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PubMed1978

Modified bases in the DNAs of unicellular eukaryotes: an examination of distributions and possible roles, with emphasis on hydroxymethyluracil in dinoflagellates.

The occurrence of small amounts of one or more of several modified bases in the DNA of an organism is widespread in nature. Prominent among these bases are 5-methylcytosine, N6-methyladenine and 5-hydroxymethyluracil. All can be found in varying amounts in DNA of viral, prokaryotic and eukaryotic origin. In some organisms, modified nucleotides comprise a large fraction of DNA nucleotides and in others there is complete replacement of one of the common four nucleotides by a modified one. This article discusses the distributions and possible roles of the several modified bases found in prokaryote and eukaryote DNAs. Emphasis is given (1) methylcytosine in a broad variety of eukaryotes, (2) methyladenine in certain protozoa and protophyta and (3) hydroxymethyluracil in dinoflagellates. Attention is focused on the phenomenology and the possible consequences of the presence of hydroxymethyluracil in DNA.

Adenine↗
PubMed1991

Modified Bielschowsky and immunohistochemical studies on senile plaques in aged dogs.

Aged dogs developed senile plaques (SP) in the brain which were similar to those occurring in aged humans. These SP were studied with a modified Bielschowsky stain and immunohistochemical methods using polyclonal antibodies raised against beta-protein and glial fibrillary acidic protein (GFAP). Serial sections stained by immunohistochemical and modified Bielschowsky stains showed that all areas of slight beta-protein immunoreactivity were intensely stained by the modified Bielschowsky stain. Most SP were observed in the neocortex of the cerebrum. Plaque densities were highest in the cingulate and temporal cortices. There were occasional SP in the subcortical nuclei including the caudate nucleus and putamen, and hippocampus. Based on the morphological characteristics demonstrated by the modified Bielschowsky stain, SP in the brains of the dogs were grouped into 3 types: diffuse, mature and perivascular plaques, of which diffuse plaques were predominant. Various degrees of astroglial reaction were observed in all subtypes of SP except diffuse plaques. These findings indicate that dog may serve as a model for study of the pathogenesis of SP.

Aging↗
PubMed1981

An H-2 linked difference in the binding of dexamethasone to murine hepatic cytosol receptor. A possible role of endogenous modifier(s).

The binding of dexamethasone to its receptor in hepatic cytosol preparations from pregnant mice of four congenic and recombinant strains, C57BL/10, B10.A, B10.A(2R) and B10.A(5R), which have almost identical genetic backgrounds other than the H-2 complex, on day 12 of gestation was analyzed by plotting the binding of ligand against cytosol concentration. The plots of C57BL/10 and B10.A(5R) mice were straight lines, but those of the strains B10.A and B10.A(2R) were upward concave curves. The curvature probably did not result from denaturation of the receptor, as indicated by the time course of the dexamethasone binding and by the fact that at a lower concentration of the ligand, at which the receptor would be less stable, there was less curvature than at a higher concentration of the ligand. The curvature can be explained by the presence of endogenous modifier(s) using an analogy from enzymology. Mathematical analysis, partial removal of the modifier(s) by gel filtration, and mixing of the cytosols from the two types of strains indicated the presence of an unsaturated amount of a modifier(s) in the cytosol of the B10.A and B10.A(2R) strains, and the presence of a saturated amount of the cytosol of the C57BL/10 and B10.A(5R) strains. Thus, the H-2 complex contains a gene(s) which regulates the level of a modifier(s) in hepatic cytosol which affects the binding of glucocorticoid to its hepatic cytosolic receptor.

Animals↗
PubMed1983

Gating and selectivity of aconitine-modified sodium channels in neuroblastoma cells.

Currents through normal and aconitine-modified sodium channels in perfused neuroblastoma cells were measured under voltage-clamp conditions. Aconitine is shown to induce changes in channel selectivity so that channels become more permeable to NH4+ than to Na+. Aconitine induces the shift of voltage dependence of channel activation toward more negative potentials by about 20 mV. Aconitine-modified channels inactivate practically completely with a time-course similar to that for normal channels. Aconitine is effective when applied to either side of the membrane. Steady-state characteristics of the gating machinery of aconitine-modified channels are discussed in terms of three-state model. According to the model, aconitine increases the probability of finding the channel in open state, which is reflected in negative shift of the voltage dependence of activation. The model predicts that the larger this shift, the higher is the level of steady-state sodium conductance. The comparison of respective properties of aconitine-modified channels in neuroblastoma cell and frog nerve confirms this prediction. Aconitine is assumed to reach its receptor through the lipophilic part of the membrane.

Aconitum↗
PubMed1992

Implantation of genetically modified mesencephalic fetal cells into the rat striatum.

Transplantation of dopamine (DA) cells into the rat model of hemiparkinsonism induced by intranigral 6-hydroxydopamine (6-OHDA) injections has so far focused mainly on DA replacement via a pump-like mechanism. In the present study, we employed a model of hemiparkinsonism that uses an intrastriatal approach to lesioning the nigrostriatal DA pathway to assess the possibility of using cell transplantation to cause regeneration of that system. Toward that end, we transplanted two types of cells on the side of the 6-OHDA-induced lesions: 1) nonmodified fetal mesencephalic cells and 2) fetal mesencephalic cells that have been infected with a retrovirus vector containing a PKC beta 1 cDNA. Both types of cells cause behavioral improvement although the changes were more prominent and occurred earlier in the PKC-modified groups. Tyrosine hydroxylase (TH) immunocytochemistry revealed significantly cell survival in both groups of animals; in situ hybridization studies confirmed the continuous expression of TH mRNA in both groups. Interestingly, long TH-positive axons were observed only in the striata of animals implanted with PKC-modified cells. More importantly, surviving endogenous nigral TH-positive cell bodies were found only on the lesioned side in the latter group. The observations in these animals were associated with significantly smaller decreases in [3H]mazindol-labeled DA uptake sites in both the striata and substantia nigra pars compacta on the side ipsilateral to the 6-OHDA-induced lesions. Furthermore, immunohistochemical studies revealed increased gliosis in the striata of animals grafted with the PKC-modified cells. When taken together, these results indicate that transplantation of normal fetal mesencephalic cells can cause behavioral improvement by providing DA to the host striata whereas PKC-modified cells can, in addition, prevent the progressive degeneration of or cause regeneration of the dying nigrostriatal DA neurons in this model of hemiparkinsonism. These results are discussed in terms of their support for a role for second messenger systems and glial cells, as well as extracellular matrix molecules in the regeneration of the CNS.

Amphetamine↗
PubMedDate not supplied

Evaluation of the modified Visuwell Strep-A enzyme immunoassay for detection of group-A Streptococcus from throat swabs.

The modified Visuwell Strep-A enzyme immunoassay (EIA) was compared with culture for detection of group-A Streptococcus from throat swabs. Throat swabs in modified Stuarts medium obtained after culture at two institutions were tested in Visuwell. Cumulative results were n = 417, sensitivity 87.8%, specificity 89.9% predictive value positive (PVP) 67.9%, predictive value negative (PVN) 96.8%, and accuracy 89.5%. At another site, swabs were delivered to the laboratory without transport medium, cultured, and subsequently tested by Visuwell (n = 202, sensitivity 79.6%, specificity 84.5%, PVP 65.2%, PVN 91.9%, accuracy 83.2%). When 1+ culture-positive specimens were considered negative, the sensitivity and PVN increased from 79.6% to 90.2% and 91.9% to 97.1% respectively. Overall performance of the modified Visuwell was comparable with that of the initial assay for throat swabs transported with or without modified Stuarts medium. Cross reaction with organisms other than group-A Streptococcus normally found in the oropharynx was negligible in Visuwell and the limit of detection of group-A Streptococcus was 5 x 10(4) colony-forming units.

Cross Reactions↗
PubMed1994

Evaluation of 99mTc-labeled modified serum albumin for tumor detection.

Serum albumin (SA) modified and labeled with 131I-tyramine N-1'-desoxysorbitol (131I-TDS) has been shown to localize in tumors [Sinn et al., (1990) Nucl. Med. Biol. Part B 17, 819-827]. We prepared similar TDS complexes labeled with 99mTc and evaluated their potential for tumor imaging. Derivatization of SA with TDS was optimized using cyanuric chloride or 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDAC) as coupling agents. A high TDS loading yield of 38 mol/mol SA was obtained with the latter reagent. Modified SA (8 and 38 mol TDS/mol SA) were labeled with 99mTc via the stannous reduction method and injected i.v. into EMT-6 tumor bearing mice. 125I-TDS-SA (8 mol 125I-TDS/mol SA) revealed a high tumor uptake of 10% ID/g at 3 h post-injection. The 99mTc-labeled SA and TDS-SA complexes lacked tumor specificity, instead TDS loading of SA resulted in increased liver/spleen uptake, suggesting colloid formation. This study confirms the potential of modified SA for tumor imaging but highlights the importance of choice of radioisotope, as well as site of attachment of the radiolabel to the modified SA for optimal tumor localization.

Animals↗
PubMed1995

A modified liquid diet of chronic ethanol administration: validation by ethanol withdrawal syndrome in rats.

The validity of a modified liquid diet prepared from cow's milk, 7.2% ethanol, vitamin A and sucrose mixture has been investigated for chronic ethanol administration in rats. The rats fed by the modified liquid diet lost 3.8% of their body weight along 20 days. The mean ethanol consumption was in the range of 12.6 to 17.6 g kg-1 day-1. The blood ethanol level just before the withdrawal of ethanol was found to be 301.38 +/- 36.68 mg dl-1. A severe ethanol withdrawal syndrome was observed after 20-day exposure to ethanol in the modified liquid diet. The results suggest that the modified liquid diet can be used satisfactorily for chronic ethanol administration in rats.

Alcohol Drinking↗
PubMed2006

Diagnosis of lower limb deep venous thrombosis in emergency department patients: performance of Hamilton and modified Wells scores.

STUDY OBJECTIVE: We validate and compare the Hamilton score for assessment of lower limb deep venous thrombosis with the modified Wells score. METHODS: Consecutive patients presenting to the emergency department of a tertiary center for suspected lower limb deep venous thrombosis were prospectively recruited. Hamilton score and modified Wells score calculations, D-dimer, and complete (calf veins included), single lower limb ultrasonographic examination were performed for all patients. All patients with a negative ultrasonographic examination result for deep venous thrombosis were followed up for 3 months. RESULTS: The study population consisted of 116 men and 193 women, with an average age of 55.6 years (SD 20.1). A total of 67 (21.7%) patients were diagnosed with deep venous thrombosis. Forty (59.7%) of these patients had isolated calf deep venous thrombosis, and the other 27 (40.3%) patients had proximal deep venous thrombosis. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (LR+), and negative likelihood ratio (LR-) for an unlikely Hamilton score (score < or = 2) and D-dimer were 99% (95% confidence interval [CI] 92% to 99.96%), 42 % (95% CI 36% to 49%), 32% (95% CI 26% to 39%), 99% (95% CI 95% to 99.98%), 1.7 (95% CI 1.52% to 1.9%), and 0.04 (95% CI 0.01 to 0.25), respectively. The sensitivity, specificity, PPV, NPV, LR+ and LR- for an unlikely modified Wells score (score < or = 1) and D-dimer were 99% (95% CI 92% to 99.96%), 33 % (95% CI 27% to 39%), 29% (95% CI 23% to 35%), 99% (95% CI 93% to 99.97%), 1.47 (95% CI 1.34 to 1.62), and 0.05 (95% CI 0.01 to 0.32), respectively. CONCLUSION: An unlikely probability of Hamilton score and a negative D-dimer may effectively exclude a lower limb deep venous thrombosis. Hamilton and modified Wells scores have similar performance characteristics.

Data Collection↗
PubMed2007

Evaluation of a modified prediction instrument to identify significant pediatric intracranial injury after blunt head trauma.

STUDY OBJECTIVE: We evaluate the effect of a modification of the University of California-Davis Pediatric Head Injury Rule on the ability of the decision instrument for pediatric head injury to predict clinically important intracranial injury in an external cohort. METHODS: We analyzed data prospectively recorded in 1,666 pediatric patients enrolled in the derivation set of the National Emergency X-Radiography Utilization Study II (NEXUS II). Treating physicians at 21 emergency departments recorded the presence or absence of clinical predictors on all patients who received a head computed tomography (CT) scan after experiencing blunt head trauma. Predictors included 3 exact elements of the University of California-Davis Rule (abnormal mental status, signs of skull fracture, and scalp hematoma in children < or = 2 years of age), some with different wording, and 2 modified elements with new definitions (the presence of high-risk vomiting or severe headache, rather than any vomiting or headache). RESULTS: A significant intracranial injury was identified by CT in 138 (8.3%) patients. Sensitivity of the modified instrument to detect significant intracranial injury was 90.4% (95% confidence interval [CI] 85.4% to 95.4%); 13 children with such an injury were misclassified as low risk. Specificity of the modified instrument was 42.7% (95% CI 40.1% to 45.3%). CONCLUSION: In the NEXUS II cohort, a modified version of the University of California-Davis Rule misclassified a substantial proportion of pediatric patients with clinically important blunt head injury. Although we cannot evaluate the exact University of California-Davis Rule, we demonstrate that using stricter definitions of "headache" and "vomiting" and different wording than in the original study may have unintended or negative consequences. We emphasize the importance of careful attention to precise definitions of clinical predictors when a decision instrument is used.

Adolescent↗
PubMed2006

Native pentameric C-reactive protein displays more potent pro-atherogenic activities in human aortic endothelial cells than modified C-reactive protein.

Inflammation is pivotal in atherogenesis. Numerous prospective studies have shown that levels of high sensitive C-reactive protein (CRP) predict cardiovascular events. Recently, data suggests that CRP could be a mediator in atherothrombosis. Loss of pentameric symmetry in CRP has been shown to result in the formation of modified CRP (mCRP). The main aim of this study was to examine the biological effects of the native, pentameric form of CRP compared to a modified form in human aortic endothelial cells. Human pentameric native CRP (n-CRP) from two different sources (recombinant and serum) was purified and used. It was then subjected to EDTA chelation and urea treatment to prepare modified CRP (m-CRP). Purity of both n-CRP and m-CRP preparations was checked by gel electrophoresis. Both n-CRP and m-CRP were incubated with human aortic endothelial cells (HAEC) and biological activities was tested by assaying for interleukin-8 (IL-8), plasminogen activator inhibitor-1(PAI-1), cyclic GMP and prostaglandin F1-alpha. n-CRP significantly upregulated IL-8 at concentrations > or = 10 microg/mL while m-CRP upregulated IL-8 only at concentrations of 50 microg/mL (p < 0.05). PAI-1 levels were significantly increased to a greater extent with native compared to m-CRP (p < 0.05). While both decreased PGF1-alpha at concentrations of 50 microg/mL, the effect of native CRP was more pronounced and was evident at 10 microg/mL (p < 0.05). The most pronounced difference was observed with regard to inhibition of eNOS activity as assessed by cGMP which was observed at 10 microg/ml of native CRP but only at 50 microg/mL for m-CRP (native CRP versus mCRP: p < 0.001). Thus, native pentameric CRP compared to modified CRP exerts more potent atherogenic effects in human aortic endothelial cells.

Aorta↗
PubMed2006

Associations between HDL-cholesterol and polymorphisms in hepatic lipase and lipoprotein lipase genes are modified by dietary fat intake in African American and White adults.

Polymorphisms in genes involved in HDL-cholesterol (HDL-C) metabolism influence plasma HDL-C concentrations. We examined whether dietary fat intake modified relations between HDL-C and polymorphisms in hepatic lipase (LIPC-514C-->T), cholesteryl ester transfer protein (CETP TaqIB), and lipoprotein lipase (LPL S447X) genes. Diet (food frequency questionnaire), plasma lipids, and LIPC, CETP, and LPL genotypes were assessed in approximately 12,000 White and African American adults. In both races and all genotypes studied, minor allele homozygotes had highest HDL-C concentrations compared to the other genotypes (P<0.001). However, main effects were modified by usual dietary fat intake. In African Americans - women somewhat more strongly than men -LIPC TT homozygotes with fat intake >or=33.2% of energy had approximately 3-4 mg/dL higher HDL-C concentrations than CC and CT genotypes. In contrast, when fat intake was <33.2% of energy, TT homozygotes had HDL-C concentrations approximately 3.5mg/dL greater than those with the CC genotype but not different from those with the CT genotype (P(interaction)=0.013). In Whites, LPLGG homozygotes had greatest HDL-C at lower total, saturated, and monounsaturated fat intakes but lowest HDL-C at higher intakes of these fats (P(interaction)<or=0.002). Dietary fat did not modify associations between CETP and HDL-C. In conclusion, these data show that plasma HDL-C differs according to LIPC, LPL, and CETP genotypes. In the case of LIPC and LPL, data suggest dietary fat modifies these relations.

Black or African American↗
PubMed2005

High flow rates during modified ultrafiltration decrease cerebral blood flow velocity and venous oxygen saturation in infants.

BACKGROUND: The intracranial hemodynamic effects of modified ultrafiltration in children are unknown. We investigated the effects of different blood flow rates during modified ultrafiltration on the cerebral hemodynamics of children with weights above and below 10 kg. METHODS: Thirty-one children (weights: < or = 10 kg, n = 21; > 10 kg, n = 10) undergoing cardiopulmonary bypass were studied. Middle-cerebral artery blood flow velocities and cerebral mixed venous oxygen saturations were measured before, five minutes from the beginning, and at the end of ultrafiltration. Patients were classified according to their blood flow rates during ultrafiltration in three groups: high (> or = 20 mL/kg/min), moderate (10-19 mL/kg/min), and low flow rates (< 10 mL/kg/min). RESULTS: During modified ultrafiltration, blood pressures and hematocrit increased (p < 0.001), but cerebral blood flow velocities and mixed venous oxygen saturations decreased (p < 0.001). A significant correlation was found between blood flow rates of ultrafiltration and the decline in mean cerebral blood flow velocity (r = - 0.48; p = 0.005) and cerebral oxygen saturation (r = - 0.49; p = 0.005) or hematocrit increase (r = 0.59; p = 0.001). Infants exposed to high flow rates had greater reduction of cerebral blood flow velocity and regional mixed venous saturation and higher hematocrit at the end of ultrafiltration compared with those subjected to moderate and low flow rates (p < 0.04). No significant difference was found between moderate and low flow groups. The flow rate of ultrafiltration was the only independent predictor of the changes in cerebral mixed venous oxygen saturation (p = 0.033). CONCLUSIONS: High blood flow rates through the ultrafilter during modified ultrafiltration transiently decrease the cerebral circulation in young infants compared with lower blood flow rates. These effects may be related to an increased diastolic runoff from the aorta into the ultrafiltration circuit that leads to a "stealing" effect from the intracranial circulation, which may be important in infants with dysfunctional cerebral autoregulation.

Blood Flow Velocity↗
PubMed2006

LC-MS display of the total modified amino acids in cataract lens proteins and in lens proteins glycated by ascorbic acid in vitro.

We previously reported chromatographic evidence supporting the similarity of yellow chromophores isolated from aged human lens proteins, early brunescent cataract lens proteins and calf lens proteins ascorbylated in vitro [Cheng, R. et al. Biochimica et Biophysica Acta 1537, 14-26, 2001]. In this paper, new evidence supporting the chemical identity of the modified amino acids in these protein populations were collected by using a newly developed two-dimensional LC-MS mapping technique supported by tandem mass analysis of the major species. The pooled water-insoluble proteins from aged normal human lenses, early stage brunescent cataract lenses and calf lens proteins reacted with or without 20 mM ascorbic acid in air for 4 weeks were digested with a battery of proteolytic enzymes under argon to release the modified amino acids. Aliquots equivalent to 2.0 g of digested protein were subjected to size-exclusion chromatography on a Bio-Gel P-2 column and four major A330nm-absorbing peaks were collected. Peaks 1, 2 and 3, which contained most of the modified amino acids were concentrated and subjected to RP-HPLC/ESI-MS, and the mass elution maps were determined. The samples were again analyzed and those peaks with a 10(4) - 10(6) response factor were subjected to MS/MS analysis to identify the daughter ions of each modification. Mass spectrometric maps of peaks 1, 2 and 3 from cataract lenses showed 58, 40 and 55 mass values, respectively, ranging from 150 to 600 Da. Similar analyses of the peaks from digests of the ascorbylated calf lens proteins gave 81, 70 and 67 mass values, respectively, of which 100 were identical to the peaks in the cataract lens proteins. A total of 40 of the major species from each digest were analyzed by LC-MS/MS and 36 were shown to be identical. Calf lens proteins incubated without ascorbic acid showed several similar mass values, but the response factors were 100 to 1000-fold less for every modification. Based upon these data, we conclude that the majority of the major modified amino acids present in early stage brunescent Indian cataract lens proteins appear to arise as a result of ascorbic acid modification, and are presumably advanced glycation end-products.

Amino Acids↗
PubMed2004

A study on the fabrication of chemically modified bacteriorhodopsin film and its photochemical properties.

Chemically modified bacteriorhodopsin (BR) films embedded in gelatin matrix were fabricated. It was found that chemically modified BR/gelatin film remained the original conformation of BR and possessed homogeneity. Then, the photochemical conversion from all-trans O state to 9-cis P state in the chemically modified BR film/gelatin was investigated. For comparison purpose, the same conversion in the wild-type BR (BRwt) film was also presented here. To our know, it is the first report to show that the absorption changes of the P state in the chemically modified BR film were larger than in the BRwt film upon illumination with red light at the low actinic power density.

Bacteriorhodopsins↗
PubMed2004

Macrophage phagocytosis of apoptotic neutrophils is compromised by matrix proteins modified by cigarette smoke and lipid peroxidation products.

Clearance of apoptotic cells by phagocytosis plays an important role in the resolution of an inflammatory response. Macrophages interacting with extracellular matrix (ECM) proteins upregulate their phagocytic capacity. Cigarette smoke contains highly reactive carbonyls that modify proteins which directly/indirectly affects cellular function. We observed, in vitro, that human macrophages interacting with carbonyl or cigarette smoke modified ECM proteins dramatically down regulated their ability to phagocytose apoptotic neutrophils. We also show that this interaction with carbonyl-adduct modified ECM proteins led to increased macrophage adhesion in vitro. We hypothesise that changes in the ECM environment as a result of cigarette smoking affect the ability of macrophages to remove apoptotic cells. Moreover, we postulate that this decreased phagocytic activity was as a result of sequestration of receptors involved in the uptake of apoptotic cells towards that of recognition of carbonyl adducts on the modified ECM proteins leading to increased macrophage adhesion.

Aldehydes↗
PubMed2004

Oligomeric Aip2p/Dld2p forms a novel grapple-like structure and has an ATP-dependent F-actin conformation modifying activity in vitro.

In order to investigate the molecular mechanism of the F-actin conformation modifying activity [Biochem. Biophys. Res. Commun. 319 (2004) 78] of actin-interacting protein 2 (Aip2p) [Nat. Struct. Biol. 2 (1995) 28]/D-lactate dehydrogenase protein 2 (Dld2p) [Yeast 15 (1999) 1377; Biochem. Biophys. Res. Commun. 295 (2002) 910], the ultrastructure and the regulatory mechanism of the activity were further examined. Interestingly, a novel oligomeric grapple-like structure of 10-12 subunits with an ATP-dependent opening was observed. ATP regulates the opening and closing of the "gate" that forms the opening within oligomeric Aip2p/Dld2p, where binding to the substrate occurs while in the open form. In the presence of ATP (open state of oligomeric Aip2p/Dld2p), oligomeric Aip2p/Dld2p bound the F-actin fiber within the opening, whereas in the absence of ATP (closed state of oligomeric Aip2p/Dld2p), no binding was observed. Simultaneously, the oligomeric Aip2p/Dld2p increased the trypsin susceptibility of F-actin in an ATP-dependent manner. Use of the non-hydrolyzable ATP analogue AMP-PNP yielded similar results to those observed with ATP, suggesting that ATP binding rather than ATP hydrolysis is required for the protein conformation modifying reaction of oligomeric Aip2p/Dld2p. Endogenous Aip2p/Dld2p purified from Saccharomyces cerevisiae also exhibited such protein conformation modifying activity, but monomeric Aip2p/Dld2p with a C-terminal coiled-coil region-truncation failed to exhibit the activity. These data suggest that the oligomerization of Aip2p/Dld2p, which exhibits the unique grapple-like structure with an ATP-dependent opening, is required for the F-actin conformation modifying activity.

Actins↗
PubMed2006

LNA-modified oligonucleotides effectively drive intramolecular-stable hairpin to intermolecular-duplex state.

Sequence-specific hybridization of antisense and antigene agent to the target nucleic acid is an important therapeutic strategy to modulate gene expression. However, efficiency of such agents falls due to inherent intramolecular-secondary-structures present in the target that pose competition to intermolecular hybridization by complementary antisense/antigene agent. Performance of these agents can be improved by employing structurally modified complementary oligonucleotides that efficiently hybridize to the target and force it to transit from an intramolecular-structured-state to an intermolecular-duplex state. In this study, the potential of variably substituted locked nucleic acid-modified oligonucleotides (8mer) to hybridize and disrupt highly stable, secondary structure of nucleic acid has been biophysically characterized and compared with the conventionally used unmodified DNA oligonucleotides. The target here is a stem-loop hairpin oligonucleotide-a structure commonly present in most structured-nucleic acids and known to exhibit an array of biological functions. Using fluorescence-based studies and EMSA we prove that LNA-modified oligonucleotides hybridize to the target hairpin with higher binding affinity even at lower concentration and subsequently, force it to assume a duplex conformation. LNA-modified oligonucleotides may thus, prove as potential therapeutic candidates to manipulate gene expression by disruption of biologically relevant nucleic acid secondary structure.

Nucleic Acid Conformation↗