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At least 1,153 records · Page 64Linked to original sources
PubMed1997

6-(alkylamino)-9-alkylpurines. A new class of potential antipsychotic agents.

A series of 6-(alkylamino)-9-alkylpurines was synthesized and evaluated for the property of antagonizing the behavioral effects in animals of the dopamine agonist apomorphine. This model for identifying potential antipsychotic agents is based on the hypothesis that agents that antagonize apomorphine-induced aggressive behavior in rats and apomorphine-induced climbing in mice, but that do not block stereotyped behavior, could have an antipsychotic effect in humans without producing extrapyramidal side effects. The antiaggressive-behavior activity of lead compound 1 (6-(dimethylamino)-9-(3-phenylalaninamidobenzyl)-9H-purine) was improved 48-fold with 6-(cyclopropylamino)-9-(cyclopropylmethyl)-2-(trifluoromethyl)-9H- purine (80) (po ED50 of 2 mg/kg), which was obtained through an iterative sequence of structure--activity relationship studies that encompassed evaluation of the effects of structure variations at the purine 9-, 6-, and 2-positions. Potency was enhanced with a 9-cyclopropyl group, the duration of action was improved with the 6-(cyclopropylamino) substituent, potency was further enhanced with an N-formyl prodrug, and an agent with reduced cardiovascular effect emerged with the 2-trifluoromethyl purine 80. This potential antipsychotic agent was not developed further due to undesirable effects on the stomach.

Aggression↗
PubMed1993

Affinity labelling of the Ca(2+)-activated neutral proteinase (calpain) in intact human platelets.

Two irreversible calpain inhibitors, benzyloxycarbonyl (Cbz)-Leu-Leu-Tyr-Ch2F and Cbz-Leu-Leu-Tyr-CHN2, were shown earlier [Anagli, Hagmann and Shaw (1991) Biochem. J. 274, 497-502] to penetrate intact platelets and to inactivate calpain. This permitted an evaluation of certain functions attributed to this proteinase. For example, in platelets pretreated with these inhibitors, talin and actin-binding protein were protected from subsequent degradation when the Ca2+ level was raised. On the other hand, additional properties of stimulated platelets attributed to calpain remained unaffected by this treatment, and such hypotheses may be dismissed. Radioiodinated inhibitors permitted confirmation of the labelling of calpain by the procedures used. Although Cbz-Leu-Leu-Tyr-CHN2 is more effective in vitro than the corresponding fluoromethyl ketone, we now show that the latter penetrates more readily. These two inhibitors, and two additional ones, t-butyloxycarbonyl-Val-Lys(Cbz)-Leu-Tyr- CHN2 and Cbz-Leu-Tyr-CH2F, have been radioiodinated to permit a comparison of their intracellular labelling patterns in activated platelets. Calpain is the major target of all four inhibitors. Although they are closely related peptide structures, variations with respect to the labelling of additional proteins were observed. These were minor in the case of the peptidyl diazomethyl ketones, but were major in the case of the fluoromethyl ketones. However, in contrast to calpain, this labelling was neither time-dependent nor Ca(2+)-dependent. Radiolabelling and cellular fractionation studies were used to localize active calpain during platelet activation. Calpain appears to be activated in the cytosol and translocated to the membrane or cytoskeletal sites.

Affinity Labels↗
PubMed1987

Comparative specificity of porcine pancreatic kallikrein and bovine pancreatic trypsin. Importance of interactions N-terminal to the scissible bond.

Hydrolyses catalyzed by bovine pancreatic trypsin and porcine pancreatic kallikrein were studied using synthetic peptide substrates of the type E chi-L chi 2-L chi 1 decreases Y and E chi-L chi 3-L chi 2-L chi 1 decreases Y with L chi 1 = Arg defining the hydrolysis position (indicated by the arrow). The leaving moiety Y was -OCH3, -NH-C6H4-p-NO2 and -Ala-NH2. Insight into interactions occurring between the active site of the enzymes and the acyl moiety of the substrates was gained by studying the influence on hydrolysis rate of structural variation of residues L chi 2 and L chi 3. Parallel analyses of the hydrolyses of the ester, anilide, and peptide substrates having the same acyl moiety considerably facilitated the interpretation of the kinetic data. Trypsin, but not kallikrein, displayed high reactivity even with relatively short substrates. Ac-Ala-Arg-Ala-NH2, for example, was a better substrate for trypsin than for kallikrein by a factor of 1.3 X 10(4) in terms of kcat and 5.9 X 10(4) in terms of kcat/Km. Reactivity differences of such magnitude were related to two main differences in enzyme-substrate interactions: the interaction of the arginine side chain of the substrate with the specificity pocket of the enzyme is optimal for trypsin but poor for kallikrein and the number of hydrogen bonds formed by the enzyme with the backbone section of the substrate on both sides of the specific residue is larger in the case of trypsin. The latter difference is found to be related to the structure of amino-acid residue 192 which is glutamine in trypsin and methionine in kallikrein.

Amino Acid Sequence↗
PubMed1992

Insect glycolipids.

Systematic elucidations of the chemical structures of glycosphingolipids from members of the phyla Arthropoda (class:insecta) of the Protostomia have shown several characteristic differences to those of the Deuterostomia, e.g., the Vertebrata. The ceramide constituents of the arthropod sphingolipids are C14:1- and C16:1-sphingoid and a majority of saturated C18-, C20-, C22- and C24-fatty acids. The GSL of the dipteran insects, L. caesar and C. vicina, consist of a series of homologous compounds of increasing sugar chain length. The carbohydrate moieties of these arthropod GSL are all derived from one unique neutral sugar core sequence, the arthro-series. The longest member known, an arthrononaosylceramide has the structure Gal beta,3GalNAc beta,3GlcNAc beta,3Gal beta,3GalNAc alpha,4GalNAc beta,4GlcNAc beta,3Man beta,4Glc beta Cer. Three pentahexosylceramides have been characterized that differ in their nonreducing terminus, i.e., IV4GalNAc alpha-Ap4Cer, IV3Gal alpha-Ap4Cer and IV3Gal beta-Ap4Cer. A large repertoire of structural variations of the arthro-series GSL is created by two types of derivatisations of the neutral carbohydrate core: addition of a zwitterionic 2-aminoethylphosphate group in phosphodiester linkage to the 6-position of the III-N-acetylglucosamine of the arthrotriaosylceramide core and/or substitution of a terminal galactose in 3-position by a glucuronic acid residue. The latter acidic arthro-series GSL were given the name arthrosides. Preliminary results have indicated that the blowfly GSL component distribution is strongly organ specific. GSL of various larval organs are distinguished by the length of their neutral core carbohydrate chain, as well as, the degree of PEtn- and GlcA-substitutions. Normal human sera contain antibodies that recognize epitopes on arthro-series GSL. Thereby, sites of the neutral carbohydrate chain, as well as, the zwitterionic and acidic epitopes are involved in the immune recognition. In a pathological condition, a M-protein of patients with autoallergic demyelinating peripheral neuropathy was found to react strongly with a glucuronic acid-containing molecular structure on arthrosides. Some indication was obtained for a possible functional role of glucuronic acid in dipteran-cell adhesion by using a mouse monoclonal antibody, mAb CAF-I. This antibody, directed against an arthroside epitope involving glucuronic acid, could induce an in vitro detachment of insect cells from one another or from their substratum. Obviously, present research on the GSL of insects is only at an early stage. Nevertheless, from the results available so far it was become increasingly apparent that a new chapter in our knowledge of GSL structures has been opened.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1998

32-Ascomycinyloxyacetic acid derived immunosuppressants. Independence of immunophilin binding and immunosuppressive potency.

The potent immunosuppressant ascomycin (1b) was selectively alkylated at the C-32 carbinol, thus providing esters and amides of 32-ascomycinyloxyacetic acid (4, AOAA). These compounds present structural variation at the FKBP/calcineurin interface. While the native carboxylic acid 4 shows no activity in vitro, esters and simple amides of 4 exhibit potent immunosuppression in the human MLR assay. Moreover, amides show inhibitory activity in the rat popliteal lymph node hyperplasia assay. Surprisingly, FKBP binding was weakened by several orders of magnitude when secondary hydrophobic aryl amides of 4 were tested, while maintaining potent immunosuppressive efficacy in vitro.

Animals↗
PubMed1994

The des(1-6)antennapedia homeodomain: comparison of the NMR solution structure and the DNA-binding affinity with the intact Antennapedia homeodomain.

The nuclear magnetic resonance (NMR) solution structure of an N-terminally truncated mutant Antennapedia homeodomain, des(1-6)Antp(C39S), has been determined from 935 nuclear Overhauser effect upper distance constraints and 148 dihedral angle constraints by using the programs DIANA and OPAL. Twenty conformers representing the solution structure of des(1-6)Antp(C39S) have an average root-mean-square distance relative to the mean coordinates of 0.56 A for the backbone atoms of residues 8-59. Comparison with the intact Antp(C39S) homeodomain shows that the two proteins have identical molecular architectures. The removal of the N-terminal residues 1-6, which are flexibly disordered in the intact homeodomain, causes only strictly localized structure variations and does not noticeably affect the adjoining helix I from residues 10-21. The DNA-binding constant of des(1-6)Antp(C39S) is approximately 10-fold reduced relative to the intact Antp(C39S) homeodomain, which can now be attributed to the absence of the previously reported contacts of the N-terminal polypeptide segment of the intact Antp(C39S) homeodomain with the minor groove of the DNA duplex.

Amino Acid Sequence↗
PubMed2004

Molecular dynamics simulations of 14 HIV protease mutants in complexes with indinavir.

The molecular mechanisms of HIV drug resistance were studied using molecular dynamics simulations of HIV-1 protease complexes with the clinical inhibitor indinavir. One nanosecond molecular dynamics simulations were run for solvated complexes of indinavir with wild type protease, a control variant and 12 drug resistant mutants. The quality of the simulations was assessed by comparison with crystallographic and inhibition data. Molecular mechanisms that contribute to drug resistance include structural stability and affinity for inhibitor. The mutants showed a range of structural variation from 70 to 140% of the wild type protease. The protease affinity for indinavir was estimated by calculating the averaged molecular mechanics interaction energy. A correlation coefficient of 0.96 was obtained with observed inhibition constants for wild type and four mutants. Based on this good agreement, the trends in binding were predicted for the other mutants and discussed in relation to the clinical data for indinavir resistance. [figure: see text]. Poincare map representation for WT protease-indinavir complex. The side chain of Tyr 59 showing the positions of hydrogen atoms.

Binding Sites↗
PubMed2006

Exploring QSAR on 3-aminopyrazoles as antitumor agents for their inhibitory activity of CDK2/cyclin A.

Chemical inhibitors of cyclin-dependent kinases have great therapeutic potential against various proliferative and neurodegenerative disorders. The pharmacophoric requirement of 3-aminopyrazole, inhibitors of CDK2/cyclin A as antitumor agents was explored. QSAR study was performed using ETSA index, RTSA index, indicator parameters and atomic charges to consider quantitatively the effect of the structural variation on the antitumor activity of 3-aminopyrazole. Result showed that atom number 5 is important for the activity. It plays some electronic roles in the interaction of these compounds with enzymes as well as assumed to be involved through the dispersive/van der Waals interactions with enzyme. Presence of meta substitutions on the phenyl ring indicate the detrimental effects towards the activity. The presence of substituted biphenyl/2-thenyl phenyl at R1 are favorable towards the activity. QSAR study also indicates that with increasing the electronegativity of oxygen at position 8, the activity increases.

Antineoplastic Agents↗
PubMed2005

Chemokine-glycosaminoglycan binding: specificity for CCR2 ligand binding to highly sulfated oligosaccharides using FTICR mass spectrometry.

Glycosaminoglycans (GAGs) have recently been demonstrated to be required for the in vivo activity of several chemokines. Minimally, the interaction is thought to provide a mechanism for retention at the site of secretion and the formation of chemokine gradients that provide directional cues for receptor bearing cells, particularly in the presence of shear forces. Thus, a key issue will be to determine the sequence and structure of the GAGs that bind to specific chemokines. Herein, we describe a mass spectrometry assay that was developed to detect protein-oligosaccharide noncovalent complexes, in this case chemokine-GAG interactions, and to select for high affinity GAGs. The process is facilitated by the ability of electrospray ionization to transfer the intact noncovalent complexes from solution into the gas phase. The elemental composition as well as the binding stoichiometry can be calculated from the mass of the complex. Ligands of the chemokine receptor, CCR2 (MCP-1/CCL2, MCP-2/CCL8, MCP-3/CCL7, MCP-4/CCL13, and Eotaxin/CCL11), and the CCR10 ligand CTACK/CCL27 were screened against a small, highly sulfated, heparin oligosaccharide library with limited structural variation. The results revealed heparin octasaccharides with 11 and 12 sulfates as binders. Oligomerization of some chemokines was observed upon GAG binding, whereas in other instances only the monomeric noncovalent complex was identified. The results indicate that, in contrast to the apparent redundancy in the chemokine system, where several chemokines bind and activate the same receptor, these chemokines could be differentiated into two groups based on the stoichiometry of their complexes with the heparin oligosaccharides.

Animals↗
PubMed1992

Modulation of electrolyte excretion by potassium retaining diuretics.

Triamterene and amiloride belong to the potassium retaining diuretics of the cycloamidine type. These agents exert natriuretic as well as antikaliuretic effects. After administration of high doses an additional magnesium-sparing property also becomes evident. Whereas amiloride is only metabolized to a minor extent, triamterene is rapidly bio-transformed to the phase-I metabolite, hydroxytriamterene, and the phase-II metabolite, hydroxytriamterene sulphuric acid ester. This acidic phase-II metabolite is still diuretically active, but its electrolyte excretion profile is different from the parent compound: although the natriuretic properties are not altered, the potassium retention is very weak. Further studies in rats with cycloamidine derivatives of the triamterene type containing neutral, acidic or basic side chains at the phenyl moiety as well as with basic pteridine derivatives, revealed further evidence that the natriuretic, antikaliuretic and antimagnesiuretic effects can be influenced almost independently by structural variations of the parent drug. Thus, it was possible to obtain compounds predominantly increasing sodium excretion without affecting potassium or magnesium excretion. On the other hand, substances could be developed with mainly antikaliuretic effects, or compounds, which enhanced sodium and reduced magnesium excretion and did not interfere with the potassium elimination. Based on these findings, it can be concluded that distal tubular transport of sodium, potassium and magnesium may be influenced independently from each other. These renal effects of triamterene and its derivatives seem to be independent of their antiarrhythmic actions, as suggested by recent studies.

Animals↗
PubMed2003

Trimethyl phosphite as a trap for alkoxy radicals formed from the ring opening of oxiranylcarbinyl radicals. Conversion to alkenes. Mechanistic applications to the study of C-C versus C-O ring cleavage.

Trimethyl phosphite, (MeO)(3)P, is introduced as an efficient and selective trap in oxiranylcarbinyl radical (2) systems, formed from haloepoxides 8-13 under thermal AIBN/n-Bu(3)SnH conditions at about 80 degrees C. Initially, the transformations of 8-13, in the absence of phosphite, to allyl alcohol 7 and/or vinyl ether 5 were measured quantitatively (Table 1). Structural variations in the intermediate oxiranylcarbinyl (2), allyloxy (3), and vinyloxycarbinyl (4) radicals involve influences of the thermodynamics and kinetics of the C-O (2 --> 3, k(1)) and C-C (2 --> 4, k(2)) radical scission processes and readily account for the changes in the amounts of product vinyl ether (5) and allyl alcohol (7) formed. Added (MeO)(3)P is inert to vinyloxycarbinyl radical 4 and selectively and rapidly traps allyloxy radical 3, diverting it to trimethyl phosphate and allyl radical 6. Allyl radicals (6) dimerize or are trapped by n-Bu(3)SnH to give alkenes, formed from haloepoxides 8, 9, and 13 in 69-95% yields. Intermediate vinyloxycarbinyl radicals (4), in the presence or absence of (MeO)(3)P, are trapped by n-Bu(3)SnH to give vinyl ethers (5). The concentrations of (MeO)(3)P and n-Bu(3)SnH were varied independently, and the amounts of phosphate, vinyl ether (5), and/or alkene from haloepoxides 10, 11, and 13 were carefully monitored. The results reflect readily understood influences of changes in the structures of radicals 2-4, particularly as they influence the C-O (k(1)) and C-C (k(2)) cleavages of intermediate oxiranylcarbinyl radical 2 and their reverse (k(-1), k(-2)). Diversion by (MeO)(3)P of allyloxy radicals (3) from haloepoxides 11 and 12 fulfills a prior prediction that under conditions closer to kinetic control, products of C-O scission, not just those of C-C scission, may result. Thus, for oxiranylcarbinyl radicals from haloepoxides 11, 12, and 13, C-O scission (k(1), 2 --> 3) competes readily with C-C cleavage (k(2), 2 --> 4), even though C-C scission is favored thermodynamically.

Alcohols↗
PubMed1995

The matching of electrostatic extrema: a useful method in drug design? A study of phosphodiesterase III inhibitors.

Ligands which bind to a specific protein binding site are often expected to have a similar electrostatic environment which complements that of the binding site. One method of assessing molecular electrostatic similarity is to examine the possible overlay of the maxima and minima in the electrostatic potential outside the molecules and thereby match the regions where strong electrostatic interactions, including hydrogen bonds, with the residues of the binding site may be possible. This approach is validated with accurate calculations of the electrostatic potential, derived from a distributed multiple analysis of an ab initio charge density of the molecule, so that the effects of lone pair and pi-electron density are correctly included. We have applied this method to the phosphodiesterase (PDE) III substrate adenosine-3',5'-cyclic monophosphate (cAMP) and a range of nonspecific and specific PDE III inhibitors. Despite the structural variation between cAMP and the inhibitors, it is possible to match three or four extrema to produce relative orientations in which the inhibitors are sufficiently sterically and electrostatically similar to the natural substrate to account for their affinity for PDE III. This matching of extrema is more apparent using the accurate electrostatic models than it was when this approach was first applied, using semiempirical point charge models. These results reinforce the hypothesis of electrostatic similarity and give weight to the technique of extrema matching as a useful tool in drug design.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2003

Structure- and function-based characterization of a new phosphoglycolate phosphatase from Thermoplasma acidophilum.

The protein TA0175 has a large number of sequence homologues, most of which are annotated as unknown and a few as belonging to the haloacid dehalogenase superfamily, but has no known biological function. Using a combination of amino acid sequence analysis, three-dimensional crystal structure information, and kinetic analysis, we have characterized TA0175 as phosphoglycolate phosphatase from Thermoplasma acidophilum. The crystal structure of TA0175 revealed two distinct domains, a larger core domain and a smaller cap domain. The large domain is composed of a centrally located five-stranded parallel beta-sheet with strand order S10, S9, S8, S1, S2 and a small beta-hairpin, strands S3 and S4. This central sheet is flanked by a set of three alpha-helices on one side and two helices on the other. The smaller domain is composed of an open faced beta-sandwich represented by three antiparallel beta-strands, S5, S6, and S7, flanked by two oppositely oriented alpha-helices, H3 and H4. The topology of the large domain is conserved; however, structural variation is observed in the smaller domain among the different functional classes of the haloacid dehalogenase superfamily. Enzymatic assays on TA0175 revealed that this enzyme catalyzed the dephosphorylation of phosphoglycolate in vitro with similar kinetic properties seen for eukaryotic phosphoglycolate phosphatase. Activation by divalent cations, especially Mg2+, and competitive inhibition behavior with Cl- ions are similar between TA0175 and phosphoglycolate phosphatase. The experimental evidence presented for TA0175 is indicative of phosphoglycolate phosphatase.

Amino Acid Sequence↗
PubMed2005

Inhibition of vesicular glutamate uptake by Rose Bengal-related compounds: structure-activity relationship.

Synaptic vesicular accumulation of glutamate is a vital initial step in glutamate transmission. We have previously shown that Rose Bengal, a polyhalogenated fluorescein analog, is a potent inhibitor of glutamate uptake into synaptic vesicles. Here, we report the structural features of Rose Bengal required for this inhibition. Various Rose Bengal-related compounds, with systematic structural variations, were tested. Results indicate that the four iodo groups and the phenyl group attached to the xanthene moiety are critical for potent inhibitory activity. Replacement of these groups with two iodo groups and an alkyl group, respectively, results in substantial reduction in potency. Of further interest in creating high potency is the critical nature of the oxygen atom which links the two benzene rings of xanthene. Thus, the phenyl group and multiple iodo groups, as well as the bridging oxygen of xanthene, are crucial elements of Rose Bengal required for its potent inhibitory action.

Animals↗
PubMed2006

5'-O-tritylinosine and analogues as allosteric inhibitors of human thymidine phosphorylase.

On the basis of our previous findings that 5'-O-tritylinosine (KIN59) behaves as an allosteric inhibitor of the angiogenic enzyme thymidine phosphorylase (TPase), we have undertaken the synthesis and enzymatic evaluation of a novel series of nucleoside analogues modified at positions 1, 2, or 6 of the purine ring and at the 5'-position of the ribose moiety of the lead compound KIN59. SAR studies indicate that quite large structural variations can be performed on KIN59 without compromising TPase inhibition. Thus, incorporation of a cyclopropylmethyl or a cyclohexylmethyl group at position N(1) of 5'-O-tritylinosine increases the inhibitory activity against TPase 10-fold compared to KIN59. Moreover, the trityl group at the 5'-position of the ribose seems to be crucial for TPase inhibition. The here reported results further substantiate that 5'-O-trityl nucleosides represent a new class of TPase inhibitors that should be further explored in those biological systems where TPase plays an instrumental role (i.e. angiogenesis).

Allosteric Regulation↗
PubMed1997

Hepatocyte-directed MR contrast agents. Can we take advantage of bile acids?

A series of gadolinium complexes conjugated to bile acids was prepared and investigated as possible hepatospecific MR imaging contrast agents. In the design of such compounds, features such as the nature of the bile acid, the site of conjugation on the bile acid skeleton, and the global charge of the conjugate were taken into account. Relaxivity measurements carried out in human serum indicate interaction of the conjugates with human serum proteins; even small structural variations significantly affect relaxivity in human serum. Pharmacokinetic data (biliary elimination in the range of 18.4-45.6%) show that bile acids can be used as address moieties to transport gadolinium complexes through hepatocytes. For a homogeneous series of compounds, differing only in the bile acid residue conjugated, it was unexpectedly found that cholic acid is twice as efficient an address moiety as cholylglycine or cholyltaurine. Preliminary results show that none of the conjugates is transported through the basolateral membrane of hepatocytes by the Na+/taurocholate carrier.

Animals↗
PubMed1996

Structure of tris(cyclohexylammonium) phosphoenolpyruvate monohydrate and crystal chemistry of phosphoenolpyruvates.

The crystal structure of (C6H11NH3+)3. Pep3-.H2O, where Pep3- = (O-)2P(O)-O-C(CH2)-CO2-, is reported and the systematic structural variations among 19 crystallographic occurrences of H3Pep, H2Pep-, HPep2- and Pep3- species, which are important phosphate donors in the ATP cycle of bioenergetics, are reviewed. Tris(cyclohexylammonium) phosphoenolpyruvate monohydrate, (C6H11NH3+)3.-[O3POC(CH2)CO2]3-.H2O, M(r) = 483.6, m.p. 418-420K; T = 296(1)K; orthorhombic, P2(1)2(1)2(1); a = 16.7042(5), b = 24.4881 (6), c = 6.38910 (10) A; V = 2613.49(11) A3, Z = 4, Dx = 1.23, Dm = 1.22 mg mm-3, mu = 0.14 mm-1 for lambda(MoK alpha) = 0.7107 A; F(000) = 1056 e; R(magnitude of F) = 0.0608 for 6056 hkl and hkl data with (sin theta)/lambda < or = 0.65 A-1.

Crystallography, X-Ray↗
PubMed2026

Novel epigenetic loci identified from an epigenome-wide association study underlying brain structural changes in bipolar disorder.

BACKGROUND: DNA methylation influences gene-environment interactions and brain development in bipolar disorder (BD). We aimed to identify BD-associated epigenetic loci and examine their associations with brain structural variation. METHODS: We conducted an epigenome-wide association study (BD group, n = 90; healthy controls group, n = 161) to identify BD-associated DNA methylation loci, and we additionally performed copy number alteration and functional enrichment analyses. The correlations between epigenetic loci and cortical thickness (CT) were assessed using Pearson's partial correlation analysis, and the co-methylation effect of the epigenetic loci identified in the neuroimaging-epigenetic analysis was investigated. FINDINGS: A total of 156 differentially methylated positions (DMPs) and 7 differentially methylated regions were identified, and the genes associated with them were observed to be enriched in biological processes related to muscle hypertrophy and neuronal activity. Significant correlations between the methylation levels of 13 DMPs associated with three genes (miR886, PLEC1, and ICAM5) and the CT of the right postcentral gyrus and inferior frontal gyrus were identified. Specifically, 10 DMPs associated with the CpG island in the upstream region of the miR886 gene showed negative correlations with the right postcentral gyrus CT, implicating miR886-associated CpG-island methylation in regional cortical thinning. CONCLUSION: Epigenetic changes might play an important role in brain structural changes in BD. These multimodal findings nominate miR886-related methylation as a candidate molecular correlate of cortical thinning and warrant replication and mechanistic follow-up in larger, state-diverse cohorts.

Humans↗