A Systematic Analysis of Cell Cycle Regulators in Yeast Reveals That Most Factors Act Independently of Cell Size to Control Initiation of Division

Upstream events that trigger initiation of cell division, at a point called START in yeast, determine the overall rates of cell proliferation. The identity and complete sequence of those events remain unknown. Previous studies relied mainly on cell size changes to identify systematically genes required for the timely completion of START. Here, we evaluated panels of non-essential single gene deletion strains for altered DNA content by flow cytometry. This analysis revealed that most gene deletions that altered cell cycle progression did not change cell size. Our results highlight a strong requirement for ribosomal biogenesis and protein synthesis for initiation of cell division. We also identified numerous factors that have not been previously implicated in cell cycle control mechanisms. We found that CBS, which catalyzes the synthesis of cystathionine from serine and homocysteine, advances START in two ways: by promoting cell growth, which requires CBS's catalytic activity, and by a separate function, which does not require CBS's catalytic activity. CBS defects cause disease in humans, and in animals CBS has vital, non-catalytic, unknown roles. Hence, our results may be relevant for human biology. Taken together, these findings significantly expand the range of factors required for the timely initiation of cell division. The systematic identification of non-essential regulators of cell division we describe will be a valuable resource for analysis of cell cycle progression in yeast and other organisms

New Pharmacological Agents to Aid Smoking Cessation and Tobacco Harm Reduction: What has been Investigated and What is in the Pipeline?

A wide range of support is available to help smokers to quit and aid attempts at harm reduction, including three first-line smoking cessation medications: nicotine replacement therapy, varenicline and bupropion. Despite the efficacy of these, there is a continual need to diversify the range of medications so that the needs of tobacco users are met. This paper compares the first-line smoking cessation medications to: 1) two variants of these existing products: new galenic formulations of varenicline and novel nicotine delivery devices; and 2) twenty-four alternative products: cytisine (novel outside of central and eastern Europe), nortriptyline, other tricyclic antidepressants, electronic cigarettes, clonidine (an anxiolytic), other anxiolytics (e.g. buspirone), selective 5-hydroxytryptamine (5-HT) reuptake inhibitors, supplements (e.g. St John’s wort), silver acetate, nicobrevin, modafinil, venlafaxine, monoamine oxidase inhibitors (MAOI), opioid antagonist, nicotinic acetylcholine receptors (nAChR) antagonists, glucose tablets, selective cannabinoid type 1 receptor antagonists, nicotine vaccines, drugs that affect gamma-aminobutyric acid (GABA) transmission, drugs that affect N-methyl-D-aspartate receptors (NMDA), dopamine agonists (e.g. levodopa), pioglitazone (Actos; OMS405), noradrenaline reuptake inhibitors, and the weight management drug lorcaserin. Six criteria are used: relative efficacy, relative safety, relative cost, relative use (overall impact of effective medication use), relative scope (ability to serve new groups of patients), and relative ease of use (ESCUSE). Many of these products are in the early stages of clinical trials, however, cytisine looks most promising in having established efficacy and safety and being of low cost. Electronic cigarettes have become very popular, appear to be efficacious and are safer than smoking, but issues of continued dependence and possible harms need to be considered

Explaining state development: Indonesia from its pre-independence origins to contemporary democracy.

Explaining State Development: Indonesia from Pre-Independence Origins to Contemporary Democracy. This thesis uses the Indonesian case to present a new paradigm for explaining the state development of new or relatively new (post-World War II) states. The first chapter describes this paradigm of organic and mechanical types of state development, argues that the development of the Indonesian state from the 1950s to 1990s is a good example of the mechanical type of development and shows how this can be confirmed by assessing and comparing the capabilities of the four different versions of a modern state developed by Indonesia since independence. The next chapter examines Indonesia’s pre-independence debates about the form of state to be adopted, which led to Indonesia accepting a Western model of the state that has since undergone a development process involving four different versions of a ‘modern’ state. These four versions of the state are defined according to their type of regime and policymaking institutions: I) parliamentary democracy, II) Sukarno’s civilian presidential monarchy, III) Suharto’s military presidential monarchy and IV) presidential democracy. Chapters Three to Six assess and compare these four versions’ capability in three key areas: 1) achieving legal legitimacy, 2) control of the military and 3) dealing with political disorder – a crucial area of state capability that requires two chapters. Then Chapter Seven examines and explains the pre-democratic origins of the present version of the Indonesian state, the presidential democracy of Version IV. The Conclusion collates the findings of Chapters Three to Six on capabilities and summarises the arguments of Chapters Two and Seven regarding the 1940s acceptance of the Western model of the state and the late 1990s opportunity for democratisation. Finally, there is a concluding assessment of the potential of the organic/mechanical typology as a new paradigm for studying state development in other countries, regions and eras