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W D Wilson

Publications and source records attributed to W D Wilson.

At least 19 recordsLinked to original sources
PubMed1992

Substituent position dictates the intercalative DNA-binding mode for anthracene-9,10-dione antitumor drugs.

Molecular modeling studies [Islam, S.A., Neidle, S., Gandecha, B.M., Partridge, M., Patterson, L.H., & Brown, J.R. (1985) J. Med. Chem. 28, 857-864] have suggested that anthracene-9,10-dione (anthraquinone) derivatives substituted at the 1,4 and 1,8 positions with-NH(CH2)2NH(CH2CH3)2+ side chains intercalate with DNA with both substituents in the same groove (classical intercalation) while a similarly substituted 1,5 derivative intercalates in a threading mode with one side chain in each groove. Modeling studies also suggested that anthracene-9,10-dione (anthraquinone) derivatives substituted at the 2,6 positions with -NHCO(CH2)R (where R is a cationic group) should bind to DNA by the threading mode, and several such derivatives have been synthesized [Agbandjie, M., Jenkins, T.C., McKenna, R., Reszka, A., & Neidle, S. (1992) J. Med. Chem. 35, 1418-1429]. We have conducted stopped-flow kinetics association and dissociation experiments on the interaction of these anthraquinones with calf thymus DNA and with DNA polymers with alternating AT and GC base pairs to experimentally determine the binding mode and how the threading mode affects intercalation rates relative to similarly substituted classical intercalators. The binding modes, determined by analysis of relative rates, energies of activation, and effects of salt concentration on association and dissociation rate constants, agree completely with the modes predicted by molecular modeling methods. Association and dissociation rate constants for the threading mode are approximately a factor of 10 lower than constants for the classical intercalation mode, and the two modes, thus, have similar binding constants. Variations in rate constants for changes in cationic substituents at the 2 and 6 positions of the anthraquinone ring were surprisingly small.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Stereoelectronic factors in the interaction with DNA of small aromatic molecules substituted with a short cationic chain: importance of the polarity of the aromatic system of the molecule.

We have performed a quantitative analysis of the interaction with DNA of several unfused aromatic compounds synthesized in our laboratory and substituted with one or two short cationic chains. These and similar literature compounds, for which DNA binding data are available, bind with DNA by partial intercalation of the aromatic system, groove interaction of the linker chain, and groove electrostatic interactions of the terminal cationic group. Several independent quantitative and qualitative approaches show consistently that the strength of the interaction of the aromatic unit of the molecule with DNA binding sites depends on the direction and magnitude of polarity of the aromatic system. The phenomenon is explained in terms of the greatest negative potential in the DNA grooves, a concept extensively elaborated by Pullman and Pullman [cf. Lavery, R. and Pullman, B. [(1985) J. Biomol. Struct. Dyn. 2, 1021-1032] and references therein]. Classical, fused-ring planar intercalators do not follow the polarity-DNA affinity correlation, presumably because the intercalative forces depend more strongly on polarizability than on polarity of the aromatic system.

Animals↗
PubMed1992

Prepurchase evaluation of horses: 134 cases (1988-1990).

To quantify some components of prepurchase evaluations in horses, records from 134 evaluations performed during a 2-year period were reviewed and the outcome was determined via telephone follow-up interview. Sixty-two percent of the prepurchase evaluations had been performed at the clinic and 38% had been performed in the field by the ambulatory service. All evaluations included physical and lameness examinations, whereas radiography (49%), endoscopy (15%), nerve blocking (5%), transrectal palpation (3%), hematologic analysis (2%), electrocardiography (2%), drug testing for analgesic agents (2%), and ultrasonography of the flexor tendons (1%) were not always performed. Fifty-nine percent of horses evaluated at the clinic were radiographed, compared with 33% of horses evaluated in the field (P less than 0.05). Thirty-seven percent of horses evaluated were judged serviceable for their intended use. Thirty-five percent of horses evaluated at the clinic were assessed to be serviceable, compared with 41% of those evaluated in the field (P less than 0.05). Horses used for pleasure riding (48%) tended to be considered serviceable more often than horses used for more athletic endeavors (3-day eventing, 33%; hunter/jumper, 24%; show, 31%; dressage, 30%). The most common basis for finding a horse unserviceable was lameness (88%).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

DAPI (4',6-diamidino-2-phenylindole) binds differently to DNA and RNA: minor-groove binding at AT sites and intercalation at AU sites.

The interaction of DAPI and propidium with RNA (polyA.polyU) and corresponding DNA (polydA.polydT) sequences has been compared by spectroscopic, kinetic, viscometric, Tm, and molecular modeling methods. Spectral changes of propidium are similar on binding to the AT and AU sequences but are significantly different for binding of DAPI. Spectral changes for DAPI with the DNA sequence are consistent with the expected groove-binding mode. All spectral changes for complexes of propidium with RNA and DNA and for DAPI with RNA, however, are consistent with an intercalation binding mode. When complexed with RNA, for example, DAPI aromatic protons signals shift significantly upfield, and the DAPI UV-visible spectrum shows significantly larger changes than when complexed with DNA. Slopes of log kd (dissociation rate constants) versus-log [Na+] plots are similar for complexes of propidium with RNA and DNA and for the DAPI-RNA complex and are in the range expected for an intercalation complex. The slope for the DAPI-DNA complex, however, is much larger and is in the range expected for a groove-binding complex. Association kinetics results also support an intercalation binding mode for the DAPI-RNA complex. The viscosity of polyA.polyU solutions increases significantly on addition of both propidium and DAPI, again in agreement with an intercalation binding mode for both molecules with RNA. Molecular modeling studies completely support the experimental findings and indicate that DAPI forms a very favorable intercalation complex with RNA. DAPI also forms a very stable complex in the minor groove of AT sequences of DNA, but the stabilizing interactions are considerably reduced in the wide, shallow minor groove of RNA. Modeling studies,thus,indicate that DAPI interaction energetics are more favorable for minor-groove binding in AT sequences but are more favorable for interaction in RNA.

Adenine Nucleotides↗
PubMed1992

A molecular mechanics investigation of RNA complexes. I. Ethidium intercalation in an HIV-1 TAR RNA sequence with an unpaired adenosine.

Nucleic acid complexes with ethidium intercalated into different sites in a segment of HIV-1 TAR RNA with an unpaired A base, along with corresponding complexes with a normal RNA sequence without an unpaired base were studied by molecular mechanics energy minimization methods. Different intercalation geometries as well as different orientations of the ethidium molecule in the intercalation sites were tested. A general binding affinity enhancement for the ethidium binding to the bulge sequence compared with the normal RNA segment was obtained. With the unpaired adenosine base stacked in the duplex, the binding site adjacent to the 3' side of the bulge was found to be the most energetically favorable binding site, and the intercalation site 5' to the bulge in the same sequence is much less favorable. Unique correlated backbone conformational changes on binding of ethidium to the intercalation site 3' to the bulge were found to relieve backbone strains caused by the stacking of the unpaired base into the helix. These backbone conformational changes present a plausible molecular basis for the experimentally observed ethidium binding preference in this bulge RNA segment (L.S. Ratmeyer, R. Vinayak, G. Zon and W.D. Wilson, J. Med. Chem. 35, 966, 1992).

Base Sequence↗
PubMed1991

Structures of 1-(3,3-dimethylamino)propyl naphtho[2,1-b]thiophene-4- carboxylate and N-(3,3-dimethylamino)propyl-8-methoxynaphtho[2,1- b]thiophene-4-carboxamide, intercalators into double-helical DNA.

(1) C18H19NO2S, Mr = 313.42, monoclinic, P2(1)/c, a = 11.503 (3), b = 15.932 (2), c = 9.133 (2) A, beta = 102.17 (2) degrees, V = 1636.1 A3, lambda(Cu K alpha) = 1.54178 A, mu = 1.762 mm-1, F(000) = 664, T = 293 (1) K, R = 0.047 for 2044 significant reflections. (2) C19H21NO3S, Mr = 343.45, triclinic, Pl, a = 9.873 (2), b = 13.163 (3), c = 14.065 (3) A, alpha = 101.33, beta = 94.30 (3), gamma = 91.35 (3) degrees, V = 1785.8 A3, Z = 4, Dx = 1.28 Mg m-3, lambda(Cu K alpha) = 1.54178 A, mu = 1.699 mm-1, F(000) = 728, T = 293 (1) K, R = 0.052 for 1787 significant reflections. The torsion angle between the naphthothiophene ring and the carbonyl O atom of the side chain is 5.5 (4) degrees in structure (1) and 25 (2) and -32 (2) degrees in the two independent molecules of (2). This difference is due to out-of-plane distortions in (2) that arise from steric hindrance between H atoms on the amide and the ring system, at position 2.

Intercalating Agents↗
PubMed1991

Thermodynamics of DNA duplexes with adjacent G.A mismatches.

The sequence 5'-d(ATGAGCGAAT) forms a very stable self-complementary duplex with four G.A mismatch base pairs (underlined) out of ten total base pairs [Li et al. (1991) Proc. Natl. Acad. Sci. U.S.A. 88, 26-30]. The conformation is in the general B-family and is stabilized by base-pair hydrogen bonding of an unusual type, by favorable base dipole orientations, and by extensive purine-purine stacking at the mismatched sites. We have synthesized 13 decamers with systematic variations in the sequence above to determine how the flanking sequences, the number of G.A mismatches, and the mismatch sequence order (5'-GA-3' or 5'-AG-3') affect the duplex stability. Changing A.T to G.C base pairs in sequences flanking the mismatches stabilizes the duplexes, but only to the extent observed with B-form DNA. The sequence 5'-pyrimidine-GA-purine-3', however, is considerably more stable than 5'-purine-GA-pyrimidine-3'. The most stable sequences with two pairs of adjacent G.A mismatches have thermodynamic parameters for duplex formation that are comparable to those for fully Watson-Crick base-paired duplexes. Similar sequences with single G.A pairs are much less stable than sequences with adjacent G.A mismatches. Reversing the mismatch order from 5'-GA-3' to 5'-AG-3' results in an oligomer that does not form a duplex. These results agree with predictions from the model derived from NMR and molecular mechanics and indicate that the sequence 5'-pyrimidine-GA-purine-3' forms a stable conformational unit that fits quite well into a B-form double helix.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenine↗
PubMed1991

Duplex stabilities of phosphorothioate, methylphosphonate, and RNA analogs of two DNA 14-mers.

The duplex stabilities of various phosphorothioate, methylphosphonate, RNA and 2'-OCH3 RNA analogs of two self-complementary DNA 14-mers are compared. Phosphorothioate and/or methylphosphonate analogs of the two sequences d(TAATTAATTAATTA) [D1] and d(TAGCTAATTAGCTA) [D2] differ in the number, position, or chirality (at the 5' terminal linkage) of the modified phosphates. Phosphorothioate derivatives of D1 are found to be less destabilized when the linkage modified is between adenines rather than between thymines. Surprisingly, no base sequence effect on duplex stabilization is observed for any methylphosphonate derivatives of D1 or D2. Highly modified phosphorothioates or methylphosphonates are less stable than their partially modified counterparts which are less stable than the unmodified parent compounds. The 'normal' (2'-OH) RNA analog of duplex D1 is slightly destabilized, whereas the 2'-OCH3 RNA derivative is significantly stabilized relative to the unmodified DNA. For the D1 sequence, at approximately physiological salt concentration, the order of duplex stability is 2'-OCH3 RNA greater than unmodified DNA greater than 'normal' RNA greater than methylphosphonate DNA greater than phosphorothioate DNA. D2 and the various D2 methylphosphonate analogs investigated all formed hairpin conformations at low salt concentrations.

Base Sequence↗
PubMed1991

Kinetic and equilibrium analysis of a threading intercalation mode: DNA sequence and ion effects.

The interaction of a symmetric naphthalene diimide with alkylamino substituents at each imide position was investigated with the alternating sequence polymers, poly[d(A-T)]2 and poly[d(G-C)]2. Spectrophotometric binding studies indicate strong binding of the diimide to both sequences although the GC binding constant is 20-25 times larger than the AT binding constant. Analysis of the effects of salt concentration on the binding equilibria shows that the diimide forms two ion pairs in its complex with both polymers as expected for a simple dication. Stopped-flow kinetics experiments demonstrate that the diimide both associates and dissociates from DNA more slowly than classical intercalators with similar binding constants. Analysis of salt concentration effects on dissociation kinetics rate constants (kd) reveals that slopes in log kd versus log [Na+] plots are only approximately half the value obtained for classical dicationic intercalators that have both charged groups in the same groove. These kinetics results support a threading intercalation model, with one charged diimide substituent in each of the DNA grooves rather than with both side chains in the same groove, for the diimide complex with DNA. In the rate-determining step of the mechanism for dissociation of a threading complex only one ion pair is broken; the free side chain can then slide between base pairs to put both diimide side chains in the same groove, and this is followed by rapid full dissociation of the diimide. This sequential release of ion pairs makes the dissociation slope for dicationic threading intercalators more similar to the slope for classical monocationic intercalating ligands.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1991

Hairpin formation within the enhancer region of the human enkephalin gene.

The 3',5'-cyclic adenosine monophosphate (cAMP)-inducible enhancer of the human enkephalin gene is located within an imperfect palindrome of 23 base pairs. We have found that a 23-base-pair oligonucleotide duplex containing the enhancer undergoes a reversible conformational transition from the duplex to two individual hairpin structures each formed from one strand of the duplex. Each individual hairpin forms with mismatched base pairs, one containing two GT pairs and the other containing two AC pairs. The conformational transition is stabilized by proton transfer to the hairpin containing AC mismatched pairs. The unique physical and thermodynamic properties of the enkephalin enhancer DNA suggest a model in which DNA secondary structure within the enhancer region plays an active role in cAMP-inducible activation of the human enkephalin gene via formation of cruciform structures.

Animals↗
PubMed1991

NMR and molecular modeling evidence for a G.A mismatch base pair in a purine-rich DNA duplex.

1H NMR experiments indicate that the oligomer 5'-d(ATGAGCGAATA) forms an unusual 10-base-pair duplex with 4 G.A base pairs (underlined) and a 3' unpaired adenosine. NMR results indicate that guanosine imino protons of the G.A mismatches are not hydrogen bonded but are stacked in the helix. A G----I substitution in either G.A base pair causes a dramatic decrease in duplex stability and indicates that hydrogen bonding of the guanosine amino group is critical. Nuclear Overhauser effect spectroscopy (NOESY) and two-dimensional correlated spectroscopy (COSY) results indicate that the overall duplex conformation is in the B-family. Cross-strand NOEs in two-dimensional NOESY spectra between a mismatched AH2 and an AH1' of the other mismatched base pair and between a mismatched GH8 and GNH1 of the other mismatch establish a purine-purine stacking pattern, adenosine over adenosine and guanosine over guanosine, which strongly stabilizes the duplex. A computer graphics molecular model of the unusual duplex was constructed with G.A base pairs containing A-NH2 to GN3 and G-NH2 to AN7 hydrogen bonds and B-form base pairs on both sides of the G.A pairs [5'-d(ATGAGC)]. The energy-minimized duplex satisfies all experimental constraints from NOESY and COSY results. A hydrogen bond from G-NH2 of the mismatch to a phosphate oxygen is predicted.

Adenine↗
PubMed1991

Partial intercalation with DNA of peptides containing two aromatic amino acids.

The interactions with DNA of tetrapeptide amides containing lysine at the N-terminal position and aromatic amino acids at the second and fourth positions (Ala at position three), 1-6, have been investigated by nmr, CD, and viscometric methods. Tetrapeptides with N-terminal lysine and a single aromatic amino acid, 7-10, were investigated as controls. Significant decreases in DNA viscosity occurred on addition of 7, with the aromatic group at the second position, but not with any of the other single aromatic amino acid peptides. All of the tetrapeptides with two aromatic groups caused DNA viscosity decreases which were two to three times larger than with 7. Peptides with p-nitrophenylalanine (p-NO2Phe) as the aromatic group were synthesized for nmr studies because of its simpler aromatic nmr spectrum relative to Phe. Large upfield shifts of the aromatic proton signals were obtained when the amino acid in the second position was L-p-NO2Phe, and the fourth position contained either p-NO2Phe or Phe. Such peptides also caused the largest DNA viscosity decreases on complex formation. Smaller upfield shifts of the aromatic signals were obtained when the amino acid in the second position was L-Phe or a D isomer of Phe or p-NO2Phe. With all peptides, larger upfield nmr shifts were obtained with heat-denatured, recooled DNA than with native DNA under the same conditions. As with nmr, CD results are quite different for the peptides with L and D amino acids at the second position. All of the results can be interpreted in terms of a model in which lysine interacts stereospecifically with the backbone in a DNA double helix and the aromatic group at the second position stacks strongly with the base pairs when the amino acid is an L isomer. The aromatic group at the fourth position can also interact with the base pairs, but primarily through a sideways stacking of the aromatic group with base pairs for either L or D isomers. Because of covalent constraints on the separation distance for the two aromatic groups in the tetrapeptides, they must stack on opposite sides of the same base pair in violation of the neighbor exclusion principle observed with classical intercalators. This stacking at the same base pair no doubt accounts for the larger viscosity decreases in DNA with the peptides containing two aromatic groups relative to those with a single aromatic group.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1991

Intercalation binding of 6-substituted naphthothiopheneamides to DNA: enthalpy and entropy components.

N-(3-dimethylaminopropyl)naphtho[2,1-b]thiophene-4-carboxamide and the 6-substituted methoxy, methyl, fluoro, chloro, bromo, trifluoromethyl, and cyano derivatives have been shown to bind to DNA via intercalation with binding constants in the 35-900 X 10(3) range at 25 degrees C, pH 7, and [Na+] = 0.019M. Both electron-donating and -withdrawing substituents enhance intercalation binding, but the binding affinity is most enhanced by the cyano substituent. Calorimetric titrations for calf thymus DNA differ dramatically from those reported for ethidium [Hopkins et al. (1990) Biopolymers Vol. 29, pp. 449-459]. Apparent enthalpy parameters (delta HB) for intercalation are constant only at low coverage of sites and become much more positive as saturation is approached. In the plateau region, delta HB values for the parent and the cyano-, fluoro-, chloro-, and bromo-substituted compounds are nearly the same (approximately -5.9 kcal/mol). For the methyl- (-6.8 kcal/mol) and methoxy- (-7.5 kcal/mol) substituted compounds, the delta HB values are more exothermic than that for the unsubstituted compound, whereas delta HB for the trifluoromethyl compound is approximately 1 kcal/mol less exothermic. The corresponding delta SB values, corrected for mixing effects, are in the 7-15-cal/deg/mol range and are approximately linearly related to delta HB if the cyano derivative is excluded.

Calorimetry↗
PubMed1991

Quantitative structure-activity relationship analysis of cation-substituted polyaromatic compounds as potentiators (amplifiers) of bleomycin-mediated degradation of DNA.

A set of 21 polyheteroaromatic compounds substituted with flexible cationic groups and of similar molecular size has been analyzed for binding with DNA and for effects of the bleomycin-mediated degradation of the DNA double helix. Increases in apparent rates of the DNA digestion were observed in all cases under the experimental conditions of noncompetitive binding of these compounds and bleomycin to DNA. Surprisingly, the quantitative structure-activity relationship analysis revealed two distinct correlations despite close structural similarities for the set of bleomycin amplifiers. These unusual results are explained in terms of the formation of two stereochemically different ternary complexes of activated bleomycin-DNA-amplifier. The relevance of this finding for the design of new bleomycin amplifiers is discussed.

Amplifiers, Electronic↗
PubMed1991

Modeling of nucleic acid complexes with cationic ligands: a specialized molecular mechanics force field and its application.

A potential energy force field designed for modeling nucleic acids and particularly their complexes with cationic ligands is presented. The force field is a modified version of that developed by Weiner, S.J., Kollman, P.A., Nguyen, D.T. and Case, D.A.,J. Comp. Chem. 7,230-252 (1986) and is based upon the use of a distance dependent dielectric constant, epsilon = 4rij, and partially neutralized phosphates to represent solvent and counterion. Changes from the Weiner et al. force field include additional atom types and modifications to van der Waals, electrostatic, hydrogen bonding and torsional parameters. Molecular modeling test cases of the force field are presented for a number of simple small molecules, as well as uracil and benzene dimerization, thymine-adenine and cytosine-guanine base pair formation, and adenosine/deoxyadenosine pseudorotation. Several DNA and RNA oligomers and DNA/RNA intercalation complexes with ethidium are also modeled with the force field. In all cases, the modeling results compare favorably with available experimental results. Additionally, conformational trends observed experimentally for nucleic acids by NMR and X-ray crystallographic techniques are reproduced. The modeling results for ethidium intercalation indicate a complex in which the favorable interactions are primarily van der Waals contacts, and in which electrostatic interactions are a relatively minor component. We feel the force field is particularly useful for molecular mechanics aided drug design, and an analysis of modeling results with respect to design of drugs which bind selectively to RNA is presented.

Base Sequence↗
PubMed1991

Pharmacokinetics and bioavailability of ticarcillin and clavulanate in foals after intravenous and intramuscular administration.

The pharmacokinetics and bioavailability of ticarcillin and clavulanate were determined after intravenous (i.v.) or intramuscular (i.m.) administration of ticarcillin disodium (50 mg/kg) combined with clavulanate potassium (1.67 mg/kg) to groups of healthy foals at 3 days and 28 days of age. After i.v. administration of the combination to five foals, the disposition kinetics of ticarcillin and clavulanate were best described using a two-compartment open model. Mean plasma elimination-rate constant (beta) and clearance (ClB) for ticarcillin were significantly less (P less than 0.01), and volume of distribution at steady state (Vd(ss)) was significantly larger (P less than 0.05), in the foals at 3 days compared with 28 days of age. This indicated that renal excretion mechanisms were immature and ticarcillin was more widely distributed in 3-day-old foals. The mean elimination rate constant for clavulanate was significantly less (P less than 0.01) at 3 days than at 28 days of age. Values of the major kinetic terms describing the disposition of ticarcillin after i.m. administration to five 3-day-old foals were not significantly different from values of these parameters in the same foals at 28 days of age. After i.m. administration of the drug combination, plasma clavulanate concentrations peaked significantly later (P less than 0.01), and the elimination-rate constant (kd) for clavulanate was significantly less (P less than 0.01), in 3-day-old foals than in 28-day-old foals. The bioavailabilities of ticarcillin and clavulanate after i.m. administration in 3-day-old foals were 100% and 88.3%, respectively, and in 28-day-old foals were 100% and 27.4%, respectively. Mean plasma ticarcillin concentrations exceeded 16 micrograms/ml for a longer period after i.m. administration of the drug combination than after i.v. administration to foals of both age groups. By virtue of the frequency of administration required and the painful response elicited by i.m. injection, it is recommended that when the combination of ticarcillin disodium (50 mg/kg) and clavulanate potassium (1.67 mg/kg) is used in foals to treat infections caused by susceptible organisms (MIC less than or equal to 16 micrograms/ml), it should be administered i.v. four times daily.

Age Factors↗
PubMed1991

Influence of age on the disposition kinetics of chloramphenicol in equine neonates.

The effect of age on the pharmacokinetics of chloramphenicol was determined after IV administration of chloramphenicol sodium succinate (25 mg/kg of body weight) to 6 foals at 1 day and 3, 7, 14, and 42 days of age. The disposition of chloramphenicol was best described, using a two-compartment open model in all foals at all ages evaluated. Significant age-related changes were observed in values for the major kinetic terms describing the disposition of chloramphenicol in foals; the greatest changes were observed between 1 day and 3 days of age. The mean +/- SD value for elimination rate constant (beta) for chloramphenicol in 1-day-old foals (0.131 +/- 0.06 h-1) was significantly (P less than 0.005) lower than the value in 3-day-old foals (0.514 +/- 0.156 h-1), and both values were significantly (P less than 0.05) lower than values for beta in 7-, 14-, and 42-day-old foals. With increasing age, the increase in the mean value for beta resulted in decrease in the harmonic mean elimination half-time (t1/2 beta) for chloramphenicol, from 5.29 hours in 1-day-old foals to: 1.35 hours in 3-day-old foals; 0.61 hour in 7-day-old foals; 0.51 hour in 14-day-old foals; and 0.34 hour in 42-day-old foals. At 1, 3, and 7 days of age, values for t1/2 beta of chloramphenicol in a premature foal born after parturition was induced with oxytocin, were considerably longer than comparable t1/2 beta values for term foals born naturally.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗