seco-Pregnane Glycosides from Australian Caustic Vine (Cynanchum viminale subsp. australe).

Cynanchum viminale subsp. australe, more commonly known as caustic vine, is a leafless succulent that grows in the northern arid zone of Australia. Toxicity toward livestock has been reported for this species, along with use in traditional medicine and its potential anticancer activity. Disclosed herein are novel seco-pregnane aglycones cynavimigenin A (5) and cynaviminoside A (6), together with new pregnane glycosides cynaviminoside B (7) and cynavimigenin B (8). Cynavimigenin B (8) contains an unprecedented 7-oxobicyclo[2.2.1]heptane moiety in the seco-pregnane series, likely arising from a pinacol-type rearrangement. Interestingly, these isolates displayed only limited cytotoxicity in cancer and normal human cell lines, in addition to low activity against acetylcholinesterase and Sarcoptes scabiei bioassays, suggesting that 5-8 are not associated with the reported toxicity of this plant species.

Squaramides as Bioisosteres in Contemporary Drug Design.

Squaramides represent a class of vinylogous amides that are derived from the squarate oxocarbon dianion. While they have been known since the 1950s, squaramides have only recently emerged (in the last 10-20 years) as particularly useful chemical entities in a variety of applications. They have found particular use as bioisosteric replacements of several heteroatomic functional groups, notably ureas, thioureas, guanidines, and cyanoguanidines, owing in part to their similar capacity toward hydrogen bonding and ability to reliably engender defined conformations in drug ligands. This Review aims to provide a comprehensive overview of the deployment of squaramides as bioisosteres within the drug design landscape. Their utility in this space is further rationalized through an examination of the physicochemical properties of squaramides in contrast to other functional groups. In addition, we consider the deployment of related cyclic oxocarbanion derivatives as potential bioisosteric replacements of ureas and related functional groups.

Commercial AHAS-inhibiting herbicides are promising drug leads for the treatment of human fungal pathogenic infections.

The increased prevalence of drug-resistant human pathogenic fungal diseases poses a major threat to global human health. Thus, new drugs are urgently required to combat these infections. Here, we demonstrate that acetohydroxyacid synthase (AHAS), the first enzyme in the branched-chain amino acid biosynthesis pathway, is a promising new target for antifungal drug discovery. First, we show that several AHAS inhibitors developed as commercial herbicides are powerful accumulative inhibitors of Candida albicans AHAS (Ki values as low as 800 pM) and have determined high-resolution crystal structures of this enzyme in complex with several of these herbicides. In addition, we have demonstrated that chlorimuron ethyl (CE), a member of the sulfonylurea herbicide family, has potent antifungal activity against five different Candida species and Cryptococcus neoformans (with minimum inhibitory concentration, 50% values as low as 7 nM). Furthermore, in these assays, we have shown CE and itraconazole (a P450 inhibitor) can act synergistically to further improve potency. Finally, we show in Candida albicans-infected mice that CE is highly effective in clearing pathogenic fungal burden in the lungs, liver, and spleen, thus reducing overall mortality rates. Therefore, in view of their low toxicity to human cells, AHAS inhibitors represent a new class of antifungal drug candidates.

Humulene Diepoxides from the Australian Arid Zone Herb Dysphania: Assignment of Aged Hops Constituents.

Dysphania is an abundant genus of plants, many of which are endemic to the Australian continent, occurring primarily in arid and temperate zones. Despite their prevalence, very few investigations into the phytochemistry of native Dysphania have been undertaken. Described herein, is the isolation and elucidation of two enantiomeric diastereomers of humulene diepoxide C from D. kalpari and D. rhadinostachya, of which unassigned diastereomers of humulene diepoxide C have been previously reported as components in beer brewed from aged hops. In addition, two (+)-humulene diepoxiols (humulene diepoxiol C-I and C-II) were isolated from D. rhadinostachya. Analysis of Chinook hops oil confirmed the presence of both humulene diepoxide C-I and C-II as trace components, and in turn enabled GC-MS peak assignment to the relative stereochemistry. Anticancer assays did not reveal any significant activity for the (+)-humulene diepoxides. Antifungal assays showed good activity against a drug-resistant strain of C. auris, with MIC50 values of 8.53 and 4.91 µm obtained for (+)-humulene diepoxide C-I and C-II, respectively.

Kalparinol, a Salvialane (Isodaucane) Sesquiterpenoid Derived from Native Australian Dysphania Species That Suggests a Putative Biogenetic Link to Zerumbone.

Dysphania is a genus of plants endemic to the Australian continent, occurring primarily in arid and temperate zones. Despite their prevalence, very little in the way of phytochemical and/or bioactivity investigation of native Dysphania has been performed. Herein reported is the isolation and elucidation of (6E,9E)-zerumbone epoxide and a hitherto unreported isomer, (6Z,9E)-zerumbone epoxide, from D. kalpari. In addition, a novel isodaucane sesquiterepene, kalparinol, was isolated from both D. kalpari and D. rhadinostachya. The coisolation of the humulene and isodaucane skeletons, combined with the lack of any cadalane systems, could suggest an alternate novel biogenetic pathway originating from zerumbone, which is unlike any other proposals for the isodaucene system.

Testing a stepped care model for binge-eating disorder: a two-step randomized controlled trial.

BACKGROUND: A stepped care approach involves patients first receiving low-intensity treatment followed by higher intensity treatment. This two-step randomized controlled trial investigated the efficacy of a sequential stepped care approach for the psychological treatment of binge-eating disorder (BED). METHODS: In the first step, all participants with BED (n = 135) received unguided self-help (USH) based on a cognitive-behavioral therapy model. In the second step, participants who remained in the trial were randomized either to 16 weeks of group psychodynamic-interpersonal psychotherapy (GPIP) (n = 39) or to a no-treatment control condition (n = 46). Outcomes were assessed for USH in step 1, and then for step 2 up to 6-months post-treatment using multilevel regression slope discontinuity models. RESULTS: In the first step, USH resulted in large and statistically significant reductions in the frequency of binge eating. Statistically significant moderate to large reductions in eating disorder cognitions were also noted. In the second step, there was no difference in change in frequency of binge eating between GPIP and the control condition. Compared with controls, GPIP resulted in significant and large improvement in attachment avoidance and interpersonal problems. CONCLUSIONS: The findings indicated that a second step of a stepped care approach did not significantly reduce binge-eating symptoms beyond the effects of USH alone. The study provided some evidence for the second step potentially to reduce factors known to maintain binge eating in the long run, such as attachment avoidance and interpersonal problems.

Structure-activity relationships of bensulfuron methyl and its derivatives as novel agents against drug-resistant Candida auris.

With the emergence of the human pathogen Candida auris as a threat to human health, there is a strong demand to identify effective medicines to prevent the harm caused by such drug-tolerant human fungi. Herein, a series of 33 new derivatives of bensulfuron methyl (BSM) were synthesized and characterized by 1 H NMR, 13 C NMR, and HRMS. Among the target compounds, 8a possessed the best Ki value of 1.015 µM against C. auris acetohydroxyacid synthase (CauAHAS) and an MIC value of 6.25 µM against CBS10913, a clinically isolated strain of C. auris. Taken together the structures of BSM and the synthesized compounds, it was found that methoxy groups at both meta-position of pyrimidine ring are likely to provide desirable antifungal activities. Quantum calculations and molecular dockings were performed to understand the structure-activity relationships. The present study has hence provided some interesting clues for the discovery of novel antibiotics with this distinct mode of action.

Herbicides That Target Acetohydroxyacid Synthase Are Potent Inhibitors of the Growth of Drug-Resistant Candida auris.

Acetohydroxyacid synthase (AHAS, EC 2.2.1.6), the first enzyme in the branched chain amino acid biosynthesis pathway, is the target for more than 50 commercially available herbicides, and is a promising target for antimicrobial drug discovery. Herein, we have expressed and purified AHAS from Candida auris, a newly identified human invasive fungal pathogen. Thirteen AHAS inhibiting herbicides have Ki values of <2 µM for this enzyme, with the most potent having Ki values of <32 nM. Six of these compounds exhibited MIC50 values of <1 µM against C. auris (CBS10913 strain) grown in culture, with bensulfuron methyl (BSM) being fungicidal and the most potent (MIC50 of 0.090 µM) in defined minimal media. The MIC50 value increases to 0.90 µM in media enriched by the addition of branched-chain amino acids at the expected concentration in the blood serum. The sessile MIC50 for BSM is 0.6 µM. Thus, it is also an excellent inhibitor of the growth of C. auris biofilms. BSM is nontoxic in HEK-293 cells at concentrations >100 µM and thus possesses a therapeutic index of >100. These data suggest that targeting AHAS is a viable strategy for treating C. auris infections.

Cognitive behavioural therapy and applied relaxation for generalized anxiety disorder: a time series analysis of change in worry and somatic anxiety.

The present study examined symptom change profiles in patients with generalized anxiety disorder (GAD) receiving either cognitive behavioural therapy (CBT) or applied relaxation (AR). It was hypothesized that (a) changes in worry would uniquely predict changes in somatic anxiety for most participants receiving CBT and (b) changes in somatic anxiety would uniquely predict changes in worry for most participants in the AR condition. Twenty participants (CBT n = 10; AR n = 10) completed daily ratings of worry and somatic anxiety during therapy, and multivariate time series analysis was used to assess the causal impact of each variable on the other. The hypotheses were not supported because we found no evidence of a match between individual symptom change profiles and treatment condition. Rather, a bidirectional relationship between worry and somatic anxiety was observed in 80% of participants receiving CBT and 70% of participants receiving AR. When only treatment responders were considered, 83% of participants receiving CBT and 86% of those receiving AR had such a bidirectional effect. The findings are discussed in terms of models of psychopathology that posit dynamic interactions between symptom clusters and in terms of the value of examining treatment mechanisms at the individual level.

Can the components of a cognitive model predict the severity of generalized anxiety disorder?

Over the past decade, a number of well-controlled studies have supported the validity of a cognitive model of generalized anxiety disorder (GAD) that has four main components: intolerance of uncertainty, positive beliefs about worry, negative problem orientation, and cognitive avoidance. Although these studies have shown that the model components are associated with high levels of worry in nonclinical samples and with a diagnosis of GAD in clinical samples, they have not addressed the question of whether the model components can predict the severity of GAD. Accordingly, the present study sought to determine if the model components are related to diagnostic severity, worry severity, and somatic symptom severity in a sample of 84 patients with a primary diagnosis of GAD. All model components were related to GAD severity, although positive beliefs about worry and cognitive avoidance were only modestly associated with the severity of the disorder. Intolerance of uncertainty and negative problem orientation had more robust relationships with the severity of GAD (and with worry severity, in particular). When participants were divided into Mild, Moderate, and Severe GAD groups, intolerance of uncertainty and negative problem orientation distinguished the Moderate and Severe GAD groups from the Mild GAD group, even when age, gender, and depressive symptoms were statistically controlled. Overall, the results lend further support to the validity of the model and suggest that intolerance of uncertainty and negative problem orientation are related to the severity of GAD, independently of sociodemographic and associated clinical factors. The theoretical and clinical implications of the findings are discussed.

An exploration of Intolerance of Uncertainty and memory bias.

BACKGROUND AND OBJECTIVES: Research suggests that individuals high in Intolerance of Uncertainty (IU) have information processing biases, which may explain the close relationship between IU and worry. Specifically, high IU individuals show an attentional bias for uncertainty, and negatively interpret uncertain information. However, evidence of a memory bias for uncertainty among high IU individuals is limited. This study therefore explored the relationship between IU and memory for uncertainty. METHODS: In two separate studies, explicit and implicit memory for uncertain compared to other types of words was assessed. Cognitive avoidance and other factors that could influence information processing were also examined. RESULTS: IUS Factor 1 was a significant positive predictor of explicit memory for positive words, and IUS Factor 2 a significant negative predictor of implicit memory for positive words. Stimulus relevance and vocabulary were significant predictors of implicit memory for uncertain words. Cognitive avoidance was a significant predictor of both explicit and implicit memory for threat words. Female gender was a significant predictor of implicit memory for uncertain and neutral words. LIMITATIONS: Word stimuli such as those used in these studies may not be the optimal way of assessing information processing biases related to IU. In addition, the predominantly female, largely student sample may limit the generalizability of the findings. CONCLUSIONS: Future research focusing on IU factors, stimulus relevance, and both explicit and implicit memory, was recommended. The potential role of cognitive avoidance on memory, information processing, and worry was explored.

Changes in Defense Mechanism Functioning During Group Therapy for Binge-Eating Disorder.

OBJECTIVE: This study examined change in defensive mechanism functioning during group psychodynamic interpersonal psychotherapy (GPIP) for women with binge-eating disorder (BED). PROCEDURE: Women with BED (N = 85) received 16 weeks of GPIP. Five group therapy sessions (sessions 1, 3, 8, 12, and 16) from each of the 12 groups were video recorded and transcribed. Participants were rated on an observer-based measure of defensive functioning, the Defense Mechanism Rating Scale (DMRS). Symptom outcomes were assessed pre- and posttreatment. RESULTS: Overall defensive functioning (ODF) scores improved significantly during group treatment, with specific defense level improvements in high adaptive, major image distorting, and action defenses. The linear increase in ODF mediated a decrease in binge-eating episodes and depressive symptoms. Reverse mediation was also noted. A cubic growth curve best modeled ODF data such that ODF improved in the early stage, followed by a slower rate of improvement in the middle stage, and a further increase in rate of improvement at the end of treatment. DISCUSSION: Change in defense mechanism functioning may be an important aspect of group psychotherapy that is related to improved symptoms for women with BED who receive GPIP. The cubic trend that represented nonlinear growth in ODF is consistent with psychodynamic theory and a stage model of psychotherapy.

What clinicians want: findings from a psychotherapy practice research network survey.

Practice research networks may be one way of advancing knowledge translation and exchange (KTE) in psychotherapy. In this study, we document this process by first asking clinicians what they want from psychotherapy research. Eighty-two psychotherapists in 10 focus groups identified and discussed psychotherapy research topics relevant to their practices. An analysis of these discussions led to the development of 41 survey items. In an online survey, 1,019 participants, mostly practicing clinicians, rated the importance to their clinical work of these 41 psychotherapy research topics. Ratings were reduced using a principal components analysis in which 9 psychotherapy research themes emerged, accounting for 60.66% of the variance. Two postsurvey focus groups of clinicians (N = 22) aided in interpreting the findings. The ranking of research themes from most to least important were-Therapeutic Relationship/Mechanisms of Change, Therapist Factors, Training and Professional Development, Client Factors, Barriers and Stigma, Technology and Adjunctive Interventions, Progress Monitoring, Matching Clients to Therapist or Therapy, and Treatment Manuals. Few differences were noted in rankings based on participant age or primary therapeutic orientation. Postsurvey focus group participants were not surprised by the top-rated items, as they were considered most proximal and relevant to therapists and their work with clients during therapy sessions. Lower ranked items may be perceived as externally imposed agendas on the therapist and therapy. We discuss practice research networks as a means of creating new collaborations consistent with KTE goals. Findings of this study can help to direct practitioner-researcher collaborations.

Group psychotherapy levels of interventions: a clinical process commentary.

Trainees may experience greater effectiveness as therapists by conceptualizing group therapy interactions as occurring at different levels of functioning. We teach group therapy trainees to be aware of and flexibly direct their interventions to three levels of the group: (a) the intraindividual level, (b) the interpersonal level, and (3) the group-as-a-whole level. Within this conceptualization, we also encourage trainees to reinforce the group structure especially related to safety and secure base and to help group members to self-reflect about their interactions within the group. In this clinical process commentary, we describe a process of pregroup assessment and preparation that includes evaluating individual core relational patterns (CRPs) and how these patterns might express themselves in the three levels of group functioning. A running case presentation provides examples of a CRP formulation, levels of group functioning, and therapist interventions that are specific to each level. Making use of each group level within every session may allow the novice group therapist to sort the complex information they receive in a meaningful way. A therapist who can flexibly attend to and work within each group level will optimize the effectiveness of their interventions.

Validity and reliability of the behavior rating inventory of executive function - adult version in a clinical sample with eating disorders.

This study is a preliminary investigation of the reliability and validity of the Behavior Rating Inventory of Executive Function - Adult Version (BRIEF-A) in a clinical sample of patients with eating disorders (ED). Participants were 252 adult females who were referred to a centre for the treatment of EDs, as well as 31 individuals who completed the informant version of the BRIEF-A. Patients completed the BRIEF-A and other psychological measures on one occasion during their initial clinic visit, and informants nominated by patients completed the informant version at home. Reliability analyses revealed high internal consistency (Cronbach's alpha) of the two indices (Metacognition Index and Behavioral Regulation Index), and for the Global Executive Composite (GEC) of the BRIEF-A (α = .96). Convergent validity was shown by a high positive relationship between the self-report and informant-report versions of the BRIEF-A, and between the GEC and the Anxiety and Depression scales. Construct validity was assessed by an exploratory and confirmatory factor analysis. The BRIEF-A may be a reliable and valid tool for measuring executive functioning (EF) in an ED population, and may serve as an initial screening tool of EF for clinicians and researchers.