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49. Genome Replikin Count™ Predicts Increased Lethality of Malaria
April 3, 2012
(From Nature Precedings: doi:10.1038/npre.2012.7142.1 April 2012)


Samuel Bogoch and Elenore S. Bogoch, Foundation for Research on the Nervous System, Boston University School of Medicine, Bioradar UK Ltd, and Replikins Ltd. 36 The Fenway, Boston, MA 02215

REPLIKIN COUNT CYCLES IN MALARIA AND METHODS OF PREDICTING INCREASED MORTALITY

An increase in virulence, morbidity, and/or mortality of a placidium that causes malaria may be predicted by identifying a cycle of Replikin concentration among a plurality of isolates of the species of and identifying a peak in that cycle. An increase in virulence, morbidity, and/or mortality is predicted following the time point or time period when the peak is identified. This communication is one of four submitted together:

Genome Replikin Count™ Predicts Increased Lethality of Resistant Tuberculosis
Genome Replikin Count™ Predicts Increased Lethality of Malaria
Genome Replikin Count™ Predicts Increased Lethality of Cancer
Genome Replikin Count™ Predicts Increased Infectivity/Lethality of Virus

Replikin Count Cycles Predict Increased Mortality

A cycle of Replikin concentration or "Replikin cycle" of may be seen in Supplement Figure 1. A Replikin cycle is identified by initially isolating at least four isolates or groups of isolates from at least four time points or time periods, for example, an isolate or group of isolates may be obtained in 1999, 2001, 2002, and 2004, or may be obtained in January, May, September, and December of a given year. Isolates may be obtained from more than four time points or time periods and precision of a Replikin Cycle generally will improve with increases in the number of isolates per time point or time period and with increases in the number of time points or time periods. The Replikin Count of the genome or expressed proteins of each isolate is determined. Replikin Count may be determined in a Replikin Peak Gene, in the entire genome, in a particular gene or gene segment, or in a particular protein or protein fragment of each of the isolates. Mean Replikin Count for a given time point or given time period is determined if a plurality of isolates has been obtained for the given time point or given time period. Replikin Count may then be analyzed per unit time. A cycle in Replikin concentration is identified by four time points or time periods, where the Replikin Count at a second time point or time period is higher than at first time point or time period, the Replikin Count at a third time point or time period is lower than at second time point or time period, and Replikin Count at a fourth time point or time period is higher than at the third time point or time period; or where the Replikin Count at a second time point or time period is lower than at first time point or time period, the Replikin Count at a third time point or time period is higher than at second time point or time period, and Replikin Count at a fourth time point or time period is lower than at the third time point or time period.

A peak in a Replikin cycle is identified within the cycle at a second time point or time period within a Replikin cycle, wherein the Replikin concentration at a first time point or time period immediately preceding the second time point or time period is lower than the Replikin concentration at the second time point or time period, and the Replikin concentration at a third time point or time period immediately following the second time point or time period is lower than the Replikin concentration at the second time point or time period. Replikin peptides of the discovery identified at a peak of the Replikin cycle include Replikin peptides identified at or near the peak of the Replikin cycles including prior to and subsequent to the precise point of the peak. A rising portion of a Replikin cycle is any point at which trend of Replikin concentration in the Replikin cycle is increasing from at least a first time point or time period to at least a second time point or time period and can include a peak. As may be seen in Figures 1-5, an increase in virulence, morbidity, or mortality may be predicted following a rising portion or peak in a Replikin cycle.

Figure 1 illustrates cycling between 1986 and 2007 of annual mean Replikin concentration in the histidine rich protein of Plasmodium falciparum. P. falciparum is a trypanosome that is most commonly associated with malaria. Two cycles are observable at peaks in 1987 and 1999. A third cycle appears to have begun between 2005 and 2007. Publicly available accession numbers at www.pubmed.com containing amino acid sequence listings for P. falciparum were queried using the automated FluForecast® software (Replikins, Ltd., Boston, MA). The software analyzed the Replikin Count of each available sequence in Pubmed between 1986 and 2007. The area of the P. falciparum genome observed to have the highest concentration of continuous Replikin sequences per 100 amino acids was determined to be the histidine rich protein. The histidine rich proteins include the knob-associated histidine rich protein

Analysis of the mean annual Replikin Count of the histidine rich protein between 1986 and 2007 revealed two cycles of Replikin Count. The first cycle was observed from 1986 to 1995. The second was observed from 1996 to 2005. The peak of the first cycle was identified in 1987 with a mean annual Replikin Count of 38.2 and standard deviation of 23.5. The peak of the second cycle was identified in 1999 with an even higher mean annual Replikin Count of 62.9 and standard deviation of 62.9 (branching and stacking of Replikin sequences within an amino acid sequence generates a Replikin Count of greater than 100 Replikin sequences per 100 amino acids in some sequences). Both the 1987 peak and the 1999 peak were observed to be related to higher human mortality. Following the 1999 peak, mean annual Replikin Counts were observed to fall to a low of 7.4 in 2005 with a standard deviation of 6.5. Mortality rates likewise fell between 2000 and 2005. A third malaria Replikin cycle appears to have begun in 2005 with the observed annual mean Replikin Count increasing from 7.46.5 in 2005 to 17.219 in 2007. The beginning of the third cycle provides a prediction that Replikin Count may continue to increase along with an increase in malaria mortality rate.

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