How does hostile resistance interfere with the benefits of cognitive-behavioral therapy for panic disorder? The role of therapist adherence and working alliance.

Objective Although clients' hostile behavior directed at therapists (hostile resistance) predicts worse outcomes in cognitive-behavioral therapy (CBT) for panic disorder, the process by which this happens remains unknown. This study examines two putative mechanisms: working alliance and therapist adherence. Method: Seventy-one adults with primary panic disorder received CBT in a larger trial. Hostile resistance and adherence in Sessions 2 and 10 were reliably coded using observer-rated measures; client- and therapist-rated questionnaires assessed working alliance. Outcome measures were attrition and symptomatic improvement, assessed at multiple timepoints with the Panic Disorder Severity Scale. Results: Hostile resistance was significantly related to both preexisting (r = -.36, p = .04) and subsequent declines (r = -.58, p < .0001) in the working alliance. Nevertheless, hierarchical linear modeling revealed that neither a declining alliance nor therapist adherence (whether treated as linear or curvilinear) was independently predictive of symptom change, nor did these factors mediate hostile resistance's association with worse symptomatic improvement. Exploratory logistic regressions similarly indicated that neither adherence nor alliance moderated whether hostilely resistant clients dropped out. Conclusion: This is the first study to establish a bidirectional association between hostile resistance and a declining working alliance. Findings also add to a mixed literature on the adherence-outcome relationship.

Testing Clinical Intuitions About Barriers to Improvement in Cognitive-Behavioral Therapy for Panic Disorder.

Although clinical intuitions influence psychotherapeutic practice and are a rich source of novel hypotheses for research, many remain to be empirically tested. This study evaluates whether clinicians' beliefs about barriers to progress in cognitive-behavioral therapy (CBT) for panic disorder are supported by data. Data from a randomized-controlled trial comparing CBT to panic-focused psychodynamic psychotherapy (PFPP) for adults with primary panic disorder (N = 161) were used to evaluate 15 factors endorsed by clinicians as impediments to CBT in a recent survey. Panic severity was assessed before, during (at Weeks 1, 5, and 9), and at termination of treatment (Week 12) using the Panic Disorder Severity Scale. Hierarchical linear modeling revealed that none of the perceived barriers were predictive of poor outcome. Contrary to clinicians' intuitions, dissociation during panic attacks was associated with greater symptomatic improvement in both treatment arms (ß = -0.69, p < .05), above the effect of established predictors. Moderation analyses revealed that when patients had PTSD diagnosed with the Anxiety Disorders Interview Schedule (ß = 1.71, p < .05) or less severe panic disorder (ß = 0.45, p = .04), they changed more rapidly in CBT than in PFPP. Overall, clinician agreement was inversely related to the strength of a predictor (r = -.24, p = .39). Although clinical intuitions can be useful as clinical and empirical signals, such beliefs should be critically examined before informing practice. Dialogue between academics and clinicians might be enhanced through research that incorporates input from front-line practitioners.

Patient, therapist, and relational antecedents of hostile resistance in cognitive-behavioral therapy for panic disorder: A qualitative investigation.

Hostile resistance (clients' openly combative behavior directed at therapists) predicts poor outcomes in cognitive-behavioral therapy (CBT) for panic disorder, but its origins are poorly understood. It is important to have a holistic understanding of the etiology of hostile resistance that incorporates the therapeutic context if these behaviors-and their negative consequences-are to be prevented and effectively addressed. Of the 71 adults who received CBT for panic disorder as part of larger trial, 8 exhibited hostile resistance. Grounded theory methodology was used to develop a theoretical framework to understand why these patients became hostile in session. The 10 minutes of session preceding instances of hostile resistance and matched portions of sessions from five never hostile controls were coded. Two pathways to hostile resistance emerged-one in which patient characteristics were primary and one wherein therapist failures (particularly of empathy) were primary. Being a challenging patient (i.e., narcissistic, obsessive, angry, resistant) moderated which pathway was followed. However, even among challenging patients, rarely was hostile resistance attributable to patients' dispositions alone. Most often, patient factors interacted with therapist (e.g., displays of frustration) and treatment (e.g., directiveness, degree of structure) factors to produce such resistance. Contrary to the view of hostile resistance as simply a product of a hostile patient, the picture is more complex. Findings indicate that greater attention to common factors in CBT and more flexible applications of treatment protocols is warranted. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Client resistance predicts outcomes in cognitive-behavioral therapy for panic disorder.

Objective: Little is known about how therapy processes relate to outcome in cognitive-behavioral therapy (CBT) for panic disorder (PD). This study examined whether client resistance predicts CBT for PD outcomes beyond the effects of established pre-treatment predictors. A secondary aim was to assess the consistency of resistance over treatment. Method: Data were from 71 adults participating in up to 24 biweekly sessions of CBT in a randomized controlled trial. Panic severity was assessed before, during (at Weeks 1, 5, and 9), and at termination of treatment (Week 12) using the Panic Disorder Severity Scale. Trained coders reliably rated resistance in videos of Sessions 2 and 10 using the Client Resistance Code. Results: Resistance was found to be moderately consistent (r = .64). Although overall resistance was unrelated to outcomes, hierarchical linear modeling revealed that openly hostile resistance at Session 10 predicted significantly diminished symptom change (r = .28, CI95% = [.01, .51]), beyond the effects of pretreatment predictors. Hostile resistance at Session 2 predicted attrition (rrb = -.30, p = .001), even after established predictors were controlled. Conclusions: Although some forms of resistance may be benign, openly hostile resistance is an important therapy marker that warrants increased clinical and research attention.

Attributions and perceptions of criticism: An examination of patients with anxiety and normal control participants.

Perceived criticism from relatives predicts poor clinical outcomes for patients with a variety of psychological disorders. Research indicates the attributions individuals make about motives for relatives' criticism are linked to perceived criticism from this relative. Accordingly, attributions may be an important target of intervention to reduce perceived criticism and improve clinical outcomes, but this association requires testing in a clinical sample. We examined relationships among attributions of criticism, perceived criticism, and upset due to criticism among individuals with anxiety disorders (n = 53) and with no psychopathology (n = 52). Participants completed measures of global attributions, perceived criticism, and upset due to criticism regarding criticism from a romantic partner/spouse or parent. After a 10-min problem-solving interaction with their relative, they completed measures of attributions, perceived criticism, and upset with regard to this relative's critical behavior during the interaction, and observers reliably coded interactions for relatives' criticism. Results showed that negative attributions were related to greater perceived criticism and upset for both global and interaction-specific measures. In analyses of interaction-specific measures, negative attributions added to prediction of perceived criticism and upset over and above the contribution of observed criticism. Positive attributions were not significantly related to global or interaction-specific upset in any analyses. Relationships were consistent across patients and normal controls. Our findings suggest that negative attributions of relatives' motives for their criticism are important predictors of perceived criticism and upset. Thus, interventions targeting these attributions may be helpful in mitigating the negative effect of perceived criticism for individuals with psychopathology. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Mechanisms of change in cognitive therapy for obsessive compulsive disorder: role of maladaptive beliefs and schemas.

The present study aimed to identify mechanisms of change in individuals with moderately severe obsessive-compulsive disorder (OCD) receiving cognitive therapy (CT). Thirty-six adults with OCD received CT over 24 weeks. At weeks 0, 4/6, 12, 16/18, and 24, independent evaluators assessed OCD severity, along with obsessive beliefs and maladaptive schemas. To examine mechanisms of change, we utilized a time-varying lagged regression model with a random intercept and slope. Results indicated that perfectionism and certainty obsessive beliefs and maladaptive schemas related to dependency and incompetence significantly mediated (improved) treatment response. In conclusion, cognitive changes in perfectionism/certainty beliefs and maladaptive schemas related to dependency/incompetence precede behavioral symptom reduction for OCD patients. Targeting these mechanisms in future OCD treatment trials will emphasize the most relevant processes and facilitate maximum improvement.

Adeno-associated virus replication induces a DNA damage response coordinated by DNA-dependent protein kinase.

The parvovirus adeno-associated virus (AAV) contains a small single-stranded DNA genome with inverted terminal repeats that form hairpin structures. In order to propagate, AAV relies on the cellular replication machinery together with functions supplied by coinfecting helper viruses such as adenovirus (Ad). Here, we examined the host cell response to AAV replication in the context of Ad or Ad helper proteins. We show that AAV and Ad coinfection activates a DNA damage response (DDR) that is distinct from that seen during Ad or AAV infection alone. The DDR was also triggered when AAV replicated in the presence of minimal Ad helper proteins. We detected autophosphorylation of the kinases ataxia telangiectasia mutated (ATM) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and signaling to downstream targets SMC1, Chk1, Chk2, H2AX, and XRCC4 and multiple sites on RPA32. The Mre11 complex was not required for activation of the DDR to AAV infection. Additionally, we found that DNA-PKcs was the primary mediator of damage signaling in response to AAV replication. Immunofluorescence revealed that some activated damage proteins were found in a pan-nuclear pattern (phosphorylated ATM, SMC1, and H2AX), while others such as DNA-PK components (DNA-PKcs, Ku70, and Ku86) and RPA32 accumulated at AAV replication centers. Although expression of the large viral Rep proteins contributed to some damage signaling, we observed that the full response required replication of the AAV genome. Our results demonstrate that AAV replication in the presence of Ad helper functions elicits a unique damage response controlled by DNA-PK.

Distinct requirements of adenovirus E1b55K protein for degradation of cellular substrates.

The E1b55K and E4orf6 proteins of adenovirus type 5 (Ad5) assemble into a complex together with cellular proteins including cullin 5, elongins B and C, and Rbx1. This complex possesses E3 ubiquitin ligase activity and targets cellular proteins for proteasome-mediated degradation. The ligase activity has been suggested to be responsible for all functions of E1b55K/E4orf6, including promoting efficient viral DNA replication, preventing a cellular DNA damage response, and stimulating late viral mRNA nuclear export and late protein synthesis. The known cellular substrates for degradation by E1b55K/E4orf6 are the Mre11/Rad50/Nbs1 DNA repair complex, the tumor suppressor p53, and DNA ligase IV. Here we show that the degradation of individual targets can occur independently of other substrates. Furthermore, we identify separation-of-function mutant forms of E1b55K that can distinguish substrates for binding and degradation. Our results identify distinct regions of E1b55K that are involved in substrate recognition but also imply that there are additional requirements beyond protein association. These mutant proteins will facilitate the determination of the relevance of specific substrates to the functions of E1b55K in promoting infection and inactivating host defenses.

Differential requirements of the C terminus of Nbs1 in suppressing adenovirus DNA replication and promoting concatemer formation.

Adenoviruses (Ad) with the early region E4 deleted (E4-deleted virus) are defective for DNA replication and late protein synthesis. Infection with E4-deleted viruses results in activation of a DNA damage response, accumulation of cellular repair factors in foci at viral replication centers, and joining together of viral genomes into concatemers. The cellular DNA repair complex composed of Mre11, Rad50, and Nbs1 (MRN) is required for concatemer formation and full activation of damage signaling through the protein kinases Ataxia-telangiectasia mutated (ATM) and ATM-Rad3-related (ATR). The E4orf3 and E4orf6 proteins expressed from the E4 region of Ad type 5 (Ad5) inactivate the MRN complex by degradation and mislocalization, and prevent the DNA damage response. Here we investigated individual contributions of the MRN complex, concatemer formation, and damage signaling to viral DNA replication during infection with E4-deleted virus. Using virus mutants, short hairpin RNA knockdown and hypomorphic cell lines, we show that inactivation of MRN results in increased viral replication. We demonstrate that defective replication in the absence of E4 is not due to concatemer formation or DNA damage signaling. The C terminus of Nbs1 is required for the inhibition of Ad DNA replication and recruitment of MRN to viral replication centers. We identified regions of Nbs1 that are differentially required for concatemer formation and inhibition of Ad DNA replication. These results demonstrate that targeting of the MRN complex explains the redundant functions of E4orf3 and E4orf6 in promoting Ad DNA replication. Understanding how MRN impacts the adenoviral life cycle will provide insights into the functions of this DNA damage sensor.

Processing of recombinant AAV genomes occurs in specific nuclear structures that overlap with foci of DNA-damage-response proteins.

Despite increasing utilization of rAAV vectors in gene transfer applications, several aspects of the biology of these vectors remain poorly understood. We have visualized the conversion of rAAV vector genomes from single-stranded to double-stranded DNA in real time. We report that rAAV DNA accumulates into discrete foci inside the nucleus. These rAAV foci are defined in number, increase in size over time after transduction, are relatively immobile, and their presence correlates with the efficiency of cell transduction. These structures overlap with, or lie in close proximity to, the foci in which proteins of the MRN (MRE11-RAD50-NBS1) complex as well as the MDC1 protein accumulate after DNA damage. The downregulation of MRN or MDC1 by RNA interference markedly increases both the formation of rAAV foci and the extent of rAAV transduction. Chromatin immunoprecipitation experiments indicate that the MRE11 protein associates with the incoming rAAV genomes and that this association decreases upon cell treatment with DNA damaging agents. These findings are consistent with a model whereby cellular DNA-damage-response proteins restrict rAAV transduction by negatively regulating rAAV genome processing.

The Mre11/Rad50/Nbs1 complex limits adeno-associated virus transduction and replication.

Adeno-associated virus (AAV) is a parvovirus with a small single-stranded DNA genome that relies on cellular replication machinery together with functions supplied by coinfecting helper viruses. The impact of host factors on AAV infection is not well understood. We explored the connection between AAV helper functions supplied by adenovirus and cellular DNA repair proteins. The adenoviral E1b55K/E4orf6 proteins induce degradation of the cellular Mre11 repair complex (MRN) to promote productive adenovirus infection. These viral proteins also augment recombinant AAV transduction and provide crucial helper functions for wild-type AAV replication. Here, we show that MRN poses a barrier to AAV and that the helper function provided by E1b55K/E4orf6 involves MRN degradation. Using a fluorescent method to visualize the viral genome, we show an effect at the viral DNA level. MRN components accumulate at AAV replication centers and recognize the viral inverted terminal repeats. Together, our data suggest that AAV is targeted by MRN and has evolved to exploit adenoviral proteins that degrade these cellular factors.

Using or abusing: viruses and the cellular DNA damage response.

During infection, viruses attempt to hijack the cell while the host responds with various defense systems. Traditional defenses include the interferon response and apoptosis, but recent work suggests that this antiviral arsenal also includes the cellular DNA damage response machinery. The observation of interactions between viruses and cellular DNA repair proteins has not only uncovered new complexities of the virus-host interaction but is also reinforcing the view that viruses can reveal key regulators of cellular pathways through the proteins they target.

Cyclin-dependent kinase activity is required at early times for accurate processing and accumulation of the human cytomegalovirus UL122-123 and UL37 immediate-early transcripts and at later times for virus production.

Human cytomegalovirus (HCMV) infection leads to dysregulation of multiple cell cycle-regulatory proteins. In this study, we examined the effects of inhibition of cyclin-dependent kinase (cdk) activity on viral replication. With the drug Roscovitine, a specific inhibitor of cyclin-dependent kinases 1, 2, 5, 7, and 9, we have shown that during the first 6 h of infection, cyclin-dependent kinase-dependent events occurred that included the regulated processing and accumulation of the immediate-early (IE) UL122-123 transcripts and UL36-37 transcripts. Altered processing of UL122-123 led to a loss of IE1-72 and an increase in IE2-86. The ratio of spliced to unspliced UL37 transcripts also changed. These effects did not require de novo protein synthesis or degradation of proteins by the proteasome. Addition of Roscovitine at the beginning of the infection was also associated with inhibition of expression of selected viral early gene products, viral DNA replication, and late viral gene expression. When Roscovitine was added after the first 6 h of infection, the effects on IE gene expression were no longer observed and viral replication proceeded through the late phase, but viral titers were reduced. The reduction in viral titer was observed even when Roscovitine was first added at 48 h postinfection, indicating that cyclin-dependent kinase activity is required at both IE and late times. Flavopiridol, another specific inhibitor of cyclin-dependent kinases, had similar effects on IE and early gene expression. These results underscore the importance of accurate RNA processing and reiterate the significant role of cell cycle-regulatory factors in HCMV infection.

Interactions of viruses with the cellular DNA repair machinery.

Mammalian cells are equipped with complex machinery to monitor and repair damaged DNA. In addition to responding to breaks in cellular DNA, recent studies have revealed that the DNA repair machinery also recognizes viral genetic material. We review some examples that highlight the different strategies that viruses have developed to interact with the host DNA repair apparatus. While adenovirus (Ad) inactivates the host machinery to prevent signaling and concatemerization of the viral genome, other viruses may utilize DNA repair to their own advantage. Viral interactions with the repair machinery can also have detrimental consequences for the host cells and their ability to maintain the integrity of the host genome. Exploring the interactions between viruses and the host DNA repair machinery has revealed novel host responses to virus infections and has provided new tools to study the DNA damage response.

The Mre11 complex is required for ATM activation and the G2/M checkpoint.

The maintenance of genome integrity requires a rapid and specific response to many types of DNA damage. The conserved and related PI3-like protein kinases, ataxia-telangiectasia mutated (ATM) and ATM-Rad3-related (ATR), orchestrate signal transduction pathways in response to genomic insults, such as DNA double-strand breaks (DSBs). It is unclear which proteins recognize DSBs and activate these pathways, but the Mre11/Rad50/NBS1 complex has been suggested to act as a damage sensor. Here we show that infection with an adenovirus lacking the E4 region also induces a cellular DNA damage response, with activation of ATM and ATR. Wild-type virus blocks this signaling through degradation of the Mre11 complex by the viral E1b55K/E4orf6 proteins. Using these viral proteins, we show that the Mre11 complex is required for both ATM activation and the ATM-dependent G(2)/M checkpoint in response to DSBs. These results demonstrate that the Mre11 complex can function as a damage sensor upstream of ATM/ATR signaling in mammalian cells.