Patterning by cell-to-cell communication

This thesis addresses the question of how patterning may arise through cell-to-cell communication. It combines quantitative data analysis with computational techniques to understand biological patterning processes. The fi�rst section describes an investigation into the robustness of an evolved arti�ficial patterning system. Cellular automata rules were implemented sequentially according to the instructions in a simple `genome'. In this way, a set of target patterns could be evolved using a genetic algorithm. The patterning systems were tested for robustness by perturbing cell states during their development. This exposed how certain types of patterning rule had very di�fferent levels of robustness to perturbations. Rules that generated patterns with complex divergent patterns were more likely to amplify the e�ffect of a perturbation. When smaller genomes, comprising less individual rules, were evolved to match certain target patterns, these were shown to be more likely to select complex patterning rules. As a result, the developmental systems based on smaller genomes were less robust than those with larger genome sizes. Section two provides an analysis of the patterning of microchaetes in the epithelial layer of the notum of Drosophila flies. It is shown that the pattern spacing is not sufficiently described by a model of lateral inhibition through Delta-Notch signalling between adjacent cells. A computational model is used to demonstrate the viability of long range signalling through a dynamic network of �filopodia, observed in the basal layer of the epithelium. In-vivo experiments con�rm that when fi�lopodia lengths are effected by mutations the pattern spacing reduces in accordance with the model. In the fi�nal section the behaviour of simple asynchronous cellular automata are analysed. It is shown how these diff�er to the synchronous cellular automata used in the fi�rst section. A set of rules are identifi�ed whose emergent behaviour is similar to the lateral inhibition patterning process established by the Delta-Notch signalling system. Among these rules a particular subset are found to produce patterns that adjust their spacing, over the course of their development, towards a more ordered and densely packed state. A re-examination of the Delta-Notch signalling model reveals that this type of packing optimisation could take place with either dynamic �filopodial signalling, or as an alternative, transient Delta signalling at each cell. Under certain parameter regimes the patterns become more densely packed over time, whilst maintaining a minimum zone of inhibition around each Delta expressing cell. The asynchronous CA are also used to demonstrate how stripes can be formed by cell-to-cell signalling and optimised, under certain conditions, so that they align in a single direction. This is presented as a possible novel alternative to the reaction-di�ffusion mechanism that is commonly used to model the patterning of spots and stripes

Monoclonal Antibodies to Disrupt Progression of Early Covid-19 Infection

By the end of 2020, more than 19 million Americans had received the diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although a substantial proportion of these infections remained asymptomatic, complications of coronavirus disease 2019 (Covid-19) had led to more than 330,000 deaths in the United States. During the past year, a remarkable effort has been devoted to the development of vaccines to prevent Covid-19 and to reduce morbidity and mortality among those who are infected. Equally important is the development of treatments that can prevent the progression of Covid-19 from the inception of infection

Treatment for HIV prevention, one couple at a time

The belief that treatment of HIV infection will reduce the spread of the virus was inspired by a series of observational studies of HIV serodiscordant heterosexual couples, in which HIV transmission was reduced or eliminated if the sexual partner with HIV was given antiretroviral therapy (ART), and by the results of the HPTN 052 multinational randomised controlled trial. However, these studies included few homosexual couples; therefore, the risk of HIV transmission from condomless anal intercourse could not be addressed

Early treatment to prevent progression of SARS-CoV-2 infection

As of May, 2022, the SARS-CoV-2 virus has caused 521 million COVID-19 cases and at least 6 million deaths, worldwide.1 Although the COVID-19 pandemic has led to breathtaking vaccine developments, early treatments to prevent progression of COVID-19, especially in those who are most vulnerable, are urgently needed. But to deploy such treatment will take a substantial change in the perception and management of upper respiratory infections, including COVID-19

Successful treatment of HIV eliminates sexual transmission

In December, 2011, Science recognised the findings of the HPTN 052 study as the scientific breakthrough of the year. This study showed a 96% reduction in sexual transmission of HIV in serodifferent couples (one partner HIV positive, the other HIV negative) when the HIV-positive partner was successfully treated with antiretroviral therapy (ART). However, the HPTN 052 study included only a small number of men who have sex with men (MSM), for whom HIV acquisition often includes anal exposure, an efficient route of HIV transmission. Furthermore, the couples in the HPTN 052 study were counselled to use condoms, so the observed benefits of ART also reflected the contribution of safer sexual behaviours. Accordingly, other investigators have subsequently studied HIV transmission in couples who specifically chose not to use condoms

Hydroxychloroquine for the Prevention of Covid-19 - Searching for Evidence

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19), has generated a worldwide pandemic. The interruption of its spread depends on a combination of pharmacologic and nonpharmacologic interventions. Initial SARSCoV-2 prevention includes social distancing, the use of face masks, environmental hygiene, and hand washing.1 Although the most important pharmacologic interventions to prevent SARSCoV-2 infection are likely to be vaccines, the repurposing of established drugs for short-term prophylaxis is another, more immediate option

Outpatient Antibiotic Therapy for Osteomyelitis

To the editor - The March 28, 1986, issue of JAMA contained an article offering an economic analysis of outpatient therapy for osteomyelitis.1 This article is now being distributed by representatives of the Smith Klein & French pharmaceutical company for the purpose of encouraging the use of the cephalosporin antibiotic cefonicid (Monocid) in this setting. In their introduction, the authors justify their analysis by noting that "a new. . . cephalosporin antibiotic, cefonicid sodium, has been shown to be effective in treating osteomyelitis in the outpatient setting.

The Old Foe Syphilis Strikes Again: Social Responses and Collective Mobilization

Syphilis is an ancient sexually transmitted spirochetal infection that causes a wide variety of clinical outcomes, including severe disability and death. At various times over the course of human history, syphilis has become so common in selected countries that it attracts great public attention. In this issue of AJPH, Kosenko and Polianski (p. 1318) review the use of unique communication tools to attract attention to syphilis in the first half of the 20th century in the USSR and the United States. They describe the use of stage plays called “Living Newspapers,” which the Federal Theater Project organized during the Great Depression in the United States

Broadly neutralizing antibodies to prevent HIV-1

Advances in technology—especially single-cell antibody cloning techniques — have led to the isolation and characterization of antibodies from people with HIV infection that can neutralize many variants. These are referred to as broadly neutralizing antibodies (bnAbs). Such antibodies can be detected in about 25% of persons with untreated HIV-1 infection, reflecting a host immune response to unremitting viral replication, generation of large numbers of viral variants, and shifting antigen exposure. Although bnAbs may exert some selective pressure as they develop, they generally do not reduce viral burden, improve health, or slow the progression of disease. However, they offer considerable opportunities for treatment and prevention of HIV-1 infection in others. At this time, hundreds of bnAbs have been identified; those that have attracted the most attention are bnAbs with the greatest breadth, neutralizing the largest number of HIV-1 strains, including those traditionally most neutralization resistant; or bnAbs that have the greatest potency, requiring the smallest concentration to neutralize resistant strains of HIV-1. A study by Xu et al. on page 85 of this issue and by Julg et al. in Science Translational Medicine illustrate advances in the potential use of bnAbs to prevent HIV-1 infection