Hypothesis: bacteria live on the edge of phase transitions with a cell cycle regulated by a water-clock.

A fundamental problem in biology is how cells obtain the reproducible, coherent phenotypes needed for natural selection to act or, put differently, how cells manage to limit their exploration of the vastness of phenotype space. A subset of this problem is how they regulate their cell cycle. Bacteria, like eukaryotic cells, are highly structured and contain scores of hyperstructures or assemblies of molecules and macromolecules.

Hunting the Cell Cycle .

In this very personal hunt for the meaning of the bacterial cell cycle, the , I briefly revisit and update some of the mechanisms we and many others have proposed to regulate the bacterial cell cycle. These mechanisms, which include the dynamics of calcium, membranes, hyperstructures, and networks, are based on physical and physico-chemical concepts such as ion condensation, phase transition, crowding, liquid crystal immiscibility, collective vibrational modes, reptation, and water availability. I draw on ideas from subjects such as the 'prebiotic ecology' and phenotypic diversity to help with the hunt.

Perspective Strategies for Interventions in Parkinsonism: Remedying the Neglected Role of TPPP.

Neurological disorders such as Parkinsonism cause serious socio-economic problems as there are, at present, only therapies that treat their symptoms. The well-established hallmark alpha-synuclein (SYN) is enriched in the inclusion bodies characteristic of Parkinsonism. We discovered a prominent partner of SYN, termed Tubulin Polymerization Promoting Protein (TPPP), which has important physiological and pathological activities such as the regulation of the microtubule network and the promotion of SYN aggregation.

Science and prizes : A case for rethinking the criteria for prizes in science (and for rewarding important discoveries in bacterial physiology).

Scientific prizes award those making important discoveries, define a field, further the public understanding of science, or support young and upcoming researchers. But they should also encourage scientists to take risks and venture into the unknown. [Image: see text]

Novel Principles and Methods in Bacterial Cell Cycle Physiology: Celebrating the Charles E. Helmstetter Prize in 2022.

This Special Issue celebrates the creation of the Charles E [...

Open Questions about the Roles of DnaA, Related Proteins, and Hyperstructure Dynamics in the Cell Cycle.

The DnaA protein has long been considered to play the key role in the initiation of chromosome replication in modern bacteria. Many questions about this role, however, remain unanswered. Here, we raise these questions within a framework based on the dynamics of hyperstructures, alias large assemblies of molecules and macromolecules that perform a function.

Prospects for macrolide therapy of asthma and COPD.

Macrolide compounds, many of which are derived from natural sources, all share a lactone ring structure, but of varying sizes. Their biological activities differ with structure and size but tend to overlap. Marketed macrolide drugs include immunosuppressives and antibiotics.

The Sherpa hypothesis: Phenotype-Preserving Disordered Proteins stabilize the phenotypes of neurons and oligodendrocytes.

Intrinsically disordered proteins (IDPs), which can interact with many partner proteins, are central to many physiological functions and to various pathologies that include neurodegeneration. Here, we introduce the Sherpa hypothesis, according to which a subset of stable IDPs that we term Phenotype-Preserving Disordered Proteins (PPDP) play a central role in protecting cell phenotypes from perturbations. To illustrate and test this hypothesis, we computer-simulate some salient features of how cells evolve and differentiate in the presence of either a single PPDP or two incompatible PPDPs.

The roles of nucleoid-associated proteins and topoisomerases in chromosome structure, strand segregation, and the generation of phenotypic heterogeneity in bacteria.

How to adapt to a changing environment is a fundamental, recurrent problem confronting cells. One solution is for cells to organize their constituents into a limited number of spatially extended, functionally relevant, macromolecular assemblies or hyperstructures, and then to segregate these hyperstructures asymmetrically into daughter cells. This asymmetric segregation becomes a particularly powerful way of generating a coherent phenotypic diversity when the segregation of certain hyperstructures is with only one of the parental DNA strands and when this pattern of segregation continues over successive generations.

The Ring World: Eversion of Small Double-Stranded Polynucleotide Circlets at the Origin of DNA Double Helix, RNA Polymerization, Triplet Code, Twenty Amino Acids, and Strand Asymmetry.

It is not entirely clear why, at some stage in its evolution, terrestrial life adopted double-stranded DNA as the hereditary material. To explain this, we propose that small, double-stranded, polynucleotide circlets have special catalytic properties. We then use this proposal as the basis for a 'view from here' that we term the Circlet hypothesis as part of a broader Ring World.

Challenges in Discovering Drugs That Target the Protein-Protein Interactions of Disordered Proteins.

Protein-protein interactions (PPIs) outnumber proteins and are crucial to many fundamental processes; in consequence, PPIs are associated with several pathological conditions including neurodegeneration and modulating them by drugs constitutes a potentially major class of therapy. Classically, however, the discovery of small molecules for use as drugs entails targeting individual proteins rather than targeting PPIs. This is largely because discovering small molecules to modulate PPIs has been seen as extremely challenging.

A Defective Viral Particle Approach to COVID-19.

The novel coronavirus SARS-CoV-2 has caused a pandemic resulting in millions of deaths worldwide. While multiple vaccines have been developed, insufficient vaccination combined with adaptive mutations create uncertainty for the future. Here, we discuss novel strategies to control COVID-19 relying on Defective Interfering Particles (DIPs) and related particles that arise naturally during an infection.

Generates in Bacteria and Other Living Systems.

The relevance of bacteria to subjective experiences or is underappreciated. Here, I make four proposals. Firstly, living systems traverse sequences of states that determine their behaviour; these states result from , which depends on connectivity-based competition between a process and a process, whereby elements in the active state at time are chosen between the elements in the active state at time and those elements in the developing state.

Role of Multifunctional Cytoskeletal Filaments in Infections: Therapeutic Opportunities for COVID-19 in a Nutshell.

A novel coronavirus discovered in 2019 is a new strain of the family (CoVs) that had not been previously identified in humans. It is known as SARS-CoV-2 for , whilst COVID-19 is the name of the disease associated with the virus. SARS-CoV-2 emerged over one year ago and still haunts the human community throughout the world, causing both healthcare and socioeconomic problems.

Generation of Bacterial Diversity by Segregation of DNA Strands.

The generation in a bacterial population of a diversity that is coherent with present and future environments is a fundamental problem. Here, we use modeling to investigate growth rate diversity. We show that the combination of (1) association of extended assemblies of macromolecules with the DNA strands and (2) the segregation of DNA strands during cell division allows cells to generate different patterns of growth rate diversity with little effect on the overall growth rate of the population and thereby constitutes an example of "order for free" on which evolution can act.

Hypothesis: nucleoid-associated proteins segregate with a parental DNA strand to generate coherent phenotypic diversity.

The generation of a phenotypic diversity that is coherent across a bacterial population is a fundamental problem. We propose here that the DNA strand-specific segregation of certain nucleoid-associated proteins or NAPs results in these proteins being asymmetrically distributed to the daughter cells. We invoke a variety of mechanisms as responsible for this asymmetrical segregation including those based on differences between the leading and lagging strands, post-translational modifications, oligomerisation and association with membrane domains.

An Update on Screening and Prevention for Breast and Gynecological Cancers in Average and High Risk Individuals.

Breast and gynecological cancers affect almost 900,000 women and therefore most health care providers will be involved at some point in the management of women with cancer. As the prognosis of all cancers is much more favorable when diagnosed in early stages, it is imperative that all health care providers are familiar not only with current screening guidelines for the average population, but also with the identification of high risk individuals who may benefit from more intense screening as well as available interventions to prevent disease or decrease risk. The purpose of this review article is to provide relevant information to physicians and other health care providers to aid in identifying patients that are classified as "high risk" for developing breast or a gynecologic cancer, outlining what interventions exist for adequate screening and risk reduction strategies, and to provide an update on current screening guidelines for individuals at average and high risk.

Engaging Church Leaders in the Reduction of Teen Birth Rate in High-Risk Areas.

Involving faith-based organizations in community health promotion has gained widespread interest and has been a successful approach in addressing various health disparities in vulnerable communities. However, there is comparatively little evidence regarding sexual health promotion among faith-based organizations. Some agencies have responded to the challenge of reducing teen pregnancy with broad-based initiatives involving many different sectors of the community including faith-based organizations.

Emergence of a "Cyclosome" in a Primitive Network Capable of Building "Infinite" Proteins.

We argue for the existence of an RNA sequence, called the AL (for ALpha) sequence, which may have played a role at the origin of life; this role entailed the AL sequence helping generate the first peptide assemblies via a primitive network. These peptide assemblies included "infinite" proteins. The AL sequence was constructed on an economy principle as the smallest RNA ring having one representative of each codon's synonymy class and capable of adopting a non-functional but nevertheless evolutionarily stable hairpin form that resisted denaturation due to environmental changes in pH, hydration, temperature, etc.

Does the Semiconservative Nature of DNA Replication Facilitate Coherent Phenotypic Diversity?

It has been clear for over sixty years that the principal method whereby cells replicate and segregate their DNA is semiconservative. It is much less clear why it should be like this rather than, say, conservative. Recently, evidence has accumulated that supports the hypothesis that one of the functions of the cell cycle is to generate phenotypically different daughter cells, even in nondifferentiating bacteria such as Evidence has also accumulated that the bacterial phenotype is determined by the functioning of extended assemblies of macromolecules termed hyperstructures.

Successive Paradigm Shifts in the Bacterial Cell Cycle and Related Subjects.

A paradigm shift in one field can trigger paradigm shifts in other fields. This is illustrated by the paradigm shifts that have occurred in bacterial physiology following the discoveries that bacteria are not unstructured, that the bacterial cell cycle is not controlled by the dynamics of peptidoglycan, and that the growth rates of bacteria in the same steady-state population are not at all the same. These paradigm shifts are having an effect on longstanding hypotheses about the regulation of the bacterial cell cycle, which appear increasingly to be inadequate.

Multiple links connect central carbon metabolism to DNA replication initiation and elongation in Bacillus subtilis.

DNA replication is coupled to growth by an unknown mechanism. Here, we investigated this coupling by analyzing growth and replication in 15 mutants of central carbon metabolism (CCM) cultivated in three rich media. In about one-fourth of the condition tested, defects in replication resulting from changes in initiation or elongation were detected.

Division-Based, Growth Rate Diversity in Bacteria.

To investigate the nature and origins of growth rate diversity in bacteria, we grew and in liquid minimal media and, after different periods of N-labeling, analyzed and imaged isotope distributions in individual cells with . We find a striking inter- and intra-cellular diversity, even in steady state growth. This is consistent with the strand-dependent, hyperstructure-based hypothesis that a major function of the cell cycle is to generate coherent, growth rate diversity via the semi-conservative pattern of inheritance of strands of DNA and associated macromolecular assemblies.

The Changing Age of Individuals Seeking Presymptomatic Genetic Testing for Huntington Disease.

Huntington disease (HD) is a progressive neurodegenerative disorder. Presymptomatic genetic testing allows at-risk individuals to clarify their risk status. Understanding the characteristics and motivations of individuals seeking HD presymptomatic genetic testing better equips genetic counselors and other healthcare professionals to provide comprehensive and personalized care.

Synthetic, Switchable Enzymes.

The construction of switchable, radiation-controlled, aptameric enzymes - "swenzymes" - is, in principle, feasible. We propose a strategy to make such catalysts from 2 (or more) aptamers each selected to bind specifically to one of the substrates in, for example, a 2-substrate reaction. Construction of a combinatorial library of candidate swenzymes entails selecting a set of a million aptamers that bind one substrate and a second set of a million aptamers that bind the second substrate; the aptamers in these sets are then linked pairwise by a linker, thus bringing together the substrates.