Carlos Abaete C de los Santos (original) (raw)

Papers by Carlos Abaete C de los Santos

Research paper thumbnail of Cardiovascular Risk Factors and Carotid Intima-Media Thickness in Asymptomatic Children

Pediatric Cardiology, 2009

Atherosclerosis, beginning in childhood, is dependent on several risk factors and may be predicti... more Atherosclerosis, beginning in childhood, is dependent on several risk factors and may be predictive of coronary artery disease in adulthood. The risk factors for subclinical atherosclerosis are similar to those for clinical disease. Carotid intima-media thickness is a measure of subclinical atherosclerosis and a predictor of subsequent vascular events. This study aimed to examine the relationships of carotid intima-media thickness with known risk factors in asymptomatic children. Family history of cardiovascular disease was collected, together with anthropometric, demographic, and clinical data. Body mass index zscores were calculated. Serum glucose, lipid fractions, fibrinogen, and C-reactive protein were determined. Highresolution ultrasonography was used to assess intima-media thickness. Associations and relationships of risk factors with composite intima-media thickness were explored. The study enrolled 93 children (44 girls) ranging in age from 49 to 169 months. The boys had a thicker intima-media (0.46 ± 0.06 mm) than the girls (0.43 ± 0.06 mm; p = 0.028). The unadjusted triglyceride levels were significantly higher in the overweight and obese children (p = 0.010). Body mass index and overweight/obesity were positively related to intima-media thickness (r = 0.259; p = 0.012

Research paper thumbnail of NMR Characterization of a DNA Duplex Containing the Major Acrolein-derived Deoxyguanosine Adduct gamma -OH-1,-N2-Propano-2'-deoxyguanosine

J Biol Chem, 2001

The environmental and endogenous mutagen acrolein reacts with cellular DNA to produce several iso... more The environmental and endogenous mutagen acrolein reacts with cellular DNA to produce several isomeric 1,N(2)-propanodeoxyguanosine adducts. High resolution NMR spectroscopy was used to establish the structural features of the major acrolein-derived adduct, gamma-OH-1,N(2)-propano-2'-deoxyguanosine. In aqueous solution, this adduct was shown to assume a ring-closed form. In contrast, when gamma-OH-1,N(2)-propano-2'-deoxyguanosine pairs with dC at the center of an 11-mer oligodeoxynucleotide duplex, the exocyclic ring opens, enabling the modified base to participate in a standard Watson-Crick base pairing alignment. Analysis of the duplex spectra reveals a regular right-handed helical structure with all residues adopting an anti orientation around the glycosidic torsion angle and Watson-Crick alignments for all base pairs. We conclude from this study that formation of duplex DNA triggers the hydrolytic conversion of gamma-OH-1,N(2)-propano-2'-deoxyguanosine to an open chain form, a structure that facilitates pairing with dC during DNA replication and accounts for the surprising lack of mutagenicity associated with this DNA adduct.

Research paper thumbnail of Cardiovascular Risk Factors and Carotid Intima-Media Thickness in Asymptomatic Children

Pediatric Cardiology, Jul 28, 2009

Atherosclerosis, beginning in childhood, is dependent on several risk factors and may be predicti... more Atherosclerosis, beginning in childhood, is dependent on several risk factors and may be predictive of coronary artery disease in adulthood. The risk factors for subclinical atherosclerosis are similar to those for clinical disease. Carotid intima-media thickness is a measure of subclinical atherosclerosis and a predictor of subsequent vascular events. This study aimed to examine the relationships of carotid intima-media thickness with known risk factors in asymptomatic children. Family history of cardiovascular disease was collected, together with anthropometric, demographic, and clinical data. Body mass index zscores were calculated. Serum glucose, lipid fractions, fibrinogen, and C-reactive protein were determined. Highresolution ultrasonography was used to assess intima-media thickness. Associations and relationships of risk factors with composite intima-media thickness were explored. The study enrolled 93 children (44 girls) ranging in age from 49 to 169 months. The boys had a thicker intima-media (0.46 ± 0.06 mm) than the girls (0.43 ± 0.06 mm; p = 0.028). The unadjusted triglyceride levels were significantly higher in the overweight and obese children (p = 0.010). Body mass index and overweight/obesity were positively related to intima-media thickness (r = 0.259; p = 0.012

Research paper thumbnail of Structure of an 11-mer DNA Duplex Containing the Carbocyclic Nucleotide Analog: 2′-Deoxyaristeromycin

Journal of Biomolecular Structure and Dynamics, May 15, 2012

ABSTRACT 2'-deoxyaristeromycin (dAr) is a nucleoside analogue that is resistant to the ac... more ABSTRACT 2'-deoxyaristeromycin (dAr) is a nucleoside analogue that is resistant to the action of DNA glycosylases. High-resolution NMR spectroscopy and molecular dynamics simulations were used to determine the three-dimensional structure of an 11-mer DNA containing a single dAr.T base pair at its center. Analysis of the spectra revealed the existence of a right-handed duplex in solution, stabilized by Watson-Crick hydrogen bonding and base-stacking interactions. The carbocyclic sugar adopted a C1'-exo conformation and sugars of the 3'-flanking base pair had puckers in the O4'-endo range. The dAr.T base pair was mildly propeller twisted, and the dAr analogue showed a positive roll with the 3'-flanking base. Our findings indicate that the observed resistance of dAr-containing oligodeoxynucleotides to the catalytic action of DNA glycosylases relates to its electronic properties rather than structure, and validate the use of dAr and related carbocyclic nucleoside analogues for biological and structure/function relationship studies.

Research paper thumbnail of Solution Structure of Duplex DNA Containing the Mutagenic Lesion 1,Ν2-Etheno-2'-deoxyguanine

Biochemistry, 2008

We have used high-resolution NMR spectroscopy and molecular dynamics simulations to determine the... more We have used high-resolution NMR spectroscopy and molecular dynamics simulations to determine the solution structure of DNA containing the genotoxic lesion 1, N (2)-etheno-2'-deoxyguanosine (epsilonG), paired to dC. The NMR data suggest the presence of a major, minimally perturbed structure at neutral pH. NOESY spectra indicate the presence of a right-handed helix with all nucleotides in anti, 2'-deoxyribose conformations within the C2'-endo/C1'-exo range and proper Watson-Crick base pair alignments outside the lesion site. The epsilonG residue remains deeply embedded inside the helix and stacks between the flanking base pairs. The lesion partner dC is extrahelical and is located in the minor groove of the duplex, where it is highly exposed to solvent. Upon acidification of the sample, a second conformation at the lesion site of the duplex emerges, with protonation of the lesion partner dC and possible formation of a Hoogsteen base pair. Restrained molecular dynamics simulations of the neutral-pH structure generated a set of three-dimensional models that show epsilonG inside the helix, where the lesion is stabilized by stacking interactions with flanking bases but without participating in hydrogen bonding. The lesion counterbase dC is displaced in the minor groove of the duplex where it can form a hydrogen bond with the sugar O4' atom of a residue 2 bp away.

Research paper thumbnail of Sensibilidade gustativa ao sal, natri�ria e press�o arterial em indiv�duos normotensos

Research paper thumbnail of Fenoterol inalado reduz o potássio sérico: avaliaçäo do risco e potenciais implicaöes terapêuticas

Rev Med Pucrs, Mar 1, 1998

Research paper thumbnail of Impact of the C1‘ Configuration of Abasic Sites on DNA Duplex Structure † , ‡

Biochemistry Usa, 2004

Naturally occurring abasic sites in DNA exist as an equilibrium mixture of the aldehyde, the hydr... more Naturally occurring abasic sites in DNA exist as an equilibrium mixture of the aldehyde, the hydrated aldehyde, and the hemiacetal forms (dominant). The influence of the configuration of the C1′ hydroxyl group of the hemiacetal form on duplex structure and abasic site repair has been examined using novel carbocyclic analogues. Both the Rand -forms of this novel abasic site were introduced into oligomeric DNA using the standard DMT-phosphoramidite approach in an automated solid-phase synthesizer. Solution structures of the d(CGTACXCATGC)‚d(GCATGAGTACG) duplex (where X is the Ror -anomer of the carbocyclic abasic site analogue) were determined by NMR spectroscopy and restrained molecular dynamics simulations. The structures were only minimally perturbed by the presence of either anomer of the abasic site. All residues adopted an anti conformation, and Watson-Crick alignments were observed on all base pairs of the duplexes. At the lesion site, the abasic residues and their partner adenines showed increased dynamic behavior but adopted intrahelical positions in the final refined structures. Incision of duplexes having the Ror -anomer of the carbacyclic abasic site by human AP endonuclease showed that the enzyme recognizes both configurations of the lesion and nicks the DNA backbone with similar efficiency. Our results challenge the suggestion that Ape1 is stereoselective and imply a plasticity at the active site of the enzyme for accommodating either anomer of the lesion.

Research paper thumbnail of Does viral hepatitis C-identified by polymerase chain reaction RNA incite a systemic inflammatory reaction in haemodialysis patients?

Research paper thumbnail of Solution structure of DNA containing �-OH-PdG: the mutagenic adduct produced by acrolein

Research paper thumbnail of A dynamic checkpoint in oxidative lesion discrimination by formamidopyrimidine-DNA glycosylase

Nucleic Acids Research, 2015

In contrast to proteins recognizing small-molecule ligands, DNA-dependent enzymes cannot rely sol... more In contrast to proteins recognizing small-molecule ligands, DNA-dependent enzymes cannot rely solely on interactions in the substrate-binding centre to achieve their exquisite specificity. It is widely believed that substrate recognition by such enzymes involves a series of conformational changes in the enzyme-DNA complex with sequential gates favoring cognate DNA and rejecting nonsubstrates. However, direct evidence for such mechanism is limited to a few systems. We report that discrimination between the oxidative DNA lesion, 8-oxoguanine (oxoG) and its normal counterpart, guanine, by the repair enzyme, formamidopyrimidine-DNA glycosylase (Fpg), likely involves multiple gates. Fpg uses an aromatic wedge to open the Watson-Crick base pair and everts the lesion into its active site. We used molecular dynamics simulations to explore the eversion free energy landscapes of oxoG and G by Fpg, focusing on structural and energetic details of oxoG recognition. The resulting energy profiles, supported by biochemical analysis of site-directed mutants disturbing the interactions along the proposed path, show that Fpg selectively facilitates eversion of oxoG by stabilizing several intermediate states, helping the rapidly sliding enzyme avoid full extrusion of every encountered base for interrogation. Lesion recognition through multiple gating intermediates may be a common theme in DNA repair enzymes.

Research paper thumbnail of Structural characterization of DNA duplexes having exocyclic 2'-deoxyguanosine adducts

Chemical Research in Toxicology

Research paper thumbnail of 138 2′-Deoxyguanine analogs which enhance hybridization oligonucleotides with complementary DNA

Journal of Biomolecular Structure and Dynamics, 2015

Research paper thumbnail of Incorporation of 3-Aminobenzanthrone into 2′-Deoxyoligonucleotides and Its Impact on Duplex Stability

Journal of Nucleic Acids, 2011

3-Nitrobenzanthrone (3NBA), an environmental pollutant and potent mutagen, causes DNA damage via ... more 3-Nitrobenzanthrone (3NBA), an environmental pollutant and potent mutagen, causes DNA damage via the reaction of its metabolically activated form with the exocyclic amino groups of purines and the C-8 position of guanine. The present work describes a synthetic approach to the preparation of oligomeric 2 -deoxyribonucleotides containing a 2-(2 -deoxyguanosin-N 2yl)-3-aminobenzanthrone moiety, one of the major DNA adducts found in tissues of living organisms exposed to 3NBA. The NMR spectra indicate that the damaged oligodeoxyribonucleotide is capable of forming a regular double helical structure with the polyaromatic moiety assuming a single conformation at room temperature; the spectra suggest that the 3ABA moiety resides in the duplex minor groove pointing toward the 5 -end of the modified strand. Thermodynamic studies show that the dG(N 2 )-3ABA lesion has a stabilizing effect on the damaged duplex, a fact that correlates well with the long persistence of this damage in living organisms.

Research paper thumbnail of Active destabilization of base pairs by a DNA glycosylase wedge initiates damage recognition

Nucleic acids research, 2015

Formamidopyrimidine-DNA glycosylase (Fpg) excises 8-oxoguanine (oxoG) from DNA but ignores normal... more Formamidopyrimidine-DNA glycosylase (Fpg) excises 8-oxoguanine (oxoG) from DNA but ignores normal guanine. We combined molecular dynamics simulation and stopped-flow kinetics with fluorescence detection to track the events in the recognition of oxoG by Fpg and its mutants with a key phenylalanine residue, which intercalates next to the damaged base, changed to either alanine (F110A) or fluorescent reporter tryptophan (F110W). Guanine was sampled by Fpg, as evident from the F110W stopped-flow traces, but less extensively than oxoG. The wedgeless F110A enzyme could bend DNA but failed to proceed further in oxoG recognition. Modeling of the base eversion with energy decomposition suggested that the wedge destabilizes the intrahelical base primarily through buckling both surrounding base pairs. Replacement of oxoG with abasic (AP) site rescued the activity, and calculations suggested that wedge insertion is not required for AP site destabilization and eversion. Our results suggest that ...

Research paper thumbnail of Baixa resposta da vacinação intradérmica contra hepatite B em pacientes incidentes em hemodiálise

Jornal Brasileiro de Nefrologia, 2011

ABSTRACT

Research paper thumbnail of Sensibilidade gustativa ao sal, natriúria e pressão arterial em indivíduos normotensos

Revista da Associação Médica Brasileira, 2007

Research paper thumbnail of Cat Scratch Disease in kidney transplant receptors: is it a rare or underdiagnosed pathology?

Jornal brasileiro de nefrologia : ʹorgão oficial de Sociedades Brasileira e Latino-Americana de Nefrologia

Cat Scratch Disease (CSD) is an infectious disorder which appears after cat scratching particular... more Cat Scratch Disease (CSD) is an infectious disorder which appears after cat scratching particularly in children and adolescents. Bartonella henselae is the etiologic agent more frequently involved. There are only a few recent reports demonstrating the disease after transplantation, although the illness is not infrequent in immunologically competent people. Indeed CSD in transplant receptors has only been recently emphasized in the literature and it was concluded that fever and lymphadenopathy in patients who had been exposed to cats should prompt clinicians to maintain a suspicion for the infection. In this report CSD infecting a renal transplanted adolescent complaining of headache, blurred vision and fever, presenting a cat scratching lesion in the right arm, with a bilateral painful cervical lymphadenopathy was related. He also presented indirect immunofluorescency identifying that the two subtype's titles of Bartonella--henselae and quintana--were elevated. Treatment with do...

Research paper thumbnail of Ramsay Hunt syndrome with facial vesicular rash: a unique clinical presentation in a kidney transplant patient

The Journal of Infection in Developing Countries, 2014

Ramsay Hunt Syndrome (RHS) is the result of herpes zoster virus reactivation producing hearing lo... more Ramsay Hunt Syndrome (RHS) is the result of herpes zoster virus reactivation producing hearing loss, pain and vesicles in the ear or mouth, along with ipsilateral facial palsy due to the 7th cranial nerve geniculate ganglion infectious involvement. This condition has not been previously described, particularly in transplant patients. A 38-year old man underwent kidney transplantation and two years later experienced an ache on the left side of the face and hearing loss in the ear, also exhibiting vesicular lesions and concomitant facial peripheral palsy. Acyclovir IV was initiated, and the prednisone dose was increased. The patient was discharged 15 days later, feeling better but still exhibiting dark spots on his face. At three months follow-up he was asymptomatic, showing notable palsy improvement. Until this case, herpes zoster facial lesions causing typical RHS have never been reported in literature, particularly in kidney transplant patients.

Research paper thumbnail of Streptococcus agalactiae : A rare peritoneal infection in a continuous ambulatory peritoneal dialysis patient

Renal Failure, 2010

Streptococcus agalactiae causes a rare and often fatal peritonitis in continuous ambulatory perit... more Streptococcus agalactiae causes a rare and often fatal peritonitis in continuous ambulatory peritoneal dialysis (CAPD). A 52-year-old white female with Alport and chronic kidney disease was initiated on CAPD treatment. Nineteen months later she had a S. agalactiae peritonitis identified and received initially gentamicin-cephalothin, which was changed to ceftazidime, tobramycin, and vancomycin. Recovery started after peritoneal catheter removal. After 3 weeks, severe leucopenia occurred. Granulokine and steroids were given. Six weeks later, she felt well and an abdominal video laparoscopic procedure disclosed a diffuse peritoneal fibrosis, precluding CAPD resumption. She is now doing well on hemodialysis (HD).

Research paper thumbnail of Cardiovascular Risk Factors and Carotid Intima-Media Thickness in Asymptomatic Children

Pediatric Cardiology, 2009

Atherosclerosis, beginning in childhood, is dependent on several risk factors and may be predicti... more Atherosclerosis, beginning in childhood, is dependent on several risk factors and may be predictive of coronary artery disease in adulthood. The risk factors for subclinical atherosclerosis are similar to those for clinical disease. Carotid intima-media thickness is a measure of subclinical atherosclerosis and a predictor of subsequent vascular events. This study aimed to examine the relationships of carotid intima-media thickness with known risk factors in asymptomatic children. Family history of cardiovascular disease was collected, together with anthropometric, demographic, and clinical data. Body mass index zscores were calculated. Serum glucose, lipid fractions, fibrinogen, and C-reactive protein were determined. Highresolution ultrasonography was used to assess intima-media thickness. Associations and relationships of risk factors with composite intima-media thickness were explored. The study enrolled 93 children (44 girls) ranging in age from 49 to 169 months. The boys had a thicker intima-media (0.46 ± 0.06 mm) than the girls (0.43 ± 0.06 mm; p = 0.028). The unadjusted triglyceride levels were significantly higher in the overweight and obese children (p = 0.010). Body mass index and overweight/obesity were positively related to intima-media thickness (r = 0.259; p = 0.012

Research paper thumbnail of NMR Characterization of a DNA Duplex Containing the Major Acrolein-derived Deoxyguanosine Adduct gamma -OH-1,-N2-Propano-2'-deoxyguanosine

J Biol Chem, 2001

The environmental and endogenous mutagen acrolein reacts with cellular DNA to produce several iso... more The environmental and endogenous mutagen acrolein reacts with cellular DNA to produce several isomeric 1,N(2)-propanodeoxyguanosine adducts. High resolution NMR spectroscopy was used to establish the structural features of the major acrolein-derived adduct, gamma-OH-1,N(2)-propano-2'-deoxyguanosine. In aqueous solution, this adduct was shown to assume a ring-closed form. In contrast, when gamma-OH-1,N(2)-propano-2'-deoxyguanosine pairs with dC at the center of an 11-mer oligodeoxynucleotide duplex, the exocyclic ring opens, enabling the modified base to participate in a standard Watson-Crick base pairing alignment. Analysis of the duplex spectra reveals a regular right-handed helical structure with all residues adopting an anti orientation around the glycosidic torsion angle and Watson-Crick alignments for all base pairs. We conclude from this study that formation of duplex DNA triggers the hydrolytic conversion of gamma-OH-1,N(2)-propano-2'-deoxyguanosine to an open chain form, a structure that facilitates pairing with dC during DNA replication and accounts for the surprising lack of mutagenicity associated with this DNA adduct.

Research paper thumbnail of Cardiovascular Risk Factors and Carotid Intima-Media Thickness in Asymptomatic Children

Pediatric Cardiology, Jul 28, 2009

Atherosclerosis, beginning in childhood, is dependent on several risk factors and may be predicti... more Atherosclerosis, beginning in childhood, is dependent on several risk factors and may be predictive of coronary artery disease in adulthood. The risk factors for subclinical atherosclerosis are similar to those for clinical disease. Carotid intima-media thickness is a measure of subclinical atherosclerosis and a predictor of subsequent vascular events. This study aimed to examine the relationships of carotid intima-media thickness with known risk factors in asymptomatic children. Family history of cardiovascular disease was collected, together with anthropometric, demographic, and clinical data. Body mass index zscores were calculated. Serum glucose, lipid fractions, fibrinogen, and C-reactive protein were determined. Highresolution ultrasonography was used to assess intima-media thickness. Associations and relationships of risk factors with composite intima-media thickness were explored. The study enrolled 93 children (44 girls) ranging in age from 49 to 169 months. The boys had a thicker intima-media (0.46 ± 0.06 mm) than the girls (0.43 ± 0.06 mm; p = 0.028). The unadjusted triglyceride levels were significantly higher in the overweight and obese children (p = 0.010). Body mass index and overweight/obesity were positively related to intima-media thickness (r = 0.259; p = 0.012

Research paper thumbnail of Structure of an 11-mer DNA Duplex Containing the Carbocyclic Nucleotide Analog: 2′-Deoxyaristeromycin

Journal of Biomolecular Structure and Dynamics, May 15, 2012

ABSTRACT 2'-deoxyaristeromycin (dAr) is a nucleoside analogue that is resistant to the ac... more ABSTRACT 2'-deoxyaristeromycin (dAr) is a nucleoside analogue that is resistant to the action of DNA glycosylases. High-resolution NMR spectroscopy and molecular dynamics simulations were used to determine the three-dimensional structure of an 11-mer DNA containing a single dAr.T base pair at its center. Analysis of the spectra revealed the existence of a right-handed duplex in solution, stabilized by Watson-Crick hydrogen bonding and base-stacking interactions. The carbocyclic sugar adopted a C1'-exo conformation and sugars of the 3'-flanking base pair had puckers in the O4'-endo range. The dAr.T base pair was mildly propeller twisted, and the dAr analogue showed a positive roll with the 3'-flanking base. Our findings indicate that the observed resistance of dAr-containing oligodeoxynucleotides to the catalytic action of DNA glycosylases relates to its electronic properties rather than structure, and validate the use of dAr and related carbocyclic nucleoside analogues for biological and structure/function relationship studies.

Research paper thumbnail of Solution Structure of Duplex DNA Containing the Mutagenic Lesion 1,Ν2-Etheno-2'-deoxyguanine

Biochemistry, 2008

We have used high-resolution NMR spectroscopy and molecular dynamics simulations to determine the... more We have used high-resolution NMR spectroscopy and molecular dynamics simulations to determine the solution structure of DNA containing the genotoxic lesion 1, N (2)-etheno-2'-deoxyguanosine (epsilonG), paired to dC. The NMR data suggest the presence of a major, minimally perturbed structure at neutral pH. NOESY spectra indicate the presence of a right-handed helix with all nucleotides in anti, 2'-deoxyribose conformations within the C2'-endo/C1'-exo range and proper Watson-Crick base pair alignments outside the lesion site. The epsilonG residue remains deeply embedded inside the helix and stacks between the flanking base pairs. The lesion partner dC is extrahelical and is located in the minor groove of the duplex, where it is highly exposed to solvent. Upon acidification of the sample, a second conformation at the lesion site of the duplex emerges, with protonation of the lesion partner dC and possible formation of a Hoogsteen base pair. Restrained molecular dynamics simulations of the neutral-pH structure generated a set of three-dimensional models that show epsilonG inside the helix, where the lesion is stabilized by stacking interactions with flanking bases but without participating in hydrogen bonding. The lesion counterbase dC is displaced in the minor groove of the duplex where it can form a hydrogen bond with the sugar O4' atom of a residue 2 bp away.

Research paper thumbnail of Sensibilidade gustativa ao sal, natri�ria e press�o arterial em indiv�duos normotensos

Research paper thumbnail of Fenoterol inalado reduz o potássio sérico: avaliaçäo do risco e potenciais implicaöes terapêuticas

Rev Med Pucrs, Mar 1, 1998

Research paper thumbnail of Impact of the C1‘ Configuration of Abasic Sites on DNA Duplex Structure † , ‡

Biochemistry Usa, 2004

Naturally occurring abasic sites in DNA exist as an equilibrium mixture of the aldehyde, the hydr... more Naturally occurring abasic sites in DNA exist as an equilibrium mixture of the aldehyde, the hydrated aldehyde, and the hemiacetal forms (dominant). The influence of the configuration of the C1′ hydroxyl group of the hemiacetal form on duplex structure and abasic site repair has been examined using novel carbocyclic analogues. Both the Rand -forms of this novel abasic site were introduced into oligomeric DNA using the standard DMT-phosphoramidite approach in an automated solid-phase synthesizer. Solution structures of the d(CGTACXCATGC)‚d(GCATGAGTACG) duplex (where X is the Ror -anomer of the carbocyclic abasic site analogue) were determined by NMR spectroscopy and restrained molecular dynamics simulations. The structures were only minimally perturbed by the presence of either anomer of the abasic site. All residues adopted an anti conformation, and Watson-Crick alignments were observed on all base pairs of the duplexes. At the lesion site, the abasic residues and their partner adenines showed increased dynamic behavior but adopted intrahelical positions in the final refined structures. Incision of duplexes having the Ror -anomer of the carbacyclic abasic site by human AP endonuclease showed that the enzyme recognizes both configurations of the lesion and nicks the DNA backbone with similar efficiency. Our results challenge the suggestion that Ape1 is stereoselective and imply a plasticity at the active site of the enzyme for accommodating either anomer of the lesion.

Research paper thumbnail of Does viral hepatitis C-identified by polymerase chain reaction RNA incite a systemic inflammatory reaction in haemodialysis patients?

Research paper thumbnail of Solution structure of DNA containing �-OH-PdG: the mutagenic adduct produced by acrolein

Research paper thumbnail of A dynamic checkpoint in oxidative lesion discrimination by formamidopyrimidine-DNA glycosylase

Nucleic Acids Research, 2015

In contrast to proteins recognizing small-molecule ligands, DNA-dependent enzymes cannot rely sol... more In contrast to proteins recognizing small-molecule ligands, DNA-dependent enzymes cannot rely solely on interactions in the substrate-binding centre to achieve their exquisite specificity. It is widely believed that substrate recognition by such enzymes involves a series of conformational changes in the enzyme-DNA complex with sequential gates favoring cognate DNA and rejecting nonsubstrates. However, direct evidence for such mechanism is limited to a few systems. We report that discrimination between the oxidative DNA lesion, 8-oxoguanine (oxoG) and its normal counterpart, guanine, by the repair enzyme, formamidopyrimidine-DNA glycosylase (Fpg), likely involves multiple gates. Fpg uses an aromatic wedge to open the Watson-Crick base pair and everts the lesion into its active site. We used molecular dynamics simulations to explore the eversion free energy landscapes of oxoG and G by Fpg, focusing on structural and energetic details of oxoG recognition. The resulting energy profiles, supported by biochemical analysis of site-directed mutants disturbing the interactions along the proposed path, show that Fpg selectively facilitates eversion of oxoG by stabilizing several intermediate states, helping the rapidly sliding enzyme avoid full extrusion of every encountered base for interrogation. Lesion recognition through multiple gating intermediates may be a common theme in DNA repair enzymes.

Research paper thumbnail of Structural characterization of DNA duplexes having exocyclic 2'-deoxyguanosine adducts

Chemical Research in Toxicology

Research paper thumbnail of 138 2′-Deoxyguanine analogs which enhance hybridization oligonucleotides with complementary DNA

Journal of Biomolecular Structure and Dynamics, 2015

Research paper thumbnail of Incorporation of 3-Aminobenzanthrone into 2′-Deoxyoligonucleotides and Its Impact on Duplex Stability

Journal of Nucleic Acids, 2011

3-Nitrobenzanthrone (3NBA), an environmental pollutant and potent mutagen, causes DNA damage via ... more 3-Nitrobenzanthrone (3NBA), an environmental pollutant and potent mutagen, causes DNA damage via the reaction of its metabolically activated form with the exocyclic amino groups of purines and the C-8 position of guanine. The present work describes a synthetic approach to the preparation of oligomeric 2 -deoxyribonucleotides containing a 2-(2 -deoxyguanosin-N 2yl)-3-aminobenzanthrone moiety, one of the major DNA adducts found in tissues of living organisms exposed to 3NBA. The NMR spectra indicate that the damaged oligodeoxyribonucleotide is capable of forming a regular double helical structure with the polyaromatic moiety assuming a single conformation at room temperature; the spectra suggest that the 3ABA moiety resides in the duplex minor groove pointing toward the 5 -end of the modified strand. Thermodynamic studies show that the dG(N 2 )-3ABA lesion has a stabilizing effect on the damaged duplex, a fact that correlates well with the long persistence of this damage in living organisms.

Research paper thumbnail of Active destabilization of base pairs by a DNA glycosylase wedge initiates damage recognition

Nucleic acids research, 2015

Formamidopyrimidine-DNA glycosylase (Fpg) excises 8-oxoguanine (oxoG) from DNA but ignores normal... more Formamidopyrimidine-DNA glycosylase (Fpg) excises 8-oxoguanine (oxoG) from DNA but ignores normal guanine. We combined molecular dynamics simulation and stopped-flow kinetics with fluorescence detection to track the events in the recognition of oxoG by Fpg and its mutants with a key phenylalanine residue, which intercalates next to the damaged base, changed to either alanine (F110A) or fluorescent reporter tryptophan (F110W). Guanine was sampled by Fpg, as evident from the F110W stopped-flow traces, but less extensively than oxoG. The wedgeless F110A enzyme could bend DNA but failed to proceed further in oxoG recognition. Modeling of the base eversion with energy decomposition suggested that the wedge destabilizes the intrahelical base primarily through buckling both surrounding base pairs. Replacement of oxoG with abasic (AP) site rescued the activity, and calculations suggested that wedge insertion is not required for AP site destabilization and eversion. Our results suggest that ...

Research paper thumbnail of Baixa resposta da vacinação intradérmica contra hepatite B em pacientes incidentes em hemodiálise

Jornal Brasileiro de Nefrologia, 2011

ABSTRACT

Research paper thumbnail of Sensibilidade gustativa ao sal, natriúria e pressão arterial em indivíduos normotensos

Revista da Associação Médica Brasileira, 2007

Research paper thumbnail of Cat Scratch Disease in kidney transplant receptors: is it a rare or underdiagnosed pathology?

Jornal brasileiro de nefrologia : ʹorgão oficial de Sociedades Brasileira e Latino-Americana de Nefrologia

Cat Scratch Disease (CSD) is an infectious disorder which appears after cat scratching particular... more Cat Scratch Disease (CSD) is an infectious disorder which appears after cat scratching particularly in children and adolescents. Bartonella henselae is the etiologic agent more frequently involved. There are only a few recent reports demonstrating the disease after transplantation, although the illness is not infrequent in immunologically competent people. Indeed CSD in transplant receptors has only been recently emphasized in the literature and it was concluded that fever and lymphadenopathy in patients who had been exposed to cats should prompt clinicians to maintain a suspicion for the infection. In this report CSD infecting a renal transplanted adolescent complaining of headache, blurred vision and fever, presenting a cat scratching lesion in the right arm, with a bilateral painful cervical lymphadenopathy was related. He also presented indirect immunofluorescency identifying that the two subtype's titles of Bartonella--henselae and quintana--were elevated. Treatment with do...

Research paper thumbnail of Ramsay Hunt syndrome with facial vesicular rash: a unique clinical presentation in a kidney transplant patient

The Journal of Infection in Developing Countries, 2014

Ramsay Hunt Syndrome (RHS) is the result of herpes zoster virus reactivation producing hearing lo... more Ramsay Hunt Syndrome (RHS) is the result of herpes zoster virus reactivation producing hearing loss, pain and vesicles in the ear or mouth, along with ipsilateral facial palsy due to the 7th cranial nerve geniculate ganglion infectious involvement. This condition has not been previously described, particularly in transplant patients. A 38-year old man underwent kidney transplantation and two years later experienced an ache on the left side of the face and hearing loss in the ear, also exhibiting vesicular lesions and concomitant facial peripheral palsy. Acyclovir IV was initiated, and the prednisone dose was increased. The patient was discharged 15 days later, feeling better but still exhibiting dark spots on his face. At three months follow-up he was asymptomatic, showing notable palsy improvement. Until this case, herpes zoster facial lesions causing typical RHS have never been reported in literature, particularly in kidney transplant patients.

Research paper thumbnail of Streptococcus agalactiae : A rare peritoneal infection in a continuous ambulatory peritoneal dialysis patient

Renal Failure, 2010

Streptococcus agalactiae causes a rare and often fatal peritonitis in continuous ambulatory perit... more Streptococcus agalactiae causes a rare and often fatal peritonitis in continuous ambulatory peritoneal dialysis (CAPD). A 52-year-old white female with Alport and chronic kidney disease was initiated on CAPD treatment. Nineteen months later she had a S. agalactiae peritonitis identified and received initially gentamicin-cephalothin, which was changed to ceftazidime, tobramycin, and vancomycin. Recovery started after peritoneal catheter removal. After 3 weeks, severe leucopenia occurred. Granulokine and steroids were given. Six weeks later, she felt well and an abdominal video laparoscopic procedure disclosed a diffuse peritoneal fibrosis, precluding CAPD resumption. She is now doing well on hemodialysis (HD).