A new look at an old virus: patterns of mutation accumulation in the human H1N1 influenza virus since 1918

BACKGROUND: The H1N1 influenza A virus has been circulating in the human population for over 95 years, first manifesting itself in the pandemic of 1917–1918. Initial mortality was extremely high, but dropped exponentially over time. Influenza viruses have high mutation rates, and H1N1 has undergone significant genetic changes since 1918. The exact nature of H1N1 mutation accumulation over time has not been fully explored. METHODS: We have made a comprehensive historical analysis of mutational changes within H1N1 by examining over 4100 fully-sequenced H1N1 genomes. This has allowed us to examine the genetic changes arising within H1N1 from 1918 to the present. RESULTS: We document multiple extinction events, including the previously known extinction of the human H1N1 lineage in the 1950s, and an apparent second extinction of the human H1N1 lineage in 2009. These extinctions appear to be due to a continuous accumulation of mutations. At the time of its disappearance in 2009, the human H1N1 lineage had accumulated over 1400 point mutations (more than 10% of the genome), including approximately 330 non-synonymous changes (7.4% of all codons). The accumulation of both point mutations and non-synonymous amino acid changes occurred at constant rates (μ = 14.4 and 2.4 new mutations/year, respectively), and mutations accumulated uniformly across the entire influenza genome. We observed a continuous erosion over time of codon-specificity in H1N1, including a shift away from host (human, swine, and bird [duck]) codon preference patterns. CONCLUSIONS: While there have been numerous adaptations within the H1N1 genome, most of the genetic changes we document here appear to be non-adaptive, and much of the change appears to be degenerative. We suggest H1N1 has been undergoing natural genetic attenuation, and that significant attenuation may even occur during a single pandemic. This process may play a role in natural pandemic cessation and has apparently contributed to the exponential decline in mortality rates over time, as seen in all major human influenza strains. These findings may be relevant to the development of strategies for managing influenza pandemics and strain evolution

Using Numerical Simulation to Better Understand Fixation Rates, and Establishment of a New Principle: Haldane’s Ratchet

In 1957, Haldane first described a fundamental problem with evolutionary theory. This problem eventually became widely known as “Haldane’s Dilemma”. The essence of this problem is that even given a steady supply of beneficial mutations plus deep time, the rate that such mutations reach fixation is too slow to achieve meaningful evolution. After more than 50 years, this fundamental problem remains unresolved. ReMine has gone far beyond Haldane’s original mathematical analysis, and has developed “cost theory analysis” which strongly supports Haldane’s thesis. Here we examine this long-standing problem using an entirely different approach. We employ advanced numerical simulation of the mutation/selection process to empirically measure the fixation rates of beneficial, neutral, and deleterious mutations. We do this employing both realistic and optimized population parameters. In our numerical simulations, each new mutation is tracked through time until it is either lost due to drift or becomes fixed in the population. We first confirm that our numerical simulations correctly tallying the fixation of neutral mutations. We show that neutral mutations go to fixation just as predicted by conventional theory (i.e., over deep time the fixation rate approached the gametic mutation rate). We also show that the reason the vast majority of neutral mutant alleles fail to go to fixation, is because they lost due to drift, and this rate of loss rapidly approached 100% as population size is increased. We then show that given realistic distributions of mutation fitness affects, the vast majority of all mutations (including deleterious and beneficial mutations), are similarly lost due to random drift. In terms of fixations, deleterious mutations went to fixation only slightly slower, while beneficial mutations went to fixation only slightly faster, than neutral mutations. We then perform large-scale experiments to examine the feasibility of the ape-to-man scenario over a six million year period. We analyze neutral and beneficial fixations separately (realistic Proceedings of the Seventh International Conference on Creationism. Pittsburgh, PA: Creation Science Fellowship rates of deleterious mutations could not be studied in deep time due to extinction). Using realistic parameter settings we only observe a few hundred selection-induced beneficial fixations after 300,000 generations (6 million years). Even when using highly optimal parameter settings (i.e., favorable for fixation of beneficials), we only see a few thousand selection-induced fixations. This is significant because the ape-to-man scenario requires tens of millions of selective nucleotide substitutions in the human lineage. Our empirically-determined rates of beneficial fixation are in general agreement with the fixation rate estimates derived by Haldane and ReMine using their mathematical analyses. We have therefore independently demonstrated that the findings of Haldane and ReMine are for the most part correct, and that the fundamental evolutionary problem historically known as “Haldane’s Dilemma” is very real. Previous analyses have focused exclusively on beneficial mutations. When deleterious mutations were included in our simulations, using a realistic ratio of beneficial to deleterious mutation rate, deleterious fixations vastly outnumbered beneficial fixations. Because of this, the net effect of mutation fixation should clearly create a ratchet-type mechanism which should cause continuous loss of information and decline in the size of the functional genome. We name this phenomenon “Haldane’s Ratchet”

An Overview of the Independent Histories of the Human Y Chromosome and the Human Mitochondrial chromosome

Our paper will report an analysis of the history of the human Y chromosome. Thousands of full-length Y chromosome sequences from multiple world populations have recently become available for the first time. This data gives us an unprecedented opportunity to look backwards into human history. The Y chromosome is ideal for such analysis because it combines direct paternal inheritance with no recombination along most of its length. Any newly arising mutation that first appears in any male child will be directly inherited by every descendant of that male. This means that every branch on a phylogenetic tree of the Y chromosome reveals a historical individual, who lived at a specific time, and who is the founder (patriarch) of a unique lineage. We use a technique called ancestral reconstruction to calculate the sequences of the major haplogroup and macrohaplogroup founders. We then compare the Y chromosome sequence of each founder to their descendants, and also to the other founders. We report three basic findings. First, we report the sequence of each founder patriarch. We will show that three of the earliest patriarchs were very closely related. It is clear that most human male lineages trace back to just a few men who were separated by a surprisingly few number of mutations. This is remarkably consistent with the biblical account of how all males were derived from three brothers (Shem, Ham, and Japheth). Second, we report that different lineages appear to have mutated at a different rates, suggesting that the molecular clock is not reliable. This directly contradicts one of the major assumptions behind the out-of-Africa hypothesis. Third, we approximate the sequence of the common ancestor of the three primary patriarchs. It is possible this common ancestor is the Biblical Noah, sitting at the center of our Y chromosome phylogenetic tree. The sequence of this person, in turn, may represent a reasonable approximation of Adam’s Y chromosomal sequence. Lastly, we will attempt to put a time interval between Noah/Adam and his living descendants using published y-chromosome mutation rates, while allowing for divergent mutation rates among various lineages

Adam and Eve, Designed Diversity, and Allele Frequencies

Theistic evolutionists present multiple genetic arguments against a literal Adam and Eve. One key argument asserts it would be impossible for a single human couple to give rise to the genetic diversity seen in the modern human population. This implicitly assumes Adam and Eve would have been created without internal genetic diversity. If this were true, all observed variations would have to arise recently via random mutations. This would require incredibly high mutation rates, logically leading to rapid extinction. Yet, Adam and Eve could have been created massively heterozygous. We have argued for over a decade that they could have been created with “designed diversity”. We have previously shown that a vast amount of genetic variation could have been pre-programmed into their genomes. This could logically provide the genetic basis for: 1) our human gifts and talents; 2) the many forms of human beauty; and 3) the various ways people have rapidly adapted to new habitats. It is also claimed that the currently observed human allele frequency patterns could not arise from a single couple. The logic here is that, since there were only four sets of chromosomes in Eden, all variants would have had an initial frequency of either 25%, 50%, or 75%. Today, most allelic variants have frequencies in the range of 0–10%. Therefore, it is claimed that observed human diversity disproves a literal Adam and Eve. In this paper we have critically examined these arguments. Our analyses highlight several genetic mechanisms that can help reconcile a literal Adam and Eve with the human allele frequency distributions seen today. We use numerical simulation to show that two people, if they contain designed alleles, can in fact give rise to allele frequency distributions of the very same type as are now seen in modern man. We cannot know how God created Adam and Eve, nor exactly how Adam and Eve gave rise to the current human population. However, the genetic argument that there is no way that a literal Adam and Eve could have given rise to the observed human allele frequencies is clearly over-reaching and appears to be theologically reckless. There is no compelling reason to reject Adam and Eve based on modern allele frequencies

The use of kainic acid for studying the origins of scalp-recorded auditory brainstem responses in the guinea pig

Kainic acid was injected into the medial nucleus of the trapezoid body (MNTB) of guinea pigs to evaluate its use in studying generator loci of the scalp-recorded auditory brain stem response (ABR). Sound-evoked near-field potentials from the MNTB and far-field ABRs were recorded before, during and up to 2 h after the injections. Two hours post-injection, small amounts of kainic acid (0.25 nmol in 0.1 [mu]l of Ringer solution) resulted in neuronal destruction which histologically appeared confined to the MNTB. Larger amounts (10 nmol in 1.0 [mu]l) produced more extensive lesions. Regardless of the dose of kainic acid, near-field activity evoked by contralateral ear stimulation was almost totally abolished and ABR wave III amplitude was reduced by as much as 60%. In future studies, the use of excitotoxic amino acids to produce lesions within complex nuclear subdivisions of the auditory pathway may yield valuable information as to the relative contributions that brainstem structures make to the various waves comprising the ABR and about the behavioral effects that axon sparing lesions produce.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24227/1/0000487.pd

Effects of phyto-oestrogens on tissues

Recent investigations on the effects of phyto-oestrogens on various tissues have revealed that these diverse molecules may improve human health, particularly by protecting against certain chronic diseases. After a brief examination of the food sources, structures, and general cellular actions of the major phyto-oestrogens, current research findings on cardiovascular disease, skeletal tissues, and reproductive cancers are reviewed. Phyto-oestrogen concentrations in blood may be maintained at high levels in those consuming soyabean (Glycine max)-based food daily at several meals and exert their effects on target cells through either genomic effects via the classical oestrogen receptors or non-genomic effects mediated by membrane-bound oestrogen receptors or other cellular proteins. The expression of oestrogen receptor (OR) subtypes alpha (a) and beta (beta) varies across tissues, and cells that preferentially express OR-beta, which may include bone cells, are more likely to respond to phyto-oestrogens. Conversely, reproductive tissues contain relatively more OR-a and may, thus, be differently affected by phyto-oestrogens. Soyabean phyto-oestrogens appear to prevent the progression of atherosclerosis through multiple interactions, including lowering of plasma lipids and lipoproteins, increased vasodilatation and, possibly, decreased activation of blood platelets and vascular smooth muscle cells. However, a favourable impact on cardiovascular disease morbidity and mortality by a soyabean-enriched western-type diet remains to be shown, and unresolved questions remain regarding dose and form of the phyto-oestrogens in relation to risks and benefits. The isoflavones of soyabean have been shown consistently to have bone-retentive effects in animal studies by several investigators using rodent models, although intakes must be above a relatively high threshold level for a lengthy period of time, and little or no extra benefit is observed with intakes above this threshold level. The reports of modest or no effects on prevention of bone loss in human and non-human primate studies respectively, may be due to the limited doses tested so far. The relationship between soyabean-food intake and cancer risk has been more extensively investigated than for any other disease, but with less certainty about the benefits of long-term consumption of phyto-oestrogen-containing foods on prevention of cancer. The observations that breast and prostate cancer rates are lower in Asian countries, where soyabean foods are consumed at high levels, and the high isoflavone content of soyabeans have led to examination of the potential protective effects of phyto-oestrogens. Establishing diet-cancer relationships has proved difficult, in part because of the conflicting data from various studies of effects of soyabean-diets on cancer. Epidemiological evidence, though not impressive, does suggest that soyabean intake reduces breast cancer risk. The isoflavone genistein has a potent effect on breast cancer cells in vitro, and early exposure of animals to genistein has been effective in reducing later development of mammary cancer. Thus, continuous consumption of soyabean foods in early life and adulthood may help explain the low breast cancer mortality rates in Asian countries. Although the evidence for a protective effect against prostate cancer may be slightly more supportive, more research is needed before any firm conclusions can be made about the phyto-oestrogen-cancer linkages

Potassium-induced release of endogenous glutamate and two as yet unidentified substances from the lateral line of Xenopus laevis

The release of endogenous glutamate and other primary amines from the lateral line of Xenopus laevis was studied using an in vitro superfusion technique and high performance liquid chromatography. Potassium stimulation (50 mM KCl) applied to 60 or 120 lateral-line organs dissected from the skin and pooled in a perfusion chamber induced the release of glutamate and aspartate. The release of aspartate was smaller than that of glutamate and more variable. A variable release of two, as yet, unidentified substances was also detected. In low calcium (0.1 mM CaCl2), high magnesium (10 mM MgCl2) solution, 50 mM potassium failed to induce an increase in glutamate, aspartate and the two unknowns, suggesting they are released in a transmitter-like manner. The technique presents a new and simple method for studying transmitters in hair-cell systems. Although other interpretations are possible, the results are consistent with the hypothesis that glutamate is a hair-cell transmitter and suggest a potential role for other substances in the transduction process, perhaps as neuromodulators.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27844/1/0000254.pd

Aeronautic Instruments. Section IV : Direction Instruments

Part one points out the adequacy of a consideration of the steady state gyroscopic motion as a basis for the discussion of displacements of the gyroscope mounted on an airplane, and develops a simple theory on this basis. Principal types of gyroscopic inclinometers are described and requirements stated. Part two describes a new type of stabilizing gyro mounted on top of a spindle by means of a universal joint, the spindle being kept in a vertical position by supporting it as a pendulum of which the bob is the driving motor. Methods of tests and the difficulties in designing a satisfactory and reliable compass for aircraft use in considered in part three. Part four contains a brief general treatment of the important features of construction of aircraft compasses and description of the principal types used

Improvement of Segmental Lordosis in Transforaminal Lumbar Interbody Fusion: A Comparison of Two Techniques

Study Design Retrospective review. Objective The purpose of this study was to determine the radiographic impact of a transforaminal lumbar interbody fusion (TLIF) versus a cantilever TLIF technique on segmental lordosis, segmental coronal alignment, and disk height. Methods A retrospective review was done of all patients undergoing TLIF procedures from 2006 to 2011 by three spine surgeons. Traditional TLIF versus cantilever TLIF results were compared, and radiographic outcomes were assessed. Results One hundred one patients were included in the study. Patients undergoing the cantilever TLIF procedure had a significantly greater change in segmental lordosis and disk height compared with those who underwent the traditional procedure (p \u3e 0.0001). Conclusions The cantilever TLIF technique can lead to greater change in segmental lordosis based upon radiographic outcomes