arXiv subjects

Donald R. Forsdyke

Publications and source records attributed to Donald R. Forsdyke.

11 recordsLinked to original sources

arXiv2020

SARS-CoV-2 mortality in blacks and temperature-sensitivity to an angiotensin-2 receptor blocker

Tropical climates provoke adaptations in skin pigmentation and in mechanisms controlling the volume, salt-content and pressure of body fluids. For many whose distant ancestors moved to temperate climes, these adaptations proved harmful: pigmentation decreased by natural selection and susceptibility to hypertension emerged. Now an added risk is lung inflammation from coronavirus that may be furthered by innate immune differences. Hypertension and coronavirus have in common angiotensin converting enzyme 2 (ACE2), which decreases blood pressure and mediates virus entry. In keeping with less detailed studies, a long-term case-report shows that decreased blood pressure induced by blocking a primary angiotensin receptor is supplemented, above critical blocker dosage, by a further temperature-dependent fall, likely mediated by ACE2 and secondary angiotensin receptors. Temperature-dependence suggests a linkage with tropical heritage and an influence of blockers on the progress of coronavirus infections. Positive therapeutic results should result from negation of host pro-inflammatory effects mediated by the primary angiotensin receptor and concomitant promotion of countervailing anti-inflammatory effects mediated by ACE2 through other receptors. These effects may involve innate immune system components (lectin complement pathway, NAD metabolome). Black vulnerability - more likely based on physiological than on socioeconomic differences - provides an important clue that may guide treatments.

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arXiv2019

Success of Alignment-Free Oligonucleotide (k-mer) Analysis Confirms Relative Importance of Genomes not Genes in Speciation and Phylogeny

The utility of DNA sequence substrings (k-mers) in alignment-free phylogenetic classification, including that of bacteria and viruses, is increasingly recognized. However, its biological basis eludes many twenty-first century practitioners. A path from the nineteenth century recognition of the informational basis of heredity to the modern era can be discerned. Crick's DNA "unpairing postulate" predicted that recombinational pairing of homologous DNAs during meiosis would be mediated by short k-mers in the loops of stem-loop structures extruded from classical duplex helices. The complementary "kissing" duplex loops - like tRNA anticodon-codon k-mer duplexes - would seed a more extensive pairing that would then extend until limited by lack of homology or other factors. Indeed, this became the principle behind alignment-based methods that assessed similarity by degree of DNA-DNA reassociation in vitro. These are now seen as less sensitive than alignment-free methods that are closely consistent, both theoretically and mechanistically, with chromosomal anti-recombination models for the initiation of divergence into new species. The analytical power of k-mer differences supports the theses that evolutionary advance sometimes serves the needs of nucleic acids (genomes) rather than proteins (genes), and that such differences have often played a role in early speciation events.

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arXiv2019

When acting as a reproductive barrier for sympatric speciation, hybrid sterility can only be primary

In many animals parental gametes unite to form a zygote that develops into an adult with gonads that, in turn, produce gametes. Interruption of this germinal cycle by prezygotic or postzygotic reproductive barriers can result in two independent cycles, each with the potential to evolve into a new species. When the speciation process is complete, members of each species are fully reproductively isolated from those of the other. During speciation a primary barrier may be supported and eventually superceded by a later appearing secondary barrier. For those holding certain cases of prezygotic isolation to be primary (e.g. elephant cannot copulate with mouse), the onus is to show that they had not been preceded over evolutionary time by periods of postzygotic hybrid inviability (genically determined) or sterility (genically or chromosomally determined). Likewise, the onus is upon those holding cases of hybrid inviability to be primary (e.g. Dobzhansky-Muller epistatic incompatibilities), to show that they had not been preceded by periods, however brief, of hybrid sterility. The latter, when acting as a sympatric barrier causing reproductive isolation, can only be primary. In many cases, hybrid sterility may result from incompatibilities between parental chromosomes that attempt to pair during meiosis in the gonad of their offspring (Winge-Crowther-Bateson incompatibilities). While WCB incompatibilities have long been observed on a microscopic scale, there is growing evidence for a role of dispersed finer DNA sequence differences.

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arXiv2018

Confirmation that T cell receptor activation is digital, not analog. Hence individual T cell cytolytic capacity is independent of initial stimulation strength

Whether a sub-optimum lymphocyte stimulus is achieved by lowering ligand concentration, or decreasing its affinity, initial TCR activation responses are likely to be digital. We now know for cultured peripheral blood mononuclear cells (PBMCs), when activated by plant lectins such as concanavalin-A (Con-A), that the responding cells are T cells, and that early transcriptional and metabolic changes closely resemble those found with T cells responding to specific peptides complexed to MHC proteins (pMHC). Robbins long ago showed that lectin-activated PBMC responses were digital. This has now been confirmed for pMHC-activated T cells. Hence, in general, responses of individual T cells are independent of initial signal strength.

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arXiv2018

Shift in Nomenclature not Thesis: Innate Immune Memory, Pathogen Dose and Opsonins

Recent writings on "innate immune memory" or "trained immunity," and on "hormetic responses," herald reinvigoration of an important research area with early 20th century roots. However, it is questionable that the thesis of a "major importance of the sensed dose of pathogen for the development of innate immune system-mediated responses," should be labelled a "paradigm shift." The works of Almroth Wright (1861-1947) should be taken into account.

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arXiv2016

Speciation: Goldschmidt's Heresy, Once Supported by Gould and Dawkins, is Again Reinstated

The view that the initiation of branching into two sympatric species may not require natural selection emerged in Victorian times (Fleeming Jenkin, George Romanes, William Bateson). In the 1980s paleontologist Steven Jay Gould gave a theoretical underpinning of this non-genic "chromosomal" view, thus reinstating Richard Goldschmidt's "heresy" of the 1930s. From modelling studies with computer-generated "biomorphs," zoologist Richard Dawkins also affirmed Goldschmidt, proclaiming the "evolution of evolvability." However, in the 1990s, while Gould and Dawkins were recanting, bioinformatic, biochemical and cytological studies were providing a deeper underpinning. In 2001 this came under attack from leaders in the field who favored Dawkins' genic emphasis. Now, with growing evidence from multiple sources, we can reinstate again Goldschmidt's view and clarify its nineteenth century roots.

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arXiv2016

Elusive preferred hosts or nucleic acid level selection? A commentary on: Evolutionary interpretations of mycobacteriophage biodiversity and host-range through the analysis of codon usage bias (Esposito et al. 2016)

While confirming the long held view that viruses do not closely imitate the use of their host's codon catalogue, Esposito and coworkers nevertheless consider it surprising that, despite having the ability to infect the same host, many mycobacteriophages share little or no genetic similarity (i.e. similarity in their GC contents and codon utilization patterns). Arguing correctly that efficient translation of a phage's proteins within a host is likely to be optimized by the phage's ability to match the host's codon usage pattern, it is concluded that the preferred host of many mycobacteriophages is not Mycobacterium smegmatis, despite their having been isolated on that organism. Thus, a virus and its elusive preferred hosts would have had similar GC percentages and codon usages, but the same virus could still infect a less-preferred host (Mycobacterium smegmatis), where the virus-host similarity would be less evident. However, there is another evolutionary interpretation.

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arXiv2014

'A Vehicle of Symbols and Nothing More.' George Romanes, Theory of Mind, Information, and Samuel Butler

Today's 'theory of mind' (ToM) concept is rooted in the distinction of nineteenth century philosopher William Clifford between 'objects' that can be directly perceived, and 'ejects,' such as the mind of another person, which are inferred from one's subjective knowledge of one's own mind. A founder, with Charles Darwin, of the discipline of comparative psychology, George Romanes considered the minds of animals as ejects, an idea that could be generalized to 'society as eject' and, ultimately, 'the world as an eject' - mind in the universe. Yet, Romanes and Clifford only vaguely connected mind with the abstraction we call 'information,' which needs 'a vehicle of symbols' - a material transporting medium. However, Samuel Butler was able to address, in informational terms depleted of theological trappings, both organic evolution and mind in the universe. This view harmonizes with insights arising from modern DNA research, the relative immortality of 'selfish' genes, and some startling recent developments in brain research.

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arXiv2014

Lymphocyte repertoire selection and intracellular self/not-self discrimination: historical overview

Immunological self/not-self discrimination is conventionally seen as an extracellular event, involving interactions been receptors on T cells pre-educated to discriminate, and peptides bound to major histocompatibility complex proteins (pMHCs). Mechanisms by which not-self peptides might first be sorted intracellularly to distinguish them from the vast excess of self-peptides have long been called for. Recent demonstrations of endogenous peptide-specific clustering of pMHCs on membrane rafts are indicative of intracellular enrichment before surface display. The clustering could follow the specific aggregation of a foreign protein that exceeded its solubility limit in the crowded intracellular environment. Predominantly entropy-driven, this homoaggregation would co-localize identical peptides, so facilitating their collective presentation. Concentrations of self-proteins are fine-tuned over evolutionary time to avoid this. Disparate observations, such as pyrexia, and female susceptibility to autoimmune disease, can be explained in terms of the need to cosegregate cognate pMHC complexes internally prior to extracellular display.

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arXiv2013

Long-Term Memory: Scaling of Information to Brain Size

The material bases of information - paper, computer discs - usually scale with information quantity. Large quantities of information usually require large material bases. Conventional wisdom has it that human long-term memory locates within brain tissue, and so might be expected to scale with brain size which, in turn, depends on cranial capacity. Large memories, as in savants, should always require large heads. Small heads should always scale with small memories. While it was previously concluded that neither of these predictions was invariably true, the evidence was weak. Brain size also depends on ventricle size, which can remain large in some survivors of childhood hydrocephaly, occupying 95% of cranial volume. Yet some of these have normal or advanced intelligence, indicating little impairment of long-term memory. This paradox challenges the scaling hypothesis. Perhaps we should be looking further afield?

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arXiv2013

Role of HIV RNA structure in recombination and speciation: romping in purine A, keeps HTLV away

Extreme enrichment of the human immunodeficiency virus (HIV-1) RNA genome for the purine A parallels the mild purine-loading of the RNAs of most organisms. This should militate against loop-loop "kissing" interactions between the structured viral genome and structured host RNAs, which can generate segments of double-stranded RNA sufficient to trigger intracellular alarms. However, human T cell leukaemia virus (HTLV-1), with the potential to invade the same host cell, shows extreme enrichment for the pyrimidine C. Assuming the low GC% HIV and the high GC% HTLV-1 to share a common ancestor, it was postulated that differences in GC% arose to prevent homologous recombination between these emerging lentiviral species. Sympatrically isolated by this intracellular reproductive barrier, prototypic HIV-1 seized the AU-rich (low GC%) high ground (thus committing to purine A rather than purine G). Prototypic HTLV-1 forwent this advantage and evolved an independent evolutionary strategy. Evidence supporting this hypothesis since its elaboration in the 1990s is growing. The conflict between the needs to encode accurately both a protein, and nucleic acid structure, is often resolved in favour of the nucleic acid because, apart from regulatory roles, structure is critical for recombination. However, above a sequence difference threshold, structure (and hence recombination) is impaired. New species can then arise.

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