Sociodemographic representation in randomized controlled trials for anxiety-related disorders in the U.S.: A systematic review (1993-2023).

Cognitive behavioral therapies have been identified as evidence-based treatments for anxiety-related disorders. However, data supporting the effectiveness of these treatments have been largely collected from participants with majoritized identities, potentially limiting the extent to which they can be considered "evidence-based" for clients from minoritized groups. The current review examined sociodemographic representation and quality of sociodemographic reporting in randomized controlled trials for anxiety-related disorders in the U.S. between 1993 and 2023. We conducted a systematic literature review of U.S.-based randomized controlled trials of cognitive behavioral therapies for anxiety-related disorders, extracted data on sociodemographic variables, and rated quality of reporting. Data from 55 eligible studies (N = 4492) indicated that white and female identities were overrepresented relative to the U.S. population, with variables like disability status, sexual orientation, and religious identification consistently ignored. In addition, quality of reporting was generally poor (mean = 3.6 out of 10), with many studies failing to account for demographic variables in their analyses or description of study limitations. Publication year, sample size, and NIH funding status did not significantly predict gender representation (% women), ethnoracial representation (% white), or quality of reporting. These findings underscore the importance of critically evaluating to whom "evidence-based" treatments apply and increasing diversity of clinical samples, to ensure that evidence-based treatments are inclusive. Recommendations for future research, clinical implications, and limitations are discussed.

Clarifying the relation between mother and adolescent borderline personality disorder symptoms: The roles of maternal and adolescent emotion regulation and maladaptive maternal emotion socialization.

Despite evidence for the intergenerational transmission of borderline personality disorder (BPD) pathology from mothers to offspring, the factors underlying the relation between mother and child BPD symptoms remain unclear and little is known about the pathways through which maternal BPD symptoms may relate to BPD symptoms in their offspring. One set of factors that warrants consideration in this regard is mother and child emotion regulation (ER) difficulties. In particular, theory and research suggest an indirect relation between mother and child BPD symptoms through maternal ER difficulties (and related maladaptive emotion socialization strategies) and, subsequently, child ER difficulties. Thus, this study used structural equation modeling to examine a model wherein maternal BPD symptoms relate to offspring BPD symptoms in adolescence through maternal ER difficulties (and maladaptive maternal emotion socialization strategies) and, subsequently, adolescent ER difficulties. A nationwide community sample of 200 mother-adolescent dyads completed an online study. Results provided support for the proposed model, revealing both a direct relation between maternal and adolescent BPD symptoms and two indirect relations through (a) maternal and adolescent ER difficulties and (b) maternal ER difficulties, maternal maladaptive emotion socialization strategies, and adolescent ER difficulties. Results highlight the relevance of both mother and adolescent ER difficulties in the relation between mother and offspring BPD pathology, as well as the potential clinical utility of targeting mother and child ER in interventions aimed at preventing the intergenerational transmission of BPD pathology. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The moderating role of sexual minority status in the associations of the experience and tolerance of shame-related emotions to suicide risk.

OBJECTIVE: This study examined the associations of the experience and tolerance of shame-related emotions to suicide risk, as well as the moderating role of sexual minority status. METHODS: Community adults (N = 360) were recruited via MTurk and completed self-report questionnaires. Hierarchical regression analyses examined the main and interactive associations of sexual minority status and shame-related variables to suicide risk. RESULTS: Results revealed significant positive associations between self-disgust and suicide risk for sexual minority and heterosexual participants, although the magnitude was greater for sexual minority participants. Additionally, tolerance of shame was significantly negatively related to suicide risk only among sexual minority participants. Finally, exploratory analyses examining the three-way interaction of self-disgust, shame tolerance, and sexual minority status revealed a significant negative association between shame tolerance and suicide risk only among sexual minority participants with high levels of self-disgust. CONCLUSION: Results highlight the relevance of shame-related experiences to suicide risk among sexual minorities.

Orientation of the crotonaldehyde-derived N2-[3-Oxo-1(S)-methyl-propyl]-dG DNA adduct hinders interstrand cross-link formation in the 5'-CpG-3' sequence.

The conformation of the crotonaldehyde-derived N(2)-[3-oxo-1(S)-methyl-propyl]-dG adduct in the oligodeoxynucleotide 5'-d(G(1)C(2)T(3)A(4)G(5)C(6)X(7)A(8)G(9)T(10)C(11)C(12))-3'.5'-d(G(13)G(14)A(15)C(16)T(17)C(18)G(19)C(20)T(21)A(22)G(23)C(2)(4))-3', where X = N(2)-[3-oxo-1(S)-methyl-propyl]-dG, is reported. This adduct arises from opening of the cyclic N(2)-(S-alpha-CH(3)-gamma-OH-1,N(2)-propano-2')-dG adduct when placed opposite dC in duplex DNA. This oligodeoxynucleotide contains the 5'-CpG-3' sequence in which the N(2)-(R-alpha-CH(3)-gamma-OH-1,N(2)-propano-2')-dG but not the N(2)-(S-alpha-CH(3)-gamma-OH-1,N(2)-propano-2')-dG adduct preferentially formed an interstrand carbinolamine cross-link [Kozekov, I. D., Nechev, L. V., Moseley, M. S., Harris, C. M., Rizzo, C. J., Stone, M. P., and Harris, T. M. (2003) J. Am. Chem. Soc. 125, 50-61; Cho, Y.-J., Wang, H., Kozekov, I. D., Kurtz, A. J., Jacob, J., Voehler, M., Smith, J., Harris, T. M., Lloyd, R. S., Rizzo, C. J., and Stone, M. P. (2006) Chem. Res. Toxicol. 19, 195-208]. Analysis of (1)H NOE data, chemical shift perturbations, and deoxyribose pseudorotations and backbone torsion angles suggested the presence of a stable and ordered DNA conformation at pH 9.3 and 30 degrees C, with minimal conformational perturbation. The spectral line widths of the adduct protons were comparable to those of the oligodeoxynucleotide, suggesting that the correlation times of these protons were similar to those of the overall duplex. The crotonaldehydic-derived methyl protons showed NOEs in the 5'-direction to C(18) H1', G(19) H1', and G(19) H4' in the complementary strand of the duplex. The aldehyde proton of the adduct exhibited NOEs in the 3'-direction to A(8) H1' and A(8) H4' in the modified strand. All of these NOEs involved DNA protons facing the minor groove. Molecular dynamics calculations, restrained by distances and torsion angles derived from the NMR data, revealed that within the minor groove, the aldehyde of the N(2)-[3-oxo-1(S)-methyl-propyl]-dG adduct oriented in the 3'-direction, while the 1(S) methyl group oriented in the 5'-direction. This positioned the aldehyde distal to the G(19) exocyclic amine and provided a rationale as to why the N(2)-(S-alpha-CH(3)-gamma-OH-1,N(2)-propano-2')-dG adduct generated interstrand cross-links less efficiently than did the N(2)-(R-alpha-CH(3)-gamma-OH-1,N(2)-propano-2')-dG adduct.

Revealing the nature of the native state ensemble through cold denaturation.

Recent advances in NMR methodology have enabled the structural analysis of proteins at temperatures far below the freezing point of water, thus opening a window to the cold denaturation process. Although the phenomenon of cold denaturation has been known since the mid-1970s, the freezing point of water has prevented detailed and structurally resolved studies without application of additional significant perturbations of the protein ensemble. As a result, the cold-denatured state and the process of cold denaturation have gone largely unstudied. Here, the structural and thermodynamic basis of cold denaturation is explored with emphasis placed on the insights that are uniquely ascertained from low-temperature studies. It is shown that the noncooperative cold-induced unfolding of protein results in the population of partially folded states that cannot be accessed by other techniques. The structurally resolved view of the cold denaturation process therefore can provide direct access to the cooperative substructures within the protein molecule and provide an unprecedented structurally resolved picture of the states that comprise the native state ensemble.

Stereospecific formation of interstrand carbinolamine DNA cross-links by crotonaldehyde- and acetaldehyde-derived alpha-CH3-gamma-OH-1,N2-propano-2'-deoxyguanosine adducts in the 5'-CpG-3' sequence.

The crotonaldehyde- and acetaldehyde-derived R- and S-alpha-CH3-gamma-OH-1,N2-propanodeoxyguanosine adducts were monitored in single-stranded and duplex oligodeoxynucleotides using NMR spectroscopy. In both instances, the cis and trans diastereomers of the alpha-CH3 and gamma-OH groups underwent slow exchange, with the trans diastereomers being favored. In single-stranded oligodeoxynucleotides, the aldehyde intermediates were not detected spectroscopically, but their presence was revealed through the formation of N-terminal conjugates with the tetrapeptide KWKK. When annealed into 5'-d(GCTAGCXAGTCC)-3'.5'-d(GGACTCYCTAGC)-3' containing the 5'-CpG-3' sequence context (X = R- or S-alpha-CH3-gamma-13C-OH-PdG; Y = 15N2-dG) at pH 7, partial opening of the R- or S-alpha-CH3-gamma-13C-OH-PdG adducts to the corresponding N2-(3-oxo-1-methyl-propyl)-dG aldehydes was observed at temperatures below the T(m) of the duplexes. These aldehydes equilibrated with their geminal diol hydrates; higher temperatures favored the aldehydes. When annealed opposite T, the S-alpha-CH3-gamma-13C-OH-PdG adduct was stable. At 37 degrees C, an interstrand DNA cross-link was observed spectroscopically only for the R-alpha-CH3-gamma-OH-PdG adduct. Molecular modeling predicted that the interstrand cross-link formed by the R-alpha-CH3-gamma-OH-PdG adduct introduced less disruption into the duplex structure than did the cross-link arising from the S-alpha-CH3-gamma-OH-PdG adduct, due to differing orientations of the R- and S-CH3 groups. Modeling also predicted that the alpha-methyl group of the aldehyde arising from the R-alpha-CH3-gamma-OH-PdG adduct is oriented in the 3'-direction in the minor groove, facilitating cross-linking. In contrast, the alpha-methyl group of the aldehyde arising from the S-alpha-CH3-gamma-OH-PdG adduct is oriented in the 5'-direction within the minor groove, potentially hindering cross-linking. NMR revealed that for the R-alpha-CH3-gamma-OH-PdG adduct, the carbinolamine form of the cross-link was favored in duplex DNA with the imine (Schiff base) form of the cross-link remaining below the level of spectroscopic detection. Molecular modeling predicted that the carbinolamine linkage maintained Watson-Crick hydrogen bonding at both of the tandem C.G base pairs. Dehydration of the carbinolamine cross-link to an imine, or cyclization of the latter to form a pyrimidopurinone cross-link, required disruption of Watson-Crick hydrogen bonding at one or both of the cross-linked base pairs.

Initiation of repair of DNA-polypeptide cross-links by the UvrABC nuclease.

Although the biochemical pathways that repair DNA-protein cross-links have not been clearly elucidated, it has been proposed that the partial proteolysis of cross-linked proteins into smaller oligopeptides constitutes an initial step in removal of these lesions by nucleotide excision repair (NER). To test the validity of this repair model, several site-specific DNA-peptide and DNA-protein cross-links were engineered via linkage at (1) an acrolein-derived gamma-hydroxypropanodeoxyguanosine adduct and (2) an apurinic/apyrimidinic site, and the initiation of repair was examined in vitro using recombinant proteins UvrA and UvrB from Bacillus caldotenax and UvrC from Thermotoga maritima. The polypeptides cross-linked to DNA were Lys-Trp-Lys-Lys, Lys-Phe-His-Glu-Lys-His-His-Ser-His-Arg-Gly-Tyr, and the 16 kDa protein, T4 pyrimidine dimer glycosylase/apurinic/apyrimidinic site lyase. For the substrates examined, DNA incision required the coordinated action of all three proteins and occurred at the eighth phosphodiester bond 5' to the lesion. The incision rates for DNA-peptide cross-links were comparable to or greater than that measured on fluorescein-adducted DNA, an excellent substrate for UvrABC. Incision rates were dependent on both the site of covalent attachment on the DNA and the size of the bound peptide. Importantly, incision of a DNA-protein cross-link occurred at a rate approximately 3.5-8-fold slower than the rates observed for DNA-peptide cross-links. Thus, direct evidence has been obtained indicating that (1) DNA-peptide cross-links can be efficiently incised by the NER proteins and (2) DNA-peptide cross-links are preferable substrates for this system relative to DNA-protein cross-links. These data suggest that proteolytic degradation of DNA-protein cross-links may be an important processing step in facilitating NER.

Reaction intermediates in the catalytic mechanism of Escherichia coli MutY DNA glycosylase.

The Escherichia coli adenine DNA glycosylase, MutY, plays an important role in the maintenance of genomic stability by catalyzing the removal of adenine opposite 8-oxo-7,8-dihydroguanine or guanine in duplex DNA. Although the x-ray crystal structure of the catalytic domain of MutY revealed a mechanism for catalysis of the glycosyl bond, it appeared that several opportunistically positioned lysine side chains could participate in a secondary beta-elimination reaction. In this investigation, it is established via site-directed mutagenesis and the determination of a 1.35-A structure of MutY in complex with adenine that the abasic site (apurinic/apyrimidinic) lyase activity is alternatively regulated by two lysines, Lys142 and Lys20. Analyses of the crystallographic structure also suggest a role for Glu161 in the apurinic/apyrimidinic lyase chemistry. The beta-elimination reaction is structurally and chemically uncoupled from the initial glycosyl bond scission, indicating that this reaction occurs as a consequence of active site plasticity and slow dissociation of the product complex. MutY with either the K142A or K20A mutation still catalyzes beta and beta-delta elimination reactions, and both mutants can be trapped as covalent enzyme-DNA intermediates by chemical reduction. The trapping was observed to occur both pre- and post-phosphodiester bond scission, establishing that both of these intermediates have significant half-lives. Thus, the final spectrum of DNA products generated reflects the outcome of a delicate balance of closely related equilibrium constants.

Comparative evaluation of the bioreactivity and mutagenic spectra of acrolein-derived alpha-HOPdG and gamma-HOPdG regioisomeric deoxyguanosine adducts.

Acrolein is a bifunctional electrophile, present as an ubiquitous environmental pollutant and an endogenous cellular product of lipid peroxidation. Reaction of acrolein with deoxyguanosine produces two regioisomeric DNA adducts, specifically gamma-hydroxypropanodeoxyguanosine (gamma-HOPdG) and alpha-hydroxypropanodeoxyguanosine (alpha-HOPdG). While previous investigations have focused on the major gamma-HOPdG adduct, little is known about the properties of the minor alpha-HOPdG adduct. Therefore, this comparative investigation has assessed the following: the ability of each adduct to undergo secondary chemical reactions with biomolecules to form various cross-linked species, in vitro translesion DNA synthesis, and mutagenic properties, following replication in mammalian cells. In contrast to gamma-HOPdG, which is capable of forming DNA-DNA, DNA-peptide, and DNA-protein cross-links, alpha-HOPdG did not form any of these cross-linked species. These results can be attributed to the inability of the alpha-HOPdG adduct to undergo ring opening, whereas the gamma-HOPdG adduct forms the ring open, acyclic N(2) oxopropyl in duplex DNA, which readily reacts with nucleophilic functions. Consistent with this interpretation, when polymerase eta replication bypass of DNA containing alpha-HOPdG was assayed, this lesion posed a stronger block to replication than the gamma-HOPdG adduct, closely resembling the results for polymerase eta bypass of propanodeoxyguanosine in which the exocyclic adduct remains permanently ring-closed. Cellular replication and mutagenesis assays in COS-7 cells using single-stranded DNA containing a site specific alpha-HOPdG revealed that this adduct was significantly mutagenic, yielding a nearly identical frequency and spectrum of mutations as compared with the gamma-HOPdG adduct.

1,N2-deoxyguanosine adducts of acrolein, crotonaldehyde, and trans-4-hydroxynonenal cross-link to peptides via Schiff base linkage.

DNA-protein cross-links (DPCs) are formed upon exposure to a variety of chemical and physical agents and pose a threat to genomic integrity. In particular, acrolein and related aldehydes produce DPCs, although the chemical linkages for such cross-links have not been identified. Here, we report that oligodeoxynucleotides containing 1,N(2)-deoxyguanosine adducts of acrolein, crotonaldehyde, and trans-4-hydroxynonenal can form cross-links with the tetrapeptide Lys-Trp-Lys-Lys. We concluded that complex formation is mediated by a Schiff base linkage because DNA-peptide complexes were covalently trapped following reduction with sodium cyanoborohydride, and pre-reduction of adducted DNAs inhibited complex formation. A previous NMR study demonstrated that duplex DNA catalyzes ring opening for the acrolein-derived gamma-hydroxy-1,N(2)-propanodeoxyguanosine adduct to yield an aldehydic function (de los Santos, C., Zaliznyak, T., and Johnson, F. (2001) J. Biol. Chem. 276, 9077-9082). Consistent with this earlier observation, the adducts under investigation were more reactive in duplex DNA than in single-stranded DNA, and we concluded that the ring-open aldehydic moiety is the induced tautomer in duplex DNA for adducts exhibiting high relative reactivity. Adducted DNA cross-linked to Arg-Trp-Arg-Arg and Lys-Trp-Lys-Lys with comparable efficiency, and N(alpha)-acetylation of peptides dramatically inhibited trapping; thus, the reactive nucleophile is located at the N-terminal alpha-amine of the peptide. These data suggest that Schiff base chemistry can mediate DPC formation in vivo following the formation of stable aldehyde-derived DNA adducts.

Evidence for multiple imino intermediates and identification of reactive nucleophiles in peptide-catalyzed beta-elimination at abasic sites.

Prior investigations have demonstrated that peptides containing a single aromatic residue flanked by basic ones, such as Lys-Trp-Lys, can incise the phosphodiester backbone of duplex DNA at an AP site via beta-elimination. An amine serves as the reactive nucleophile to attack C1' on the ring-open deoxyribose sugar to form a transient peptide-DNA imino (Schiff base) intermediate, which may be isolated as a stable covalent species under reducing conditions. In the current study, we use this methodology to demonstrate that peptide-catalyzed beta-elimination proceeds via the formation of two Schiff base intermediates, one of which was covalently trapped prior to strand incision and the other following strand incision. N-Terminal acetylation of reactive peptides significantly inhibited formation of a trapped Schiff base complex; thus, we demonstrate for the first time that the preferred reactive nucleophile for peptides catalyzing strand incision is the N-terminal alpha-amino group, not an epsilon-amino group located on a lysine residue as previously postulated. Trapping reactions in which the central tryptophan residue was changed to alanine did not have a significant impact on the efficiency of Schiff base formation, indicating that the presence of an aromatic residue is dispensable for the step prior to peptide-catalyzed beta-elimination. Interestingly, the methodology presented here affords a convenient means for covalently attaching an array of peptides onto AP site-containing DNA in a site-specific fashion. We suggest that the generation of such DNA-peptide cross-links may provide utility in studying the repair of biologically significant DNA-protein cross-link damage as DNA-peptide complexes may mimic intermediate structures along a repair pathway for DNA-protein cross-links.