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Guest post by Jon Allen, Chief Compliance Officer, Bank of American Fork
The goal of financial management in a company is to maximize the value of the company's stock. Managers need ways to determine whether a project being considered will add value to their companies. This is the second in a series of three articles that discuss methods for evaluating the financial benefits of projects. The first article discussed the payback approach and noted several serious shortcomings of that method, although for quick analysis of small-dollar projects it still makes sense to use. A far-better method for larger projects is the net-present-value approach.
Net present value ("NPV") is the present value of the cash inflows of a project less (net of) the required cash outlay. An important concept in finance is that the value of money is affected by when it is received. The opportunity to do something productive with a dollar today that cannot be done without it today has value. All other things being equal, projects that generate cash earlier have more value than projects that generate the same amount of cash but later.
The process of adjusting future cash flows to a value that is relevant in the present is called "discounting" and requires the use of an interest rate. In determining the appropriate rate, companies should consider the risks of the project, the degree of confidence they have in its cash-flow projections, and what could be earned in alternative projects. Greater risk and uncertainty in financial projections warrant higher discount rates. Lower risk and more-reliable projections warrant lower discount rates. The higher the discount rate, the more cash flow a project has to generate in order for it to be accepted. In normal economic times discount rates are typically between 8% and 14%. However, in times of ultra-low interest rates, a range of 5% to 10% might be more appropriate.
Because NPV adjusts for the time value of future cash flows, it overcomes the major drawback of the payback approach and gives the appropriate weight, assuming a given discount rate, for all of a project's cash flows regardless of when they are expected to occur, and compares them to the initial cash outlay. If the discounted cash inflows exceed the initial cash outlay, then the project will have a positive NPV and should be accepted. If they are less than the initial cash outlay, then the project will have a negative NPV and should be rejected because it is not expected to earn enough, after adjusting for the time value of money, to justify the initial cost.
Consider the same example we used in the previous article: Acme, Inc. is considering buying a new machine. The initial cost of that machine is $1 million. The machine has an expected life of five years and is expected to generate cash flows, net of all expenses, of $250,000 per year for each of those years. This time assume that Acme uses the NPV approach rather than the payback approach to analyze new projects and has determined that it will only accept projects that have positive NPVs.
In Table 1, let's assume that because Acme has a high degree of confidence in the projections and believes this project has little risk, it uses a discount rate of 5%. The NPV turns out to be $82,369, meaning that the expected future cash inflows of the project, discounted to the present by a rate of 5% and added together, exceed the initial investment of $1 million by $82,369, and therefore the project should be accepted.
Table 1
Time (Years) | 0 | 1 | 2 | 3 | 4 | 5 |
Initial Cost | -$1,000,000 | |||||
Cash Flows | $250,000 | $250,000 | $250,000 | $250,000 | $250,000 | |
DiscountedCash Flows at 5% | -$1,000,000 | $238,095 | $226,757 | $215,959 | $205,676 | $195,882 |
Net Present Value(Sum of Discounted Cash Flows) | $82,369 |
Now let's assume that Acme is not so confident in its projections and believes that because of risk, the appropriate discount rate for the project should be 10%. Table 2 uses the same expected cash flows as in Table 1 but changes the discount rate to 10%. In this case the expected cash flows are discounted to a greater degree and are not enough to make up for the initial project cost. Therefore the NPV is negative and the project should be rejected.
Table 2
Time (Years) | 0 | 1 | 2 | 3 | 4 | 5 |
Initial Cost | -$1,000,000 | |||||
Cash Flows | $250,000 | $250,000 | $250,000 | $250,000 | $250,000 | |
DiscountedCash Flows at 10% | -$1,000,000 | $227,273 | $206,612 | $187,829 | $170,753 | $155,230 |
Net Present Value (Sum of Discounted Cash Flows) | -$52,303 |
Obviously the selection of a discount rate can make a big difference in the NPV of a project. If you recall from the first article, this same project reached "positive payback" at 4 years and Acme chose to accept it based on the payback approach. Table 2 shows that for a discount rate of 10%, that was the wrong decision.
The NPV approach has no significant flaws and is the preferred method for evaluating projects because it considers risk and the time value of money, and has no arbitrary cutoff.
In our next issue we will discuss internal rate of return as a way to determine whether a project adds value to a company, and if so, how much.
Jon Allen (B.S. Brigham Young University, J.D. University of Idaho), teaches Introduction to Corporate Finance as an adjunct at Utah Valley University's Woodbury School of Business. Before becoming Bank of American Fork's Chief Compliance Officer, he was a commercial loan officer at Capital Community Bank. He volunteers on the Business Incubator Board of the Commission for Economic Development in Orem.


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subset: commoncrawl


text:
Hopkins post team-high 23 points; Clark collects 1,000th career point for Vikings
FITCHBURG, Mass. (February 12, 2011) – Junior Brian Clark (Deerfield, Mass./Frontier Regional) registered 12 points and five rebounds as the Salem State men's basketball team slipped past Fitchburg State, 73-70 in MASCAC action this afternoon.
With this 12 point effort, Clark eclipsed the 1,000 career point plateau as the veteran forward was only three points shy of the milestone entering the contest. Viking sophomore Tavone Wynder (Boston, Mass./Newton South) sparked all scorers, totaling a game-high 26 points on 6-of-11 shooting from downtown , while sophomore Dan Clark (Deerfield, Mass./Frontier Regional) added eight points and five boards on the afternoon.
Senior Robert Hopkins (East Hartford, Conn./RHAM) led all Fitchburg State scorers, shooting 8-of-17 from the field for 23 points and seven boards, while senior Elliot Knower (Baldwinville, Mass./Narragansett) added 17 points with 9-of-14 shooting from the charity stripe. Junior Jeremy Kimber (Fitchburg, Mass./Fitchburg) finished with 19 points and seven caroms to round out the Falcon offense.
Salem State opened the contest strong, posting a 21-7 advantage midway through the first period, but Fitchburg State rallied back, holding Salem State to only one basket over the final five minutes of the frame. Kimber sparked the Falcons rally with an conventional three pointer with under a minute remaining, while Hopkins drained a trey to bring the Falcons within three (28-25). The Vikings got on the board late with a lay-up by Bennett, but Fitchburg State converted a free-throw down the stretch to trail only by four (30-26) at the end of the period.
In the second period, Fitchburg State came out soaring, grabbing its first lead of the contest, 31-30 with a three by Hopkins, but Salem State answered the Falcon rally, posting a 13-6 run over the next five minutes for a six point advantage.
The Falcons clawed back into contest, cutting the Viking lead to only one on several occasions, but Salem State notched a 12-0 run capped by back-to-back threes from Wynder to extend its lead to 11. In the final minutes of the match, Fitchburg State strung together a last minute rally with a pair of threes by Hopkins and a tip in by Kimber, but the Falcons effort ran dry as time expired on their final three-point attempt.
Fitchburg State (4-17, 1-9 MASCAC) will be in action again on Tuesday as it hosts MCLA at 7:30 p.m. Salem State (15-6, 9-1 MASCAC) will host Wheelock College tomorrow at 1 p.m.
Salem State 73, Fitchburg State 70
Team |
1 |
2 |
Salem State (15-6, 9-1 MASCAC) |
30 |
43 |
73 |
Fitchburg State (4-17, 1-9 MASCAC) |
26 |
44 |
70 |


text:
Interjurisdictional Competition and Public-Sector Prodigality: The Triumph of the Market over the State?
It has been argued in the literature that interjurisdictional competition forces the public sector to increase its efficiency and thus helps to tame Leviathan governments. The paper addresses this hypothesis by means of a simple tax-competition model with a Leviathan state. It is seen that the effects that increased factor mobility has on the wastefulness of the public sector are ambiguous. A calibration of the model shows that the share of public funds wasted by the public sector may increase for parameter constellations which are not unrealistic.
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Volume (Year): 57 (2000)
Issue (Month): 1 (September)
Pages: 1-89
Handle: | RePEc:mhr:finarc:urn:sici:0015-2218(200009)57:1_89:icappt_2.0.tx_2-5 |
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A new look at an old virus: patterns of mutation accumulation in the human H1N1 influenza virus since 1918
- Robert W Carter1 and
- John C Sanford2Email author
© Carter and Sanford; licensee BioMed Central Ltd. 2012
Received: 6 July 2012
Accepted: 4 October 2012
Published: 12 October 2012
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.
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.
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.
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.
Influenza H1N1 Swine flu Mutation accumulation Pandemic Evolution Error catastropheBackground
At the close of World War I, the H1N1 influenza A virus swept the world[1]. During the 1917–1918 pandemic, approximately 40% of the human population was infected, with a death rate above 2%. It is estimated that this virus killed more people than died in the world war that was just then ending. Mortality rates have dramatically declined since then[2], but the H1N1 flu has persisted. As a zoonotic pathogen, the influenza virus is able to infect multiple species. It is generally thought that aquatic waterfowl are a primary natural influenza reservoir[3], where there are usually no clinical symptoms[4], and where low level transmission probably perpetuates the viral pool[5]. All 14 influenza subtypes are maintained in waterfowl[5].
H1N1 has had an interesting history. Derivatives of the original virus circulated in humans and swine until 1957, when the human strain went extinct. In 1977, a version identical to those circulating in NE Europe in the early 1950s reappeared in Anshan, China and subsequently spread across the world[5–7]. In 2009, a swine H1N1 jumped to the human population, causing a widespread pandemic. This has increased concern that H1N1 might mutate into a more virulent form. However, since the pandemic of 1917, this has not happened. In fact, H1N1-related human mortality has declined very dramatically and very systematically[2]. Apart from the 1917 pandemic, H1N1 has failed to cause any severe global pandemic, and human H1N1 essentially went extinct from 1957–1977. Since its re-introduction, it has remained a relatively minor cause of influenza mortality[2]. This applies also to the 2009 outbreak, which caused relatively few deaths in those areas with good reporting systems in place[8].
It is therefore reasonable to ask if the striking reduction in H1N1 mortality might be due, in part, to natural attenuation resulting from deleterious mutation accumulation. Herd immunity is undoubtedly an important factor in reduced H1N1 mortality since 1918, but this may not be sufficient to explain the continuous decline in H1N1-related mortality over multiple human generations or the eventual extinction of the viral strain. Likewise, improved medical treatments, such as antibiotic treatment for flu-related pneumonia, were certainly a significant factor reducing H1N1 mortality, but these do not appear to fully explain the nature of the pattern of mortality decline seen for H1N1. For example, the exponential decline in mortality began before the invention of antibiotic treatment.
The literature suggests RNA viruses should be inherently subject to mutational degeneration[9–13]. This includes the bacteriophage MS2[14], the tobacco etch virus[15], HIV[16–19], dengue virus type-2[20], Ebola[21, 22], and SARS[23, 24]. Some have suggested that intentionally increasing the rate of mutation accumulation ("lethal mutagenesis") may be a way to control viral epidemics by hastening strain extinction[25–30]. There is some long-term historical evidence that supports the concept of natural viral attenuation through mutation accumulation[2], and theoretical studies using numerical simulation strongly support the concept of natural and accelerated genetic attenuation of RNA viruses[13].
Protein products of a consensus H1N1 influenza genome
Segment | Length* | Protein | ORF+ | Amino Acids* |
Previous genetic studies examining the history of the influenza virus have performed extensive phylogenetic analyses of influenza genomes[8, 31–35]. They have shown considerable nucleotide diversity among circulating strains, given clear evidence for adaptive selection of antigenic variants[36–42], and have shown that most of the major innovations within the flu genome have occurred via reassortment[5], by which one flu strain has recombined with another strain and obtained a segment of RNA from the second strain.
Influenza phylogenies are odd, in some respects, consisting of one main trunk with many short and short-lived side branches[36, 39, 42, 43]. There are several factors that influence strain diversity, including the mutation rate, selection, drift, and cross-immunity-mediated competition between strains[39]. Feguson, et al.[39] felt that strain-transcending immunity was essential in restricting viral diversity. Ito, et al.[42] thought that the many side branches died out because they could not compete with the main-trunk lineage viruses. Others have noted the temporal extinction of circulating strains upon the introduction of new strains or serotypes[5]. Whatever the reason, a hierarchy of strain robustness is evident in the history of influenza viruses.
While phylogenetic studies can build robust family trees, they do so by focusing only on a limited number of "informative" genomic locations[44]. Even though the influenza genome is broken into eight separate RNAs, unless an individual is infected with two strains simultaneously (providing an opportunity for reassortment), all eight sections are inherited as a set in a form of linkage[36]. Thus, neutral and slightly deleterious mutations are carried along with those mutations under positive or purifying selection. This gives us enough information to make many phylogenetic inferences, and we have a wealth of data telling us the history of the various viral lines, but these phylogenetic techniques ignore genetic change within a larger portion of the genome in order to focus on the phylogenetically-informative sites.
There is abundant evidence for multiple substitutions in specific places that are, in turn, sites of active selection[42], but what about the rest of the genome? Fitch, et al.[36] noted that the main strategy of influenza viruses was to outrun the immune system of the host by maintaining a high mutation rate. They wondered "why such a virus does not accumulate so many deleterious mutations as to die of its own ineptitude." They further wondered if the only reason influenza viruses continued to circulate in mammalian species was because of a sort of "gene therapy" through reassortment with stronger, less mutated avian viruses.
The present study is an attempt to elucidate more fully the nature of mutational change in this historically important human pathogen.
Accession numbers for all available complete flu genomes were obtained from the Influenza Research Database[45] as of June 1, 2012. This list was then compared to those available at FluGenome.org[46]. To create a list of the 2009–2010 H1N1 outbreak versions, we used the collated genome list from Kedwaii, et al.[8]. Using these two accession lists, sequence data were obtained from GenBank[47]. We removed non-human/swine, non-H1N1, and incomplete genomes from this list, obtaining 3,755 human and 351 swine genomes. Because there are few indels in these flu genomes, a simple first-pass alignment algorithm, written in Perl with the BioPerl toolkit[48], was used. Essentially, we visually picked out a 6-10-nucleotide candidate region close to the beginning of each of the eight strands of the flu genome that appeared mostly conserved. The algorithm scanned each set of sequences for this segment and added an appropriate number of spaces to the beginning of each for a rough alignment. Using BioEdit[49], we simply looked for sequences that were misaligned and inserted gaps where necessary to complete the alignment, paying close attention to codon usage. In difficult and ambiguous regions, we chose to minimize the number of changes necessary to produce each variant, similar to the methodology of Carter[44].
Once an alignment for each of the eight sections of the flu genome was completed, we used another Perl program to scan through the alignment and compare each sequence to a reference strain. Point mutations were counted individually while indels, irrespective of size, were counted as a single change[44]. There are several different ways to calculate sequence differences (discussed in[50]), but this simple measure is sufficient for the purposes of this paper. Due to variations in technique among the various studies that produced these sequences, the ends of the alignment tended to be ragged. For this reason, we compared only the section of complete alignment between each sequence and the reference genome. The few internal reassortments[32] that have occurred in H1N1 were easily seen in the alignments, but these also made up a small fraction of all sites. We did our best to create a consistent alignment through these regions.
We began by analyzing mutation accumulation during the human H1N1 outbreak of 2009–2010, using strain California/04/2009 as a reference. This was the first sequenced genome of the outbreak included in Kedwaii, et al.[8]. We then calculated the extent of mutational divergence of all subsequent genomes over the duration of the outbreak.
We did a similar, but much larger analysis of mutation accumulation in all human H1N1 strains from 1918 to 2012, using the 1918 "Brevig Mission" reference genome (A/Brevig Mission/1/1918) as a reference. This sequence was missing the last 480 nucleotides of segment 4. We amended this by appending the ending sequence of another 1918 H1N1 virus, A/South Carolina/1/18(H1N1). These two strains had only one nucleotide difference in the ORF of segment 4 (C/T at position 238). Thus, they are essentially identical and we do not expect to have introduced extra mutations in this way.
Using the amended 1918 Brevig Mission virus as a reference and including all human and porcine viruses in the database, we calculated SNPs, indels, transitions, transversions, non-synonymous amino acid changes, dN/dS ratios, predicted protein lengths (for all 11 proteins), the normalized codon scores (NCS) and relative synonymous codon usage (RSCU)[51] score for each predicted protein of each genome. To calculate the normalized codon score, we downloaded the frequency of each of the 64 codons in the human, duck and domestic pig genomes from the Codon Usage Database[52]. We then created a predicted amino acid chain from each of the respective open reading frames. We calculated NCS for each protein by simply summing the frequency of each codon, as it is used in each of the three species, and then dividing by the total number of codons in the proteins produced. RSCU is simply the number of times any particular codon appears, divided by the number of times synonymous codons appear in that genome. Anhlan, et al.[51] were the first to apply RCSU to influenza genomic data, but they only studied one of the eleven protein products of the H1N1 genome and did not analyze changes over time. Here, we extend their techniques to create a time series in which one can better study shifts in codon usage due to mutation accumulation.
Our data clearly show that some non-frozen H1N1 genotypes occasionally appeared in the human population after H1N1 dropped from public concern after 1957 (Figure2). Nine H1N1 strains that do not belong to the "frozen" lineage arose in the human population between 1976 and the 2009 H1N1 outbreak (A/Wisconsin/301/1976, A/New Jersey/8/1976, A/California/10/1978, A/California/45/1978, A/Albany/8/1979, A/Memphis/1/1979, A/USSR/46/1979, A/Ohio/3559/1988, and A/Maryland/12/1991). These fall on the same mutation-count trajectory as the H1N1 circulating before the 1957 extinction. However, these nine strains appear to represent repeated transmission events from pigs to humans that failed to cause any pandemic (the porcine lineage had no extinction event, and hence no pause in mutation accumulation). Nearest neighbor calculations (data not shown) indicate these strains are not a continuation of the human lineage. They cluster tightly with the 2009–2010 outbreak porcine viruses, all of which are more closely related to the 1918 isolate than they are to the human lineage viruses. Thus, we included the 2009–2010 viruses and the nine isolated, non-outbreak viruses in the "porcine" category. In this same figure, we can see that genotypes from the 2009 outbreak and after (Figure2, circle) fall directly on the trajectory of the non-frozen lineage. This clearly shows that the 2009 genotype was not derived from the 1976 re-introduction virus. Kedwaii, et al.[8] affirmed earlier conclusions that the 2009 genotype was due to a reassortment between two swine viruses, an H1N2 and an H1N1, from different continents, but this did not affect the mutation accumulation curve. Regardless, general attenuation due to genome-wide mutation accumulation might best explain the very low mortality[54–56] associated with the 2009 pandemic. The earliest 2009 outbreak strain had already accumulated 1,889 mutations compared to the 1918 strain.
The most obvious place to test how reassortment might affect the mutation accumulation curve is with the 2009–2010 "swine flu" outbreak samples. Despite the fact that the viral line has been attributed to reassortment with swine viruses, with partial contribution from earlier reassortments between swine and avian strains[8], it does not display a jump in mutation count. Reassortment can produce novel antigenic variants, but it does not reverse the majority of mutations, for they have accumulated in the non-reassorted areas of the genome.
Our data show that the lineage re-introduced in 1976 was the only significant human H1N1 strain from 1976 until 2009. The mutation count trajectory of the H1N1 lineage from the 1976 re-introduction stops abruptly in 2009 and does not reappear in any of the 353 H1N1 genomes published from mid-2009 through mid-2012. Human H1N1, the remnant of the 1918 lineage, appears to have gone extinct a second time.
The data in Figure3 can be used to estimate the time of arrival into the human population of the first H1N1 virus. Extrapolating total mutation count linearly backwards to zero yields a year of first introduction into the human population of approximately 1893. Interestingly, this would be in time to explain the 1889–1890 "Russian" flu outbreak, which has been considered by some to possibly be the first H1N1 outbreak (no sequence or serotype data are available for that event). While our data strongly suggest that the ancestral genotype for all human and porcine H1N1 influenza strains (and by extension, all human influenza strains), entered the human population as early as the 1890s, others have estimated the arrival date to be one or more decades later[5]. Our data strongly confirm that all human H1N1 viruses derive from a single, very recent common ancestor, just as others have concluded prior to this study[1]. Given an estimated arrival date of 1893, we infer that, by 1918, H1N1 would have accumulated roughly 375 (25 years × 15 mutations/year) mutations since the initial genotype invaded the human population. This depends, of course, on the exact arrival date.
Within the entire human H1N1 lineage, only 56% of all nucleotide sites were invariant, indicating intense mutation pressure. Before its apparent extinction in 2009, the human H1N1 lineage had accumulated approximately 1400 mutations (mostly point mutations), including 320 non-synonymous mutations, compared to the 1918 genotype. Across all 3,755 H1N1 genomes isolated from humans (i.e., including the outbreak and non-outbreak porcine versions), we found that only 41.8% of all nucleotide sites were invariant. Multiple variant forms (i.e., 3-fold and 4-fold degeneracy, meaning 3 and sometimes 4 different nucleotides observed at a given site) occurred at 21% of the variable loci, further suggesting that the mutations were primarily non-adaptive. When we included the porcine H1N1 genotypes, only 36.1% of sites remained invariant, with a similar distribution of nucleotide degeneracy. Because the re-introduced H1N1 lineage had accumulated fewer mutations than the porcine H1N1 strains, the disappearance of the human lineage and the subsequent dominance of the 2009 porcine strain in the human population resulted in even more divergence from the 1918 stain: over 1900 nucleotide differences (approximately 15% divergence) and 325 amino acids differences (approximately 7% divergence in protein sequence).
The approximately 90-nucleotide PB1-F2 protein is coded on the second genomic segment and overlaps completely the PB1 coding region[58, 59] Table1. PB1-F2 has been implicated in increasing host death rate. Yet, not all influenza viruses code for this protein, so it is not intrinsically necessary for the cycle of infection. In the case of H1N1, the majority (98.2%) of genomes in this study are predicted to fail to produce a full-length version of the protein, including most of the human versions after 1948 and none of the porcine versions prior to 1987. For this reason, only 10 of the 11 influenza proteins were included in RSCU and NCS calculations. All genomes were predicted to produce fully-formed PB2, PB1, PA, HA, NP, NA, M1, M2, and NS1 proteins. Only 14 genomes were expected to fail to produce a functioning NS2 protein due to mutation in the start codon, but all of these had another potential in-frame ATG only a few codons upstream and/or downstream. For this reason, we assumed these viruses would also produce an NS2 protein of proper length.
We note that many mutations appeared and disappeared several times over the life of H1N1. The data are too sparse over most of the range to know if this is due to repeat mutations at common loci or incomplete genetic sampling of the circulating H1N1 viruses. However, over the 2009–2010 H1N1 outbreak, Kedwaii, et al.[8] demonstrated near-complete lineage loss among the circulating viruses during a single season. Bedford, et al.[33] had similar results in their study of influenza A (H3N2). It was noted earlier that the phylogeny appears as a main trunk with many short-lived side branches. If most mutations are lost from the population quickly, variations that appear several times over the course of H1N1 are most likely due to mutations occurring multiple times in the same place. We do not have enough sequence data to get a full picture of strain diversity in most years, but this will be interesting to pursue as more data become available.
Even though each genomic segment has a slightly different mutation/substitution rate, strong, genome-wide patterns are evident, including a declining ratio of non-synonymous to synonymous codon changes (dN/dS), a declining ratio of transition to transversion mutations (Ti/Tv), and even changes in codon bias. Additional file1 includes these data on a segment-by-segment basis.
Over the history of the human H1N1 lineage, the accumulation of non-synonymous mutations was highly linear, after correcting the "frozen" samples for 21 years of dormancy (Figure3). While it is true that this simple distance metric applied to amino acid changes would be expected to underestimate evolutionary relationships at large distances due to an increasing likelihood of multiple changes at individual loci, applying the standard Poisson or Gamma corrections[60] made no improvement to the fit of the regression to two significant figures. We therefore conclude that the relationship is indeed linear, at least over the sampled timescale.
It has generally been assumed that any non-neutral mutations within the influenza genome have arisen as selective adaptations and generally help drive influenza toward a stronger and more dangerous pathogen (in terms of either pathenogenicity or transmissibility)[41]. This was probably the basis for the extreme caution exhibited during the 2009–2010 H1N1 outbreak. There is a general perception that, given enough time, H1N1 might mutate into a stronger pathogen, and hence might create another catastrophic pandemic, as it did in 1918.
Selection is evident in H1N1 and other influenza genomes. In certain sites of the HA1 genomic segment of H3, non-synonymous substitutions occur at more than twice the rate as in other sites[39]. This is seen as a major signature of adaptive change, but deleterious mutations in the areas not under selection are carried along with the ones under positive selection[36]. In this light, some perceive H1N1 to be a growing threat, with a new outbreak being just a matter of time. Despite this common perception, a more lethal version of H1N1 has not arisen via mutation within the human population during the last 90+ years. This is significant. The two major human influenza pandemics since 1918 did not arise due to mutations within H1N1, but arose via horizontal transmission of new genetic material from bird influenza strains, creating recombinant viruses. They were also less lethal than the 1918 version. It is true that the population had a degree of residual immunity and was not as immunologically naïve as it was in 1917–18, but selection has still not been able to generate a devastating pandemic from the remnants of that which swept the world at the close of WWI.
In this paper, we examine an alternative point of view regarding mutation accumulation within H1N1. We suggest that, while specific adaptive mutations commonly occur within the H1N1 virus, many more deleterious mutations are accumulating than beneficial mutations, even when there is strong selection. Consequently, H1N1 appears to have been in very gradual error catastrophe throughout its history.
Our results strongly confirm the widely recognized fact that all past and present human and swine H1N1 influenza strains derive from the 1918 strain. By extension, this applies to other human influenza strains, including H3N2 and H2N2[1].
Human influenza has such a high mutation rate that, even within a single host individual, the virus quickly becomes a genetically diverse "swarm"[61, 62]. Yet, globally human H1N1 influenza is monophyletic and all current variation is of recent origin. This is only possible if almost all human influenza lineages rapidly go extinct. Moreover, we present strong evidence that the H1N1 genome has been systematically degenerating since 1918. This is evidenced by continuous, systematic, and rapid changes in the H1N1 genome throughout its history. For example, there was an especially rapid and monotonic accumulation of mutations during a single pandemic (Figure1). Similarly, there was a continuous and rapid accumulation of mutations over the entire history of the virus (Figures2 and3), including a similar steady increase in non-synonymous amino acid substitutions (Figure3). While mutations accumulated in the human H1N1s, there was a parallel accumulation of mutations in the porcine H1N1 lineage (Figure4). Fitch, et al.[36] also showed a linear mutation accumulation curve. The "gnarled trunk" of Ito, et al.[42] should be buried in our data as well, but it will be swamped by the pervasive, genome-wide accumulation of mutations not under active selection.
Within the human lineage, there was a systematic decline in the Ti/Tv ratio (Figure5). In addition, there was a very consistent loss of codon specificity over time (Figures6 and7). We show compelling new evidence supporting the extinction of human H1N1 in the 1950s, its subsequent re-introduction in 1976, and an apparent second extinction event of the human H1N1 lineage in 2009. Strain extinction has often occurred when new strains appeared, including H1N1 replacing the circulating H3-like strains in 1917, H2N2 replacing H1N1 in 1957, and H3N2 replacing H2N2 in 1968[5]. To our knowledge, we are the first to document the replacement of the re-introduced human H1N1 with reassorted swine H1N1 in 2009. All this is consistent with the genetic attenuation hypothesis, and we feel this is the most fundamental explanation for the very smooth, systematic, and exponential decline in H1N1 mortality rates since 1918[2].
Relevance and potential objections
In light of these findings, what are the medical implications? Does mutation accumulation really have anything to do with virulence? Simonsen, et al.[2] showed mortality statistics for three influenza strains over multiple years (H1N1 from 1918 to 1987; H2N2 from 1958 to 1962; and H3N2 from 1968 to 1995). Even though there is some debate concerning the mortality burden imposed by influenza viruses[63], there has clearly been a continuous exponential decline in influenza-related mortality over time, and this is true for all three major serotypes. Since there is a strong linear correlation between mutation count and time (Figures2 and3), and since there is also a close correlation between declining virus-related death rates and time, there is obviously also a correlation between mutation count and reduced death rates. Reduction in mortality may be due to many other factors, including herd immunity, advances in medicine, and advances in hygiene, but would these other factors be expected to follow so tightly the time courses seen in Simonsen?
There have been major medical advances since 1918, and these have clearly been a factor in reducing H1N1-related mortalities. Therefore, the correlation between mutation count and reduced H1N1 mortality might be considered spurious by some. However, while it is certainly true that medical intervention has greatly improved in the developed world since 1918, such medical intervention has been much more limited in the rest of the world. Second, the observed decline in mortality is a remarkably smooth curve, while medical advances have occurred in bursts (e.g., the breakthrough in antibiotics, and the more recent development of antivirals). Third, each of the great influenza pandemics (1918, 1956, 1968) involved the emergence of a new viral strain, which then followed its own exponential decline in mortality but within its own timeframe. This uncouples reduction in mortality and stage of medical advance. Finally, the correlation between the exponential decline of H1N1-related mortalities and the linear increase in H1N1 mutations is only one of our evidences for the genetic attenuation of H1N1. Our other evidences include: a) the extinction of all human influenza strains existing prior to the H1N1 strain; b) the apparent extinction of the human lineage of H1N1 in 1956, and then again apparently in 2009; and c) the erosion of H1N1 codon specificity, approaching random codon usage.
It is our contention that all human influenza strains undergo natural attenuation due to mutation accumulation. It is too early to tell if the remaining versions of the 2009–2010 outbreak viruses will do the same, but it is likely given the known history of change in the various influenza genomes.
The decline in codon bias is especially significant for several reasons. First, since the frequency of codon usage is positively correlated with tRNA availability in the cell[64], the increased use of rare codons is expected to negatively affect protein translation rates. Alternatively, Li, et al.[65] did not notice any decrease in translational efficiency based on codon choice in bacteria, but they did see effects caused by mutation towards other genomic control motifs (i.e., anti-Shine Dalgarno sequences). Part of codon bias deals with a cell's avoidance of controlling factors that do not directly deal with translation rates (e.g., CG dinucleotides). Thus, there are multiple ways a disruption of codon bias might negatively impact the functionality of a particular stretch of any nucleic acid. Second, even though the codon usage in ducks and humans is similar[51], although less so for swine[52], this might affect the ability of a virus to cross species lines (after cellular antigenic recognition is taken into account). Third, Anhlan, et al.[51] entertained several hypotheses, including that the virus was avian in origin but transferred to pigs before it jumped to humans. Our data clearly indicate that all H1N1s studied are more duck-like in their codon usage, although we cannot comment about a pre-human swine intermediate based on our data. Finally, since we see an obvious decay in codon bias over time when compared to codon usage in either human, duck, or pig, it is clear that H1N1 is not evolving toward optimal codon usage in any of these species but is slowing drifting away from optimal translational efficiency. We concur with Anhlan, et al. that, "the issue of codon usage seems to be much more important at least for influenza viruses than previously thought."
During the last 100 years, the H1N1 influenza genome has diverged from the original genotype by roughly 15%. Might the approximately 1,900 nucleotide substitutions be primarily attributed to the genetic drift of perfectly neutral variations? This seems unlikely for several reasons. First, a viral genome of approximately 13,000 nucleotides does not have room for very much neutral RNA. Not only did 15% of the genome change, but polymorphisms arose across more than 50% of the genome. This strongly points to extreme mutational pressure, high enough, reasonably, to threaten error catastrophe. Second, if some significant portions of the viral genome are neutral, deletions of such portions of the viral genome should be regularly seen, and selection should favor such deletions, rapidly producing smaller genomes. There is no evidence of significantly smaller influenza genomes. Indeed, there is little evidence of deletion in any of the 2009–2010 genomes compared to the 1918 version. The only major indels occurred among the oldest samples (prior to 1948) in the sixth genomic segment (neuraminidase, or NA), but all of these represented deletions compared to the 1918 genome and all later genomes. Third, it is now known that even synonymous mutations are not always neutral. Even though they may not directly affect protein sequence, they can affect RNA stability, RNA architecture, speed of translation, and protein folding. Fourth, there should only be a finite number of nucleotide positions that are perfectly neutral. Because of this, neutral divergence should quickly approach a limit, causing the rate of divergence from the original genotype to slow, but this is not seen. Finally, the extensive genetic changes observed simply do not appear to be phenotypically neutral; they are tightly correlated with rapid fitness decline, attenuation, extinction of most circulating strains, and even more frequent sub-lineage extinction events.
Might the observed divergence be primarily due to adaptive mutations? We feel that the 15% divergence must be primarily non-adaptive because adaptation should occur rapidly and then reach a natural optimum. Yet, we see that divergence increases in a remarkably linear manner. Furthermore, the virus does not seem to be converging on a new optimal genotype since polymorphism remains extreme (over 50%), since many polymorphic sites have more than two alleles, and since codon specificity is declining over time. Codon patterns can inform us about the origin of the virus, and they tell us that H1N1 is not only drifting away from that original codon use, but it is also drifting away from the host codon preferences. When grown in mouse cell culture, 2009 H1N1 viruses exhibited variation in replication rates, virulence, and pathogenicity, but these did not match the severity of clinical symptoms in humans[66]. Thus, at this time, the exact relationship between mutation load and the severity of infection remains unknown. Yet, selective adaptation is limited to only those amino acids that produce significant phenotypic effects[42], and, since a viral genome in the absence of reassortment is essentially a single linkage block, it is expected that many more than just adaptive mutations occur. Some of the changes might be due to selection, but the majority certainly are not.
Is it feasible that natural selection might fail to remove a large number of deleterious mutations? It is well known that numerous factors can cause a breakdown in the selective removal of deleterious mutations. These factors include a high mutation rate, a high rate of random loss, limited sexual recombination, genetic bottlenecking, and mutations with very small fitness effects. All of these factors should be especially pronounced in an RNA virus such as influenza and all of these are either previously known or documented here. The genetic changes in H1N1 appear non-directional and are distributed quite uniformly across the genome (Additional file3), consistent with an accumulation of low-impact deleterious mutations. Error catastrophe and lethal mutagenesis are already recognized as a threat to any RNA virus. These facts, combined with the dramatic decline in H1N1 mortality and the very high rate of H1N1 strain extinction, all very strongly indicate that most of the genetic divergence from the original H1N1 genotype has been due to fixation of slightly deleterious mutations.
Could H1N1 ever back-mutate into a strain such as the ancestral genotype that caused the catastrophic 1917–1918 pandemic? Given that the modern strains of H1N1 have diverged from the original 1918 strain by nearly 2000 mutations, that many of these mutations should be slightly deleterious[67], and that natural selection was unable to stop their continuous accumulation in the first place, it is difficult to imagine how mutation/selection might ever restore full virulence. Reassortment might bring in new material, but thus far this has only applied to a limited section of the genome, and reassortment today occurs in a very different mutational/genomic context than that of 95 years ago. It is often thought that a high mutation rate translates to rapid adaptation and evolution, yet the reverse seems more commonly true. Deleterious mutations often interfere with selection for the more rare beneficial mutations[67, 68]. Thus, the rapid accumulation of mutations in all H1N1 lineages should logically lead to their eventual extinction.
The origin of human H1N1 influenza is unknown, but it is generally reasoned that it invaded the human population from a natural reservoir[5, 51], most likely an aquatic waterfowl, with pigs as a possible intermediate host. In light of the strong tendency toward natural genetic attenuation which we document here, we suggest that the natural reservoir most likely involves a very quiescent viral state, as might occur within a host where there is very little viral replication, and hence much lower mutation rates. It would be very interesting to know the rate of influenza mutation accumulation in waterfowl.
Can reassortment explain these findings? Based on our mutation count analysis, there is no evidence for reasortment in the human H1N1 lineage, and it has gone extinct, apparently twice. From other studies, various influenza strains are obviously derived from reassortment, but all this does is set the mutation clock back a little. Any reassortment between a "fresh" virus and a high-mutation-count virus will inevitably lead to, at best, an averaging of the mutational load of the two. The 2009–2010 "swine flu" virus shows evidence of multiple reassortment events in a limited portion of its genome, and it was more robust than the lingering human H1N1 strain that it replaced, but it carries a great number of non-adaptive and presumably deleterious mutations. Reassortment between two viruses of different immunological character might preserve the less degraded genome, but only temporarily.
Might pandemics be shortened by artificially accelerating the rate of genetic attenuation? The continuous and linear accumulation of mutations within a single influenza lineage, as was seen in H1N1 during the 2009–2010 influenza season (in which about 0.3% of all nucleotides mutated), supports the concept that natural genetic attenuation may be an important factor in the natural cessation of influenza pandemics. Thus, the possibility of an artificial acceleration of mutation rate deserves further investigation, and may suggest new avenues of research in terms of pandemic management[13]. It is clear that natural selection is strongly at work in the influenza genome. This can be seen by preservation of all the basic proteins and functions of the virus, in spite of the fact that every possible point mutation happens in every human individual during the course of an infection. A large fraction of all deleterious mutations clearly must be selected away. Likewise, the emergence of major antigenic variants shows that positive selection is operational. It is also clear that genetic drift is strongly in operation, with a major viral bottleneck happening at each transmission from one human host to the next, and perhaps at the start of each local outbreak[33], ensuring that most unique genotypes are very quickly lost. Yet, in addition to selection and drift, it also appears there is very strong mutational pressure on the influenza genome, potentially leading to lethal mutagenesis in most strains, and a gradual, natural genetic attenuation of human influenza in general.
Read and Taubenberger[69] called the origin of human H1N1 an "enigma" whose riddle was not yet solved. Like them, we see this as an unsolved riddle and we can only hope that our data might bring us one step closer to understanding the origins of this important disease.
Sequence analysis of historical and modern genomes of influenza H1N1 reveal a great deal about the history of the virus. The most recent common ancestor existed only about 120 years ago, and there has been universal extinction of all earlier human influenza strains. The rate of mutational divergence from that original genotype has been very constant both in human and porcine H1N1 strains (roughly 14–16 mutations fixed per year). Modern H1N1 strains have diverged from the original genotype by roughly 1,900 fixations (more than 15% of the genome has mutated). Roughly 7% of the amino acids have mutated. Mutation accumulation is also associated with the historical exponential decline in H1N1 human mortalities, which may suggest significant genetic attenuation, as might arise due to very slow error catastrophe.
Sequence analysis confirms that the human H1N1 strain went extinct in 1957, but was reintroduced in 1976, apparently from a specimen frozen in the early 1950s. The resulting "frozen" lineage appeared less mutated compared to all other contemporary H1N1 strains (i.e., porcine strains and a few rare H1N1 strains appearing in humans but not derived from the frozen strain). Consistent with the genetic attenuation model, the frozen human H1N1 lineage disappeared in 2009, and may now be extinct.
It appears that the H1N1 strains currently in circulation are significantly attenuated, and cannot reasonably be expected to back-mutate into a non-attenuated strain. The greatest influenza threat, therefore, is the introduction of a non-attenuated strain from some natural reservoir. This suggests that a better understanding of the origin of such non-attenuated strains should be a priority[5]. Our findings suggest that new strategies that accelerate natural genetic attenuation of RNA viruses may prove useful for managing future pandemics and, perhaps in the long run, precluding the genesis of new influenza strains.
Non-synonymous Codon Usage
Normalized Codon Scores.
This work was supported in part by FMS Foundation. Thanks to Tom Gault for computer hardware support, Henry Wan for critical comments on an earlier draft, and the helpful suggestions of four anonymous reviewers.
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Discussion: | Research Area |
Topic: | Drill and Kill |
Post a new topic to the Research Area Discussion discussion |
Subject: | RE: Balancing the drill |
Author: | PeterA |
Date: | Jun 17 2011 |
I have a little problem with your request that the student draw the triangle. In
the first problem, I would want the student to draw the triangle whether or not
it is a right triangle. If the student understands SSS, they should be able to
do this.
In both problems, the student would probably need to understand that you are
really asking them to draw a scaled copy of the triangle. (Or maybe you should
just ask for that.) Otherwise, the triangle will not fit on a standard 8.5 inch
by 11 inch piece of paper.
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Post a new topic to the Research Area Discussion discussion | |||||||


text:
EastWest/SoundsOnline | Forums | Studios | Company
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Selected: English
EASTWEST (soundsonline.com) is the #1 developer of virtual (software) instruments in the world. With clientele that spans the who's who of the music, film, television, games, multimedia and performing arts, EASTWEST has led the industry for more than 27 years and provides professionals with the very best music creation tools available.
Virtual instruments enable composers and others involved in music production to use music keyboards connected to computers to create music that is virtually indistinguishable from a live performance to the average person, at a fraction of the cost. A high percentage of the music produced for all media today is produced on computers using EASTWEST/QUANTUM LEAP Virtual Instruments.
EASTWEST/QUANTUM LEAP virtual instruments are considered to be the best available, and are used and endorsed by the who's who of the music, film, TV, and games industries, including James Newton Howard (The Hunger Games, Snow White and the Huntsman, The Bourne Legacy), Danny Elfman (American Hustle, Silver Linings Playbook, Alice in Wonderland), John Powell (Rio, How to Train Your Dragon, Kung Fu Panda), Brian Tyler (Thor, Iron Man 3, Now You See Me), Jeff Beal (House of Cards, Blackfish, Rome), Thomas Newman (Skyfall, Saving Mr. Banks, Wall-E), David Newman (Ice Age, Tarzan, Scooby-Doo), J.J. Abrams (Director/Creator: Star Wars VII, Star Trek, Lost), Mark "Spike" Stent (Coldplay, Lady Gaga, Bruce Springsteen, Muse), Herbie Hancock (12-time Grammy Winning Pianist and Composer), David Kahne (Producer Paul McCartney, Miley Cyrus, Lana Del Rey), Teddy Riley (Producer Michael Jackson "Dangerous" and "Invincible"), Paul 'Wix' Wickens (Keyboards/Musical Director, Paul McCartney), Rob Abernethy (Video Games: Pacific Rim, Despicable Me, Dead Space), Rene Dupere (Cirque Du Soleil, KA, Mystere), Chris Beck (Pink Panther 2, Under the Tuscan Sun), Steve Jablonsky (Desperate Housewives, Transformers), and countless others.
EASTWEST launched the first subscription service in the industry, COMPOSER CLOUD in April, 2015, which dramatically lowered the cost of entry to more than 9000 virtual instruments included in COMPOSER CLOUD, so anyone interested in exploring their musical creativity can now afford it.
EASTWEST owns Sounds Online (soundsonline.com), the #1 online source for professional sounds and virtual instruments.
EASTWEST owns and operates a large recording studio complex in Hollywood (eastweststudios.com), and sounds and software development divisions in Hollywood and Berlin, Germany.
With over 30 years experience in the audio industry, founder and producer DOUG ROGERS is the recipient of many industry awards including "Recording Engineer of the Year". "The Art of Digital Music" named him one of "56 Visionary Artists & Insiders" in the book of the same name.
In 1988 he founded EASTWEST, the most critically acclaimed virtual (software) instrument developer in the world. Since then, EASTWEST has been the recipient of over 70 international industry awards. Rogers uncompromising approach to quality, and innovative ideas has enabled EASTWEST to lead the industry for more than 27 years.
After forming EASTWEST, he produced the first commercial drum samples collection, followed with a sequel co-produced with Bob Clearmountain, which was so successful a new industry was born. Rogers and Clearmountain produced two subsequent releases that won many awards. In 1991, Rogers released the first collection to include midi driven drum loops, which enabled users to adjust each loop tempo in their sequencer without adjusting pitch or decreasing quality. During the next decade Rogers partnered with a number of top musicians to produce many more award winning collections with members of Aerosmith, Billy Idol, BT, Public Enemy, Prince, and The Cars. Many of these products introduced a new concept called construction loops, which enabled users to mix and customize each loop to fit their music.
With sampling technology improving, Rogers released the Ultimate Piano Collection in 1995, the first multi-velocity sampled piano collection, which received many industry awards. In 1997 Rogers partnered with Nemesys to create the Gigasampler software and sound libraries, which pioneered the use of "streaming from hard drive technology", a technical breakthrough without which, the high quality virtual instruments of today would not be possible.
In 2003 he co-produced the first surround sound virtual orchestra, Symphonic Orchestra, engineered by 11-time Grammy nominated classical recording engineer Keith Johnson, and recorded in a 'state of the art' concert hall (awarded Keyboard Magazine "Key Buy Award," EQ Magazine "Exceptional Quality Award," Computer Music Magazine "Performance Award," and G.A.N.G. [Game Audio Network Guild] "Best Sound Library Award"); and followed that release with Symphonic Choirs (awarded Electronic Musician "2006 Editor's Choice Award," G.A.N.G. "Best Sound Library Award," and Keyboard Magazine "Key Buy Award"). Symphonic Choirs and it's predecessor Voices of the Apocalypse were the first music software products to enable users to type in words for the choirs to sing in any key with a computer, and remains the only product capable of this innovation today. This was followed in 2007 with EastWest/Quantum Leap Pianos, the most detailed virtual piano collection ever produced, also in surround sound.
In 2005 Rogers established a software development division for EASTWEST, and released the first 64-bit virtual instruments that has become the standard today.
Rogers most recent productions include ProDrummer 1, co-produced with Mark "Spike" Stent; ProDrummer 2, co-produced with Joe Chiccarelli; Ghostwriter, co-produced with Steven Wilson; Hollywood Strings, Hollywood Brass and Hollywood Orchestral Woodwinds, co-produced with Nick Phoenix and Thomas Bergersen; Hollywood Orchestral Percussion, co-produced with Nick Phoenix; all of the Hollywood series was engineered by Shawn Murphy (Indiana Jones and the Kingdom of the Crystal Skull, Star Wars: Episode II - Attack of the Clones, Star Wars: Episode III - Revenge of the Sith, Star Wars: A Musical Journey, Jurassic Park, Jurassic Park The Lost World, Harry Potter and the Prisoner of Azkaban, Titanic, Minority Report, Saving Private Ryan, Munich, The Passion Of The Christ, X-Men: The Last Stand, Memoirs of a Geisha and Ice Age, etc.); The Dark Side (co-produced with David Fridmann), aimed at alternative musicians; and Fab Four (with Beatle's engineer Ken Scott), inspired by the sounds of the Beatles. Both Fab Four and The Dark Side won M.I.P.A Awards, judged by over 100 international music magazines.
For more historical background, read the interview with Doug Rogers in Sound On Sound magazine HERE
EASTWEST purchased the former United/Western Studios at 6000 W. Sunset Boulevard, Hollywood in 2006, and renamed it EASTWEST STUDIOS. The facility houses five recording studios, and is EASTWEST's Hollywood production facility where it's sounds and software products are created and marketed. After purchasing the famous studios EASTWEST commissioned an extensive remodel of the non-technical areas by international design superstar Philippe Starck who virtually reinvented the hotel industry. The famous acoustics of the recording studios were not changed, and remain as designed in the 60s by Bill Putnam. EastWest Studios Documentary.
EASTWEST STUDIOS is the world's premiere studio. Here is a quote from page 33 of the book "Temples of Sound": "United Western Recorders has been the scene of more hit records - from the 1960's to right now - than any other studio. No other studio has won more technical excellence awards, and no other studio has garnered as many Best Engineered Grammys as this complex of studios on Sunset Boulevard". One thing everyone agrees: The acoustics and the vibe in the recording rooms of 6000 Sunset Blvd. are unmatched.
EASTWEST STUDIOS has hosted the who's who of music for over 50 years. In the beginning artists like Bing Crosby, Frank Sinatra, Dean Martin, Sammy Davis, Nat King Cole, Johnny Mercer and Ray Charles were recording the hits of the day. Sinatra's, "Strangers In The Night", "My Way", and "That's Life" were recorded here in studio 1; the legendary Beach Boys "Pet Sounds" album, which was the inspiration for The Beatles' Sgt. Peppers album, was recorded here also. The Mamas and Papas "California Dreamin", "Monday Monday", and Scott McKenzie's "San Francisco" were recorded here, all in Studio 3. Elvis Presley recorded his 1968 Christmas special in Studio 1. Famous themes for film and television were recorded here including the MASH theme, Mission Impossible theme, Hawaii Five-O theme, Beverly Hillbillies theme, Godfather Theme, plus much of the Monkees and Partridge Family television series, all in Studios 1 & 2.
It would be impossible to name all the musical royalty who have worked at EASTWEST STUDIOS, but here are some of them (in alphabetical order) Christina Aguilera, Herb Albert, America, Paul Anka, Fiona Apple, Audioslave, Franky Avalon, Barenaked Ladies, Better Than Ezra, Blondie, Buffalo Springfield, Burt Bacharach, Beach Boys, Blink 182, Glen Campbell, Canned Heat, Vickie Carr, Carpenters, Johnny Cash, David Cassidy, Ray Charles, Chicago, Petula Clarke, Ry Cooder, Elvis Costello, Count Basie & Orchestra, Eric Clapton, Nat King Cole, Natalie Cole, Ornette Coleman, Duane Eddy, Jan & Dean, John Coltrane, Petula Clark, Joe Cocker, Sam Cooke, Bing Crosby, Bobby Darin, Sammy Davis Jnr, Jackie DeShannon, Duke Ellington, Neil Diamond, Fifth Dimension, Bob Dylan, Ellla Fitzgerald, Benny Goodman Big Band, Grateful Dead, Grass Roots, Green Day, Guess Who, Lani Hall, Herbie Hancock, Hawaii Five-O theme, Don Ho, Whitney Houston, Howlin' Wolf, Janis Ian, Ike & Tina Turner, Incubus, Isley Brothers, Michael Jackson, Elton John, Stan Keaton, Carole King, Kris Kristofferson, Franky Laine, K.D. Lang, Avril Laverne, Godfather Theme, Michel LeGrand, Peggy Lee, Little Feat, Trini Lopez, Madonna, Mamas & the Papas, Dean Martin, MASH theme, Johnny Mathis, Meatloaf, Sergio Mendez & Brazil 66, Metallica, Johnny Mercer, Paul McCartney, Barry Manilow, Scott McKenzie, Natalie Merchant, Bette Midler, Mission Impossible theme, Monkees, Alanis Morrissette, Motley Crue, Muse, Rick Nelson, Willie Nelson, Wayne Newton, Harry Nilsson, Nitty Gritty Dirt Band, Ozzy Osborne, Partridge Family, Paul Revere and the Raiders, Tom Petty and the Heartbreakers, Pointer Sisters, Iggy Pop, Elvis Presley, Lisa Marie Presley, Billy Preston, Rage Against the Machine, Red Hot Chilli Peppers, Kenny Rogers, Rolling Stones, Ronnie & the Ronettes, Bonnie Raitt, Helen Reddy, R.E.M., Nelson Riddle, Righteous Brothers, Johnny Rivers, Ronnie & the Ronnettes, Dianna Ross, Santana, Jimmy Smith, Sonny & Cher, Phil Spector, Tom Scott, Carly Simon, Frank Sinatra, Nancy Sinatra, Bruce Springsteen, Steppenwolf, Rod Stewart, Mathew Sweet, Stone Temple Pilots, Barbra Streisand, System of a Down, Temptations, The Animals, The Association, The Four Tops, The GoGos, The Kingston Trio, The O'Jays, The Vines, The Who, Mel Torme, U2, Richie Valens, Stevie Wonder, Tool, Turtles, Sarah Vaughn, Jimmy Webb, Weezer, Andy Williams, Nancy Wilson, Young Rascals, Frank Zappa.
EASTWEST STUDIOS was founded by Bill Putnam in 1961 with funding from Bing Crosby and Frank Sinatra.
Considered to be the "Father of modern recording" Putnam is acknowledged to be the first person to use artificial reverberation for commercial recording. He also developed the first multi-band equalizers, and with his company Universal Audio, was responsible for the development of classic equipment like the Urei 1176LN and Urei Time Align Monitors. He was involved in the early development of stereophonic recording and founded studios in Chicago, Hollywood and San Francisco. He was responsible for a number of innovations including: the first use of tape echo and echo chambers, the first vocal booth, the first multiple voice recording, the first use of 8-track recording, half-speed disc mastering. In 1957, he started United Recording Corp. in a building at 6050 Sunset and started new construction on new studios. Stereo was taking off and Putnam was determined to incorporate as many technological innovations into the new complex as possible.
In 1961, Western Recorders (now EastWest Studios) at 6000 Sunset was acquired and remodeled and incorporated into the complex with the facilities being known as United Western Recorders. Bill Putnam passed away in 1989. The studio was acquired by Oceanway. In 1999 Rick Adams acquired the studios and renamed it Cello, and in January 2006 it was acquired by EASTWEST.
Looking for a designer to take on the task of remodeling the non-technical areas, while preserving the historic studios, Rogers commissioned international design superstar Philippe STARCK, whose trend-setting work, and reinvention of the hotel industry, is known the world over for its sheer brilliance and coolness. STARCK jumped at the opportunity and headed to Hollywood. He insisted on restoring all historic elements inside and out, adding new designs to the interior, while restoring the exterior to it's original deco design. Rogers and Starck's restoration of the famous recording studios is a model for historic/cultural preservation, as well as providing EASTWEST with the finest recording environment in the world to create it's virtual instruments.
In addition to it's own use of the studios, eastweststudios.com is open to outside clients.
A privately held company, EASTWEST is the industry leader in Soundware Development and Distribution.


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April 10, 2001
Arguing With Bill Miller on Amazon.com Rethinking JDS Uniphase AOL and the Value of Entertainment Recession: An Opportunity for Harley? Why a Lucent Buyout Won't Happen Disney and Spy Kids Dampening That Nokia Enthusiasm A Swiss Starbucks Tale Shiny, Happy Macs Giving Up the P/E Habit
Legg Mason's Bill Miller has positive things to say about Amazon.com -- but investors on our discussion boards beg to differ.
"A few days ago TMFTribe posted his valuation analysis for JDS Uniphase. The sum of his analysis basically indicated that JDSU common stock was significantly undervalued. However, I believe that his analysis may be somewhat flawed."
How much do you pay for entertainment? And how well is AOL Time Warner positioned to profit from that spending?
Harley-Davidson did well in the last recession. If the economy slips, will history repeat itself?
Rumors have been swirling around Lucent, including suggestions that the company is ripe for a takeover. One Fool argues that it won't happen.
The movie Spy Kids is at the top of the box office lists, and it got there without being branded as a Disney film. What does this tell us about how well the Disney name sells?
From time to time it makes sense to look at the stocks you own from a bearish perspective. Come watch Nokia shareholders look for signs of trouble in their own company.
Long lines and learning about Coffee Culture marks the great Starbucks expansion in Europe. Read one Fool's report.
"Yesterday I dropped by CompUSA to buy a book and to see what was happening.... Believe me, over the years I have seen a huge difference in how Macs and accessories were presented and sold."
Is the P/E ratio obsolete? The Gorilla Game board discusses the merits of measuring the value of companies by comparing multiples of earnings with share price.


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Publisher Information
Perceval Press
Perceval Press is a publisher of young adult books. Books published by Perceval Press include Pirates, Bats, And Dragons: A Science Adventure and Land of the Lost Mammoths: A Science Adventure.
Main Address: |
1223 Wilshire Blvd. Suite F Santa Monica CA 90403 USA | Phone: |
Fax: | ||
Updated 10/2/2007 |
While JacketFlap strives to maintain up-to-date information, we recommend that you contact the publisher using the information here to confirm that the contact information is current. If you have more up-to-date information, please click the Edit or Add links on this page to edit this publisher's information and earn points, which you can redeem for Amazon.com or BookSense gift certificates.
Title, Creators, Comments / Reviews | Ages | Date Published | |||
1. Land of the Lost Mammoths: A Science Adventure (Hardcover) Author: Mike Davis Illustrator: William Simpson |
Ages 9-12 |
06/2004 Add | |||
19 Reviews | |||||
2. Pirates, Bats, And Dragons: A Science Adventure (Science Adventures) (Ha... Author: Mike Davis Illustrator: William Simpson |
Ages 9-12 |
11/2004 Add | |||
6 Reviews | |||||
Bestselling order determined by Amazon.com SalesRank(tm) |


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William Carlos Williams , was an American poet closely associated with modernism and Imagism. He was also a pediatrician and general practitioner of medicine. Williams "worked harder at being a writer than he did at being a physician," wrote biographer Linda Wagner-Martin. During his long lifetime, Williams excelled both as a poet and a physician.
More on Wikipedia…
(74 quotes found)
"Well--all things turn bitter in the endwhether you choose the right orthe left wayand--dreams are not a bad thing."
William Carlos Williams
"so much dependsupona red wheelbarrowglazed with rainwaterbeside the whitechickens."
"Times change and forms and their meanings alter. Thus new poems are necessary. Their forms must be discovered in the living language of their day, or old forms, embodying exploded concepts, will tyrannize over the imagination."
"I wanted to write a poemthat you would understand.For what good is it to meif you can't understand it?"
"Some leaves hang late, some fallbefore the first frost--so goesthe tale of winter branches and old bones."
"It is summer, it is the solsticethe crowd ischeering, the crowd is laughingin detailpermanently, seriouslywithout thought."
"Life is valuable -- when completed by the imagination. And then only."
"History, history! We fools, what do we know or care? History begins for us with murder and enslavement, not with discovery."
"When I am alone I am happy."
"My surface is myself.Under whichto witness, youth isburied. Roots?Everybody has roots."


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October is Domestic Violence Awareness Month, but in cash-strapped Topeka, Kan., victims of domestic battery are wondering if anyone is paying attention. The Topeka Capital-Journal reports that the city is not prosecuting domestic battery cases because they're too expensive, and the Shawnee County District Attorney has decreed it will not prosecute Topeka misdemeanors due to budget cuts. Abusers may be let off the hook.
Abuser, heal thyself
Trusting abusers to rehabilitate themselves appears to be the path Topeka, Kan., city officials are taking. City and county officials don't seem to be doing much else. From the Capital-Journal:
"In August, the Shawnee County Commission cut [Shawnee County District Attorney Chad] Taylor's 2012 budget by 10 percent, or $347,765, from its 2011 budget of $3,477,651. In the meantime, police spokeswoman Kristen Veverka confirmed that 16 people have been arrested on suspicion of misdemeanor domestic battery since Sept. 8 but were released from the Shawnee County Jail after charges weren't filed."
Joyce Martin, CEO of the Topeka YWCA, has sounded an alarm bell.
"The ongoing concern regarding the Shawnee County district attorney's office prosecution of misdemeanor cases, particularly domestic battery, must be resolved in the interests of victim safety," she wrote in a public statement. "The organization believes that some of the most vulnerable members of our community have been placed in danger."
Following community protocols
In 2009, the YWCA worked with the Topeka district attorney's office, police department, Shawnee County sheriff and the Third District Court Services to install "community protocols" for responding to and prosecuting domestic violence cases. According to Martin, when Topeka District Attorney Chad Taylor signed in support of these protocols, he agreed he would "aggressively prosecute domestic violence," "review domestic violence cases as first priority" and "charge the cases that meet sufficient evidence to prosecute the case."
Now officials fear these protocols will be all but abandoned as budget austerity looms.
"When an abusive partner is arrested, the victim's danger level increases," said Becky Dickinson, interim director of the YWCA Center for Safety and Empowerment. "The abuser will often become more violent in an attempt to regain control. Letting abusive partners out of jail with no consequences puts victims in incredibly dangerous positions."
Prosecution: The responsibility of local authorities
According to Jeff Wagaman, spokesman for Kansas' attorney general, Kansas law dictates that local authorities must bear the responsibility of prosecuting misdemeanor domestic abuse cases. With the budget-imposed deadlock in place, however, it remains unclear what will happen to city residents in danger of escalating incidents domestic violence.
"We hope this dispute is quickly resolved in the best interest of public safety," said Wagaman.
Kansas' legal battle over domestic abuse
Domestic Violence Awareness Month: http://www.ncadv.org/takeaction/DomesticViolenceAwarenessMonth.php
Gawker: http://gawker.com/5847619/enjoy-hitting-your-spouse-move-to-topeka
Think Progress: http://bit.ly/oJAg2M
Topeka Capital-Journal: http://bit.ly/nyGXmK
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text: 000 FPUS63 KFSD 171006 SFPSD SDZ001>074-180000- State Forecast for South Dakota National Weather Service Sioux Falls SD 505 AM CDT Fri Mar 17 2017 .TODAY...Mostly sunny, becoming mostly cloudy northeast. Windy. Highs from around 40 northeast to upper 50s southwest to south central. .TONIGHT...Mostly clear to partly cloudy. Lows 15 to 20 northeast, to near 30 far southwest. .SATURDAY...Partly cloudy in the morning, then mostly clear. Highs in the 40s northeast to 70s southwest. .SUNDAY...Increasing clouds northwest to southeast. Slight chance of rain showers far northwest in the afternoon, then a slight chance of light rain or snow at night. Breezy far east early, and northwest in the afternoon. Lows from the lower to mid 30s northeast, to near 50 south central and around the Black Hills. Highs from 55 to 65 north, to 75 to 80 south central. .MONDAY...Partly cloudy northeast to mostly cloudy southwest. Chance of rain southwest, changing to snow at night. Lows in the 30s. Highs 45 to 55. .TUESDAY...Clear to partly cloudy northeast, to mostly cloudy southwest. A chance for rain or snow southwest during the day, and central at night. Lows from the lower 20s northeast to around 30 south. Highs around 40 northeast to near 50 southwest and south central. $$


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Fox Orders Pilot Based on Cartoonist Peter Bagge's Characters; Alt-Comics Fans From 1995 Express Amazement, Joy
Posted on Friday, October 9th, 2009 by Russ Fischer
The me that is fifteen years younger is so thrilled right now. Fox has ordered a pilot for a potential animated series based on The Bradleys, which were some of the characters created by cartoonist Peter Bagge in the comics Neat Stuff, Hate and later The Bradleys. Hate was centered around the drunken, socially fumbling antics of misanthrope Buddy Bradley, who has been Bagge's signature character for years.
If you'd told me during the series' heyday that it might have an animated series on a major network, I would have laughed. Just like I'm laughing (gleefully) now.
According to long-time Bagge publisher Fantagraphics (by way of MTV) the prime-time series would take place before the events of Hate. We'd see teenage Buddy Bradley living at home. I haven't read the series The Bradleys but knowing Hate and Neat Stuff I'd expect arguments, drinking, sullen depression, angst-ridden rage and a savvy, grousing awareness of music and books.
While Bagge's writing could be jagged and misanthropic, his art always had a fluid, crazy sense of motion that would be amazing to see animated. His characters could be fairly realistic in one panel then exaggerated with long, rubbery limbs in the next. He captured both the electricity of the early '90s and the sense that it was being co-opted even as that energy flourished. No one satirized the burgeoning indie scene in music and comics better than he did. What would he produce now, many years later, as things have changed so much? I'm curious.
(I don't mean to make it sound as if Bagge is no longer active; he's still producing comics, including some work for Marvel and DC over the past few years.)
This wouldn't be Bagge's first foray into animation. His characters were animated by others for a Mad TV promo a couple years back. Years ago he designed characters for a series of animated commercials (for Round Table Pizza, no less, see tiny versions here) and also did a web series called The Murray Wilson Show, based on the life of the father of the Beach Boys' Brian Wilson. The first episode of that is below.
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