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PubMed2006

Matrix elements of N-particle explicitly correlated Gaussian basis functions with complex exponential parameters.

In this work we present analytical expressions for Hamiltonian matrix elements with spherically symmetric, explicitly correlated Gaussian basis functions with complex exponential parameters for an arbitrary number of particles. The expressions are derived using the formalism of matrix differential calculus. In addition, we present expressions for the energy gradient that includes derivatives of the Hamiltonian integrals with respect to the exponential parameters. The gradient is used in the variational optimization of the parameters. All the expressions are presented in the matrix form suitable for both numerical implementation and theoretical analysis. The energy and gradient formulas have been programmed and used to calculate ground and excited states of the He atom using an approach that does not involve the Born-Oppenheimer approximation.

Journal Article↗

PubMed2006

Functional holography analysis: simplifying the complexity of dynamical networks.

We present a novel functional holography (FH) analysis devised to study the dynamics of task-performing dynamical networks. The latter term refers to networks composed of dynamical systems or elements, like gene networks or neural networks. The new approach is based on the realization that task-performing networks follow some underlying principles that are reflected in their activity. Therefore, the analysis is designed to decipher the existence of simple causal motives that are expected to be embedded in the observed complex activity of the networks under study. First we evaluate the matrix of similarities (correlations) between the activities of the network's components. We then perform collective normalization of the similarities (or affinity transformation) to construct a matrix of functional correlations. Using dimension reduction algorithms on the affinity matrix, the matrix is projected onto a principal three-dimensional space of the leading eigenvectors computed by the algorithm. To retrieve back information that is lost in the dimension reduction, we connect the nodes by colored lines that represent the level of the similarities to construct a holographic network in the principal space. Next we calculate the activity propagation in the network (temporal ordering) using different methods like temporal center of mass and cross correlations. The causal information is superimposed on the holographic network by coloring the nodes locations according to the temporal ordering of their activities. First, we illustrate the analysis for simple, artificially constructed examples. Then we demonstrate that by applying the FH analysis to modeled and real neural networks as well as recorded brain activity, hidden causal manifolds with simple yet characteristic geometrical and topological features are deciphered in the complex activity. The term "functional holography" is used to indicate that the goal of the analysis is to extract the maximum amount of functional information about the dynamical network as a whole unit.

Algorithms↗

PubMed2006

Metalloproteinase-2, -7 and -9 and tissue inhibitor of metalloproteinase-1 and -2 expression in normal, hyperplastic and neoplastic endometrium: a clinical-pathological correlation study.

BACKGROUND: Matrix metalloproteinases (MMPs) and their inhibitors are key-players in extracellular matrix and basement membrane degradation, and are involved in both physiological and malignant processes. The aim of this study was to examine MMP-2, -7 and -9 and TIMP-1 and -2 expression in normal, hyperplastic and malignant endometrium, and their relation to clinical and histological prognostic factors. MATERIALS AND METHODS: We performed qualitative and semi-quantitative immunohistochemical analysis of 20 samples of normal endometrium (10 in the proliferative phase, 10 in the secretory phase), 39 samples of hyperplastic endometrium (17 without atypia and 22 with atypia) and 38 samples of endometrioid carcinoma, by using specific monoclonal antibodies. RESULTS: In normal endometrium, epithelial expression of MMP-2 (P = 0.0007), MMP-7 (P = 0.0002) and TIMP-2 (P = 0.0004) was increased during the proliferative phase of the menstrual cycle. MMP-2 expression correlated negatively with TIMP-2 expression (P = 0.001, rho = 0.702). Endometrial stromal cells in the secretory phase showed strong MMP-2 expression (P = 0.004) and weak MMP-7 (P = 0.001) and TIMP-1 expression (P = 0.01). In hyperplastic endometrium, the presence of atypia was associated with lower TIMP-2 expression (P = 0.005) and was also associated with a trend towards higher MMP-2 expression. Endometrial stromal cell expression of MMP-2, -7 and -9 and TIMP-1 and -2 did not differ between hyperplastic endometrium with and without atypia. A gradient of MMP-2 and -9 expression was observed from hyperplastic endometrium to endometrial carcinomas. In endometrial carcinomas, MMP-2 expression increased (P = 0.0004) and TIMP-2 expression decreased (P = 0.0005) with the histological grade. TIMP-2 expression correlated with myometrial invasion (P = 0.005), lymphovascular space involvement (P = 0.008) and lymph node involvement (P = 0.007). CONCLUSION: These results support the involvement of MMPs and TIMPs in endometrial carcinogenesis. Strong MMP-2 and weak TIMP-2 expression were the most potent markers of endometrial malignancies with a high risk of local and distant spread.

Endometrial Neoplasms↗

PubMed1992

[Rejection of physico-chemical indices for pathological matrix in a quantitative drug design].

In a quantitative drug design, correlation of coefficient matrix of physico-chemical indices Xi is often pathological when these indices are highly correlated. The regression equation of biological activity Y about these indices Xi obtained in this case is not stable. In this paper, a method is given to obtain a stable regression equation: giving a critical valne alpha and finding out the indices among which correlation coefficient is not less than alpha. The following are the rules to reject some of them. If Xi and Xj is highly correlated (magnitude of rij greater than or equal to alpha, rij is the correlation coefficient of Xi and Xj), and magnitude of rin greater than magnitude of rjn (rin and rjn are correlation coefficients of Xi and Xj about Y, respectively), than the index Xj is rejected, otherwise, Xi is rejected. Stable equation can be obtained by stepwise regression with the remaining indices.

Drug Design↗

PubMed2002

Matrix metalloproteinase-2 and -9 activities correlate with the disease-free survival of oral squamous cell carcinoma patients.

The aim of the present study was to determine whether matrix metalloproteinase (MMP) activities are associated with the clinicopathological features of oral squamous cell carcinomas (OSCCs). Forty-four samples of primary OSCCs were microdissected, incubated in serum-free cell culture medium for 16 h, and the activity of secreted MMPs analyzed by gelatin zymography and densitometry. Two major enzymes with gelatinolytic activity were produced by all tumor samples and characterized as MMP-2 and -9 by their molecular weight, immunoprecipitation using monoclonal antibodies, and specific inhibition by 1,10-phenanthroline or EDTA. Patients with tumors showing elevated activity of MMP-2 and -9 had shorter disease-free survival after treatment than patients with tumors exhibiting low MMP activities. These results suggest that the zymographic measurement of the MMP-2 and -9 activities in OSCC specimens may be useful to predict the disease-free survival period of patients affected by these tumors.

Adult↗

PubMed2002

Comparison of genetic diversity estimates within and among populations of maritime pine using chloroplast simple-sequence repeat and amplified fragment length polymorphism data.

We compared the genetic variation of Pinus pinaster populations using amplified fragment length polymorphism (AFLP) and chloroplast simple-sequence repeat (cpSSR) loci. Populations' levels of diversity within groups were found to be similar with AFLPs, but not with cpSSRs. The high interlocus variance associated with the AFLP loci could account for the lack of differences in the former. Although AFLPs revealed much lower genetic diversity than cpSSRs, the levels of among-population differentiation found with the two types of marker were similar, provided that loci showing fewer than four null-homozygotes, in any population, were pruned from the AFLP data. Moreover, the French and Portuguese populations were clearly differentiated from each other, with both markers. The Mantel test showed that the genetic distance matrix calculated using the AFLP data was correlated with the matrix derived from the cpSSRs. Because of the concordance found between markers we conclude that gene flow was indeed the predominant force shaping nuclear and chloroplastic genetic variation of the populations within regions, at the geographical scale studied.

Alleles↗

PubMedDate not supplied

[Blood, teeth and hair: 3 different materials used to evaluate exposure to lead and cadmium in children living in an industrial zone].

There is a general agreement that children are a population at increased risk with respect to lead and cadmium exposure and to adverse health effects resulting from increased exposure. Different biological indicators such as blood hair and teeth have been used to evaluate lead and cadmium exposure in humans. However, up to date, it has not been established which is the best indicator to provide an assessment of internal exposure. The aim of the present study was to examine the levels of lead and cadmium in hair, blood and teeth of children living from birth in an industrialized area near Modena. The relationship between these indicators of exposure and children characteristics such as sex, weight, height, blood pressure and smoking habits of parents was also examined. 142 children (71 males and 71 females) representing 20.8% of those aged 6-7 years living in Sassuolo (Modena) have been included in the study. The geometric means of lead in blood, hair and teeth were 11.2 micrograms/dl, 7.24 micrograms/g and 6.16 micrograms/g, respectively. Hair lead were significantly related to both blood and teeth values (r = 0.226, p = 0.007 and r = 0.186, p = 0.027, respectively). Mean cadmium concentrations were 0.47 mu/l in blood, 0.17 micrograms/g in hair and 47.9 ng/g in teeth and no significant correlation was observed between the three biological matrixes examined. Significant correlations were found between lead and cadmium in both hair (r = 0.427, p = 0.000) and teeth (r = 0.224, p = 0.007). In addition, for lead content in teeth, a significant difference between boys and girls was observed; females showed higher values than males (6.77 micrograms/g vs 5.61 micrograms/g; t = 2.23 p = 0.028). Taking into account the individual characteristics of children, a negative relationship was found between Pb levels in teeth and height (r = -0.217, p = 0.024). Systolic blood pressure values were positively associated to cadmium hair levels in males but not in females (r = 0.281; p = 0.053). From the results of the present study it appears that blood, hair and teeth provide different information to predict lead and cadmium exposure of children. Hair seem to be a useful global indicator of total environmental pollution.

Cadmium↗

PubMed1999

Matrix metalloproteinase-1 and -3 in breast cancer: correlation with progesterone receptors and other clinicopathologic features.

Although matrix metalloproteinases (MMPs) are implicated in breast cancer progression, the contribution of MMP-1 and MMP-3 to this process, has not been thoroughly investigated. Matrix metalloproteinases (MMPs) are important at several points during multistage neoplastic progression. Immunohistochemistry (Strept-ABC-HRP method) and in situ hybridization were performed to detect MMP-1, MMM-3 proteins, and MMP-3 mRNA, respectively, in 77 infiltrative breast carcinomas. MMP-1, MMP-3 protein, and MMP-3 mRNA detection were analyzed in parallel with clinicopathologic features (menopausal status, histological type, nuclear and histological grade, stage) and the immunohistochemical reactivity of estrogen (ER), progesterone (PR) receptors, and c-erbB-2 oncoprotein in breast carcinomas. Statistical analysis was performed using the multiple linear regression test. Immunoreactivity for MMP-1 and MMP-3 was observed in 59 of 77 (77%) and 22 of 77 (28.5%) breast carcinomas and was evaluated separately in cancer cells and in stromal fibroblasts. MMP-3 mRNA was detected in 72 of 77 (93.5%) carcinomas exclusively in stromal cells within the tumors or in the marginal portion of tumors. MMP-1 protein immunoreactivity in stromal fibroblasts but not in cancer cells showed a statistically significant correlation with tumor stage (P=.04). MMP-1 reactivity either in stromal or in cancer cells showed a statistically significant inverse correlation with PR expression (P=.04 and P=.04, respectively). MMP-3 protein immunoreactivity in cancer or stromal cells and MMP-3 mRNA expression was not associated with the clinicopathologic features studied. MMP-3 mRNA was detected more often in ductal carcinomas. These results indicate that MMP-1 may contribute to breast cancer invasiveness. Furthermore, they suggest differential functions for MMP-1 and MMP-3 in breast cancer progression.

Adult↗

PubMed2006

Simulating the effect of DNA polymerase mutations on transition-state energetics and fidelity: evaluating amino acid group contribution and allosteric coupling for ionized residues in human pol beta.

The control of the catalytic power and fidelity of DNA polymerases involves the complex combined effect of the protein residues, the Mg2+ ions, and the interaction between the DNA bases. In an attempt to advance the understanding of catalytic control, we analyze the effect of the protein residues, taking human DNA polymerase beta as a model system. Specifically, we examine the ability of different theoretical models to reproduce the effect of ionized residues on the transition state (TS) binding energy and the corresponding k(pol)/KD. We also explore the role of the Mg2+ ions in the binding and catalysis processes. The application of the microscopic linear response approximation (LRA) and the semimacroscopic PDLD/S-LRA methods to a benchmark of mutational studies produces a semiquantitative correlation and indicates that these methods can provide predictive power. However, pre-steady-state and steady-state kinetic studies currently available do not give a unique benchmark, owing principally to widely varying experimental conditions. We believe that a more uniform experimental benchmark is needed for further refinement of the theoretical models. The analysis of the correlation between the results obtained by a rigorous thermodynamic cycle and by simpler approximations indicates that the protein reorganization between the open, i.e., unbound, form and the closed form does not change the magnitude of the calculated mutational effects in a major way for the experimental data used in this study. The use of the PDLD/S-LRA group contributions allows us to construct energy-based correlation diagrams that can help toward understanding the coupling, i.e., transfer of information, between the base-binding and catalytic sites and to gain a deeper insight into the molecular basis of DNA replication fidelity. Our analysis suggests that the allosteric matrix obtained by subtracting the correlation matrix of the correct and incorrect base pairs should prove useful in exploring the information transfer occurring between the base-binding and catalytic sites. This type of treatment should be especially effective when coupled with structural studies of polymerase-DNA-base mispair ternary complexes and studies using polymerase double mutants. We discuss the potential of direct calculations of binding energy of the TS in a rational design of TS analogues and in drug design.

Allosteric Regulation↗

PubMed2005

Detection of interspecific competition in parasite communities.

Matrices of correlation coefficients between the abundances or intensities of all pairs of helminth species, across all individual hosts in a sample, are regularly used to detect possible cases of interspecific competition in parasite communities. In these matrices, however, the range of possible values that any correlation coefficient can take is not -1 to 1, contrary to what is generally assumed. The number and magnitude of other correlation coefficients in a matrix will constrain the values that any given correlation can achieve. This property of matrices, and of inter-related natural variables, is explained and illustrated with 2 examples from real helminth communities. As a rule, the presence of many negative correlations in a matrix raises the lower value that any of them can possibly achieve. This has important but previously overlooked implications for the interpretation of correlation coefficients, and the detection of competition in natural parasite communities.

Animals↗

PubMed2006

The cumulant two-particle reduced density matrix as a measure of electron correlation and entanglement.

Several measures of electron correlation are compared based on two criteria: (i) the presence of a unique mapping between the reduced variables in the measure and the many-electron wave function and (ii) the linear scaling of the measure and its variables with system size. We propose the squared Frobenius norm of the cumulant part of the two-particle reduced density matrix (2-RDM) as a measure of electron correlation that satisfies these criteria. An advantage of this cumulant-based norm is its ability to measure the correlation from spin entanglement, which is not contained in the correlation energy. Alternative measures based on the 2-RDM, such as the von Neumann entropy, do not scale linearly with system size. Properties of the measures are demonstrated with Be, F(2), HF, N(2), and a hydrogen chain.

Algorithms↗

PubMed1998

Specific matrix metalloproteinase profiles in the cerebrospinal fluid correlated with the presence of malignant astrocytomas, brain metastases, and carcinomatous meningitis.

BACKGROUND: Detection in tumor tissue of specific matrix metalloproteinases (MMPs), particularly gelatinases A and B, correlates with the grade and aggressiveness of primary and metastatic brain tumors. The ability to detect these enzymes in the cerebrospinal fluid (CSF) would be a minimally invasive method of evaluating brain tumors. METHODS: CSF from 66 patients with white blood cell counts of < or = 5 microL were analyzed for the presence of gelatinolytic activity by zymography. Twenty-nine patients had malignant astrocytomas, 10 had brain metastases from systemic malignancies, 4 had systemic cancer not involving the central nervous system, 4 had nonmalignant neurologic diseases, and 19 were healthy controls. Fifteen CSF samples had positive cytologies. The zymographic results were retrospectively correlated with clinical information and CSF cytologic data. RESULTS: CSF from all patients with malignant astrocytomas or brain metastases contained precursor gelatinase A (pMMP2) and precursor gelatinase B (pMMP9), whereas control CSF contained only pMMP2. All patients with positive CSF cytologies had activated MMP2. A similar correlation was observed between the presence of activated MMP9 and positive CSF cytology. CONCLUSIONS: The precursor and activated forms of gelatinases A and B can be detected in the CSF of patients with primary and metastatic brain tumors. The distribution of gelatinase activity in CSF distinguishes patients with malignant gliomas or brain metastases from those without brain tumors, and distinguishes patients with meningeal carcinomatosis from those without CSF spread of tumor, regardless of their brain tumor status. Analysis of MMPs in the CSF may be a sensitive technique for diagnosing CNS tumors and provide an early indication of tumor recurrence. This technique may also provide longitudinal information that would be useful in evaluating ongoing treatment and predicting tumor behavior.

Adult↗

PubMed2000

Expression of matrix metalloproteinase-2 in glial and neuronal tumor cell lines: inverse correlation with proliferation rate.

The expression of matrix metalloproteinases (MMPs) has been found to be positively correlated to the degree of malignancy in gliomas, indicating that poorly differentiated brain tumor cells produce more MMPs than differentiated ones. We determined the production of active MMP-2 in five glial (U138MG, U373MG, A172, C6, GOS-3), two neuronal (SK-N-SH, SK-N-MC), and two pluripotent cell lines with facultative neuronal and glial differentiation (P19 and NT2) by gelatin zymography. The MMP-2 activity profiles were compared to the proliferative activities of the cell lines. MMP-2 expression varied from barely existent (P19 cells) to strong (U138MG and SK-N-SH). Interestingly, for the cell lines with high MMP-2 expression levels, low proliferative activities were recorded, and vice versa. Retinoic acid induced neuronal differentiation and a reduction of proliferation of P19 cells; the differentiated cells produced significantly more MMP-2 than untreated cells. Upon confluency, GOS-3 cells showed reduced proliferation, but increased MMP expression. Thus, proliferative activity was inversely correlated to MMP-2 expression in the tumor cell lines analyzed.

Brain Neoplasms↗

PubMed2000

Expression of the extracellular matrix protein tenascin in laryngeal epithelial lesions: correlation with fibronectin, CD44, cathepsin D and proliferation indices.

Tenascin (TN) is an extracellular matrix glycoprotein expressed in areas of epithelial-mesenchymal interactions during embryogenesis and in neoplasia. We studied the expression of TN in a series of 35 squamous cell invasive carcinomas of the larynx, 13 in situ carcinomas, 41 cases of dysplasia, 10 papillomas and 18 cases of keratosis using the monoclonal antibody TN2 on paraffin-embedded tissue. TN expression was correlated with the expression of fibronectin, CD44 and cathepsin D (CD) proteins, with the proliferation indices Ki-67 and proliferating cell nuclear antigen (PCNA) as well as with conventional clinicopathological variables. Malignant tumours showed a significantly greater stromal TN staining than benign lesions. In invasive carcinomas, the immunoreactivity was statistically higher than that in situ (P=0.01), dysplastic lesions (P<0.0001), papillomas (P=0.004) and keratosis (P<0.0001). A statistically significant difference of TN expression between in situ and dysplastic lesions was observed (P=0.001). In invasive lesions, TN expression was statistically correlated with CD44 expression (P=0.02) and a trend for correlation with CD of tumour cells and fibronectin expression was found (P=0.06 and P=0.09, respectively). The relationship of TN expression with the histological grade and the proliferative activity was insignificant. In conclusion, stromal TN expression may be involved in the complex mechanism of development of laryngeal lesions and may help to predict the risk of progression of pre-cancerous lesions to cancer.

Cathepsin D↗

PubMed1995

Phylogeny inferred from codon usage pattern in 31 organisms.

We employed the Codonusage database to analyze the codon usage pattern in 31 organisms from all the main biological taxa. We tested the similarity in codon usage pattern between each organism and all the others by the Pearson linear correlation coefficient. The 465 values obtained were located in a 31 x 31 triangular matrix from which a correlation distance matrix was calculated. An evolutionary dendrogram was then constructed from these distances. The results showed a fair correlation between codon usage patterns and phylogenetic relationships, at least for organisms which diverged in rather recent times (end of Jurassic--beginning of Cretaceous).

Animals↗

PubMed2003

Matrix metalloproteinase inhibition alters functional and structural correlates of deafferentation-induced sprouting in the dentate gyrus.

Molecules comprising the extracellular matrix (ECM), and the family of matrix metalloproteinases (MMPs) that regulate them, perform essential functions during neuroplasticity in both developing and adult nervous systems, including substrate guidance during neuritogenesis and the establishment of boundaries for axonal terminal fields. MMP proteolysis of ECM molecules may perform a permissive or inductive role in fiber remodeling and synaptogenesis initiated by deafferentation. This study examined functional and structural effects of MMP inhibition during the early phases of deafferentation-induced sprouting, characterizing components of the degeneration/proliferation cycle that may be dependent on MMP activity. Adult rats received unilateral lesions of the entorhinal cortex to induce collateral sprouting of the crossed temporodentate fiber pathway. This was followed by intraventricular infusion of the MMP inhibitor FN-439 (2.9 mg/kg) or saline vehicle. After 7 d postlesion, rats underwent in vivo electrophysiological recording or histological processing for electron microscopic analysis. Lesioned rats receiving vehicle exhibited normal sprouting and synaptogenesis, with the emergence of the capacity for long-term potentiation (LTP) within the sprouting pathway, and the successful clearance of degenerating terminals with subsequent synaptic proliferation. In contrast, lesioned rats receiving the MMP inhibitor failed to develop the capacity for LTP and showed persistent cellular debris. Current source density analysis also revealed an FN-439-induced disruption of the current sink, normally localized to the middle region of the granule cell dendrites, corresponding to the terminal field of the crossed temporodentate fibers. These results establish a role for MMP-dependent processes in the deafferentation/sprouting cycle.

Afferent Pathways↗

PubMed2003

Expression of matrix metalloproteinase 9 (MMP-9/gelatinase B) in adenocarcinomas strongly correlated with expression of immune response genes.

Matrix metalloproteinases (MMPs) are endopeptidases considered to be important regulators of the microenvironment of cancer. While MMPs are traditionally associated with the extracellular matrix (ECM), here we provide new evidence from an analysis of gene expression profiles from human tumor tissue that MMP-9 (gelatinase B) is associated with elements of the immune system in a way analogous to the association of other MMPs, such as MMP-2 (gelatinase A), with components of the ECM. An analysis of three independent microarray datasets of lung adenocarcinomas from previous studies [Nat. Med. 8, 816-824 (2002); Proc. Natl. Acad. Sci. USA 98, 13790-13795 (2001); Proc. Natl. Acad. Sci. USA, 98, 13784-13789 (2001)] showed that, in each dataset, out of the set of genes with significant correlations in mRNA expression to the expression of MMP9 (P < 0.005), a highly disproportionate number were found to be annotated in the Locuslink database as having a role in the anti-pathogen response. By comparison, out of the set of genes significantly correlated with the expression of MMP2, a highly disproportionate number were known components of the ECM. The same patterns observed in the lung data for both MMP2 and MMP9 were found as well in an additional published dataset of colon and ovarian adenocarcinomas [Am. J. Pathol. 159, 1231-1238 (2001)]. The results of this study suggest a greater functional role for MMP-9 in the immune response to cancer than what may previously have been thought.

Adenocarcinoma↗

PubMed1995

A method to estimate effects of amino acid substitutions in blood coagulation factor IX from hemophilia B patients.

Hemophilia B is a hereditary disease caused by defects in coagulation factor IX. Accumulation of sequence data in the hemophilia B database makes it possible to study this disease at the molecular level. The most common mutations reported in the database are amino acid substitutions. Activity of factor IX in a patient's blood depends on a position of the substitution and combination of original and substituting amino acids. We have developed a method to estimate the effects of amino acid substitutions in factor IX of hemophilia B patients. We adopted two kinds of scores: (1) amino acid homology matrices, and (2) distances obtained from physical-chemical properties of amino acids. We found that: (1) the distance obtained from molecular volume shows the highest correlation with factor IX activity among four physical-chemical properties of amino acids, and (2) Dayhoff's 250PAM matrix gives the highest correlation among three homology matrices. We performed a multiple regression analysis for the estimation of factor IX activity by using four amino acid parameters and obtained a distance matrix, which gives the multiple correlation coefficient 0.6. Hemophilia is a hereditary, X-linked, recessive hemorrhagic disorder. About three-fourths of patients with hemophilia have the A type which is due to deficient factor VIII activity. The B type is less frequent than the A type and is due to deficient factor IX activity. Factor IX is a vitamin K dependent plasma protein that participates in the middle phase of blood coagulation. The entire nucleotide sequence of the factor IX gene was reported by Yoshitake et. al. There have been reported a variety of defects in the factor IX gene from hemophilia B patients, and these are summarized in the hemophilia B database. The effects of amino acid substitutions on the activities of factor IX depends on two factors. One is the combination of native and hemophilic amino acids, the differences of physical-chemical properties of the amino acids. Another is the position of mutation in factor IX protein. In this study, we analyzed missense mutations in the database described with factor IX activity values. Among them, the cases with double mutations were excluded from the analysis, leaving 255 cases. The number of unique mutations are 127. We have introduced distances between 20 amino acids by using the following four physical-chemical properties: (1) Molecular volume, (2)Hydropathy, (3) Polar requirement, and (4) Isoelectric point. We also adopted three homology matrices. These matrices are symmetric and composed of 20 x 20 elements, corresponding to amino acid pairs: (1)Dayhoff's 250 PAM matrix, (2) SCM (Structure-derived Correlation Matrix), and (3) SSM (Structure Superposition Matrix). This analysis shows that the highest correlation with factor á¿ activity is 0.47 given by molecular volume. The second one is 0.4 of Dayhoff's 250 PAM matrix. The multiple regression analysis, using four physicalchemical properties of amino acids, gives a correlation coefficient of 0.60. The amino acid distance obtained by the multiple regression analysis provides a useful measure to estimate the severity of the disease caused by a missense mutation. For example, if the distance between native and hemophilic amino acids is less than 1.5, the ratios of severe cases (activity is less than or equal to 1% of the normal), moderate cases (less than or equal to 4%), and mild cases are 67%, 27% and 6%, respectively.

Amino Acid Sequence↗