided with employee well-being options or programs and whether it has an effect on their own well-being. The conclusions of the study indicate that healthcare workers have lower general-well-being than recommended standards, that healthcare workers are unaware of wellness programs or initiatives at their place of work, and that most healthcare employers do not offer sufficient wellness programs. The recommendations collected from healthcare employees about what they would like out of a wellness program allow for further studies to analyze the implementation of such initiatives and any potential changes in the well-being of healthcare workers as a result

Unrealistic Models for Realistic Computations: How Idealisations Help Represent Mathematical Structures and Found Scientific Computing

We examine two very different approaches to formalising real computation, commonly referred to as "Computable Analysis" and "the BSS approach". The main models of computation underlying these approaches ---bit computation (or Type-2 Effectivity) and BSS, respectively--- have also been put forward as appropriate foundations for scientific computing. The two frameworks offer useful computability and complexity results about problems whose underlying domain is an uncountable space (such as R or C). Since typically the problems dealt with in physical sciences, applied mathematics, economics, and engineering are also defined in uncountable domains, it is fitting that we choose between these two approaches a foundational framework for scientific computing. However, the models are incompatible as to their results. What is more, the BSS model is highly idealised and unrealistic; yet, it is the de facto implicit model in various areas of computational mathematics, with virtually no problems for the everyday practice. The paper serves three purposes. First, we attempt to delineate what the goal of developing foundations for scientific computing exactly is. We distinguish between two very different interpretations of that goal, and on the separate basis of each one, we put forward answers about the appropriateness of each framework. Second, we provide an account of the fruitfulness and wide use of BSS, despite its unrealistic assumptions. Third, according to one of our proposed interpretations of the scope of foundations, the target domain of both models is a certain mathematical structure (namely, floating-point arithmetic). In a clear sense, then, we are using idealised models to study a purely mathematical structure (actually a class of such structures). The third purpose is to point out and explain this intriguing (perhaps unique) phenomenon and attempt to make connections with the typical case of idealised models of empirical domains

Platinum(IV)-chlorotoxin (CTX) conjugates for targeting cancer cells

Cisplatin is one of the most widely used anticancer drugs. Its side effects, however, have motivated researchers to search for equally effective analogs that are better tolerated. Selectively targeting cancer tissue is one promising strategy. For this purpose, a platinum(IV) complex was conjugated to the cancer-targeting peptide chlorotoxin (CTX, TM601) in order to deliver cisplatin selectively to cancer cells. The 1:1 Pt-CTX conjugate was characterized by mass spectrometry and gel electrophoresis. Like most platinum(IV) derivatives, the cytotoxicity of the conjugate was lower in cell culture than that of cisplatin, but greater than those of its Pt(IV) precursor and CTX in several cancer cell lines.National Cancer Institute (U.S.) (Grant CA034992)German Academic Exchange Service (Fellowship

The roles of neutrophils linking periodontitis and atherosclerotic cardiovascular diseases

Inflammation plays a crucial role in the onset and development of atherosclerosis. Periodontitis is a common chronic disease linked to other chronic inflammatory diseases such as atherosclerotic cardiovascular diseases (ASCVD). The mechanistic pathways underlying this association are yet to be fully understood. This critical review aimed at discussing the role of neutrophils in mediating the relationship between periodontitis and ASCVD. Systemic inflammation triggered by periodontitis could lead to adaptations in hematopoietic stem and progenitor cells (HSPCs) resulting in trained granulopoiesis in the bone marrow, thereby increasing the production of neutrophils and driving the hyper-responsiveness of these abundant innate-immune cells. These alterations may contribute to the onset, progression, and complication of atherosclerosis. Despite the emerging evidence suggesting that the treatment of periodontitis improves surrogate markers of cardiovascular disease, the resolution of periodontitis may not necessarily reverse neutrophil hyper-responsiveness since the hyper-inflammatory re-programming of granulopoiesis can persist long after the inflammatory inducers are removed. Novel and targeted approaches to manipulate neutrophil numbers and functions are warranted within the context of the treatment of periodontitis also to mitigate its potential impact on ASCVD

Neutrophil extracellular traps: from physiology to pathology.

At the frontline of the host defence response, neutrophil antimicrobial functions have adapted to combat infections and injuries of different origins and magnitude. The release of web-like DNA structures named neutrophil extracellular traps (NETs) constitutes an important mechanism by which neutrophils prevent pathogen dissemination or deal with microorganisms of a bigger size. At the same time, nuclear and granule proteins with microbicidal activity bind to these DNA structures promoting the elimination of entrapped pathogens. However, these toxic properties may produce unwanted effects in the host, when neutrophils uncontrollably release NETs upon persistent inflammation. As a consequence, NET accumulation can produce vessel occlusion, tissue damage, and prolonged inflammation associated with the progression and exacerbation of multiple pathologic conditions. This review outlines recent advances in understanding the mechanisms of NET release and functions in sterile disease. We also discuss mechanisms of physiological regulation and the importance of neutrophil heterogeneity in NET formation and composition.C.S.-R. receives funding from the Deutsche Forschungsgemeinschaft (SFB1123 TP A6). O.S. receives funding from the Deutsche Forschungsgemeinschaft (SFB914 TP B8, SFB1123 TP A6, TP B5, SFB1009 TP A13), the Vetenskapsra˚det (2017-01762), the Else-Kro¨ner-Fresenius Stiftung (2017_A13), the Swedish Heart–Lung Foundation (20190317), and the Leducq foundation (TNE-18CVD04). P.L. receives funding support from the National Heart, Lung, and Blood Institute (1R01HL134892), the American Heart Association (18CSA34080399), the RRM Charitable Fund, and the Simard Fund. V.P. receives core funding from the Francis Crick institute funded by UK Medical Research Council, Cancer Research UK and the Wellcome Trust (FC0010129, FC001134). I.V.A was funded by an EMBO LTF (ALTF 113-2019). A.H. is funded by Ministerio de Ciencia e Innovacion (RTI2018-095497-B-I00), La Caixa Foundation (HR17_00527), and the European Commision (FET-OPEN 861878).S

On Two Different Kinds of Computational Indeterminacy

It is often indeterminate what function a given computational system computes. This phenomenon has been referred to as “computational indeterminacy” or “multiplicity of computations”. In this paper, we argue that what has typically been considered and referred to as the (unique) challenge of computational indeterminacy in fact subsumes two distinct phenomena, which are typically bundled together and should be teased apart. One kind of indeterminacy concerns a functional (or formal) characterization of the system’s relevant behavior (briefly: how its physical states are grouped together and corresponded to abstract states). Another kind concerns the manner in which the abstract (or computational) states are interpreted (briefly: what function the system computes). We discuss the similarities and differences between the two kinds of computational indeterminacy, their implications for certain accounts of “computational individuation” in the literature, and their relevance to different levels of description within the computational system. We also examine the interrelationships between our proposed accounts of the two kinds of indeterminacy and the main accounts of “computational implementation”

Neutrophil Elastase Enhances Sputum Solubilization in Cystic Fibrosis Patients Receiving DNase Therapy

Cystic fibrosis patients suffer from chronic lung infection and inflammation due to the secretion of viscous sputum. Sputum viscosity is caused by extracellular DNA, some of which originates from the release of neutrophil extracellular traps (NETs). During NET formation neutrophil elastase (NE) partially processes histones to decondense chromatin. NE is abundant in CF sputum and is thought to contribute to tissue damage. Exogenous nucleases are a palliative treatment in CF as they promote sputum solubilization. We show that in a process reminiscent of NET formation, NE enhances sputum solubilization by cleaving histones to enhance the access of exogenous nucleases to DNA. In addition, we find that in Cf sputum NE is predominantly bound to DNA, which is known to downregulate its proteolytic activity and may restrict host tissue damage. The beneficial role of NE in CF sputum solubilization may have important implications for the development of CF therapies targeting NE

Activation of the Aryl Hydrocarbon Receptor Interferes with Early Embryonic Development.

The transcriptional program of early embryonic development is tightly regulated by a set of well-defined transcription factors that suppress premature expression of differentiation genes and sustain the pluripotent identity. It is generally accepted that this program can be perturbed by environmental factors such as chemical pollutants; however, the precise molecular mechanisms remain unknown. The aryl hydrocarbon receptor (AHR) is a widely expressed nuclear receptor that senses environmental stimuli and modulates target gene expression. Here, we have investigated the AHR interactome in embryonic stem cells by mass spectrometry and show that ectopic activation of AHR during early differentiation disrupts the differentiation program via the chromatin remodeling complex NuRD (nucleosome remodeling and deacetylation). The activated AHR/NuRD complex altered the expression of differentiation-specific genes that control the first two developmental decisions without affecting the pluripotency program. These findings identify a mechanism that allows environmental stimuli to disrupt embryonic development through AHR signaling

Rings and spirals in barred galaxies. I Building blocks

In this paper we present building blocks which can explain the formation and properties both of spirals and of inner and outer rings in barred galaxies. We first briefly summarise the main results of the full theoretical description we have given elsewhere, presenting them in a more physical way, aimed to an understanding without the requirement of extended knowledge of dynamical systems or of orbital structure. We introduce in this manner the notion of manifolds, which can be thought of as tubes guiding the orbits. The dynamics of these manifolds can govern the properties of spirals and of inner and outer rings in barred galaxies. We find that the bar strength affects how unstable the L1 and L2 Lagrangian points are, the motion within the 5A5A5Amanifold tubes and the time necessary for particles in a manifold to make a complete turn around the galactic centre. We also show that the strength of the bar, or, to be more precise, of the non-axisymmetric forcing at and somewhat beyond the corotation region, determines the resulting morphology. Thus, less strong bars give rise to R1 rings or pseudorings, while stronger bars drive R2, R1R2 and spiral morphologies. We examine the morphology as a function of the main parameters of the bar and present descriptive two dimensional plots to that avail. We also derive how the manifold morphologies and properties are modified if the L1 and L2 Lagrangian points become stable. Finally, we discuss how dissipation affects the manifold properties and compare the manifolds in gas-like and in stellar cases. Comparison with observations, as well as clear predictions to be tested by observations will be given in an accompanying paper.Comment: Typos corrected to match the version in press in MNRA