Computational Biology Dynamics of Mps1 Kinase Molecular Interactions with Isoflavones Reveals a Chemical Scaffold with Potential to Develop New Therapeutics for the Treatment of Cancer.

The protein kinase Mps1 (monopolar spindle 1) is an important regulator of the Spindle Assembly Checkpoint (SAC), the evolutionary conserved checkpoint system of higher organisms that monitors the proper bipolar attachment of all chromosomes to the mitotic spindle during cell division. Defects in the catalytic activity and the transcription regulation of Mps1 are associated with genome instability, aneuploidy, and cancer. Moreover, multiple Mps1 missense and frameshift mutations have been reported in a wide range of types of cancer of different tissue origin. Due to these features, Mps1 arises as one promising drug target for cancer therapy. In this contribution, we developed a computational biology approach to study the dynamics of human Mps1 kinase interaction with isoflavones, a class of natural flavonoids, and compared their predicted mode of binding with that observed in the crystal structure of Mps1 in complex with reversine, a small-sized inhibitor of Mps1 and Aurora B kinases. We concluded that isoflavones define a chemical scaffold that can be used to develop new Mps1 inhibitors for the treatment of cancer associated with Mps1 amplification and aberrant chromosome segregation. In a broader context, the present report illustrates how modern chemoinformatics approaches can accelerate drug development in oncology.

Examining the Factor Structure and Psychometric Properties of a Guilt Management Scale (GMS).

BACKGROUND: Guilt is commonly associated with distress and psychopathology. However, there is a lack of validated measures that assess how people cope with this aversive emotional and cognitive experience. AIMS: We therefore developed and validated a self-report measure that assesses how people manage their guilt: the Guilt Management Scale (GMS). METHOD: The GMS was administered to a non-clinical (n = 339) and clinical (n = 67) sample, alongside other validated measures of guilt severity, coping, thought control and psychological distress. Results from a principal component analysis (PCA) and assessments of test-retest reliability and internal consistency are presented. RESULTS: The PCA yielded a six subscale solution (Self-Punishment, Reparation, People-Focused, Spirituality, Avoidance and Metacognition), accounting for 56.14% of variance. Test-retest reliability and internal consistency was found to be good-excellent for the majority of subscales. Across samples, Self-Punishment was related to higher levels of guilt and distress whilst Metacognition and Reparation were related to less guilt and distress in the non-clinical sample only. CONCLUSIONS: This paper provides preliminary evidence for the psychometric properties of the GMS in a non-clinical sample. With development and validation in clinical samples, the GMS could be used to inform psychological formulations of guilt and assess therapy outcomes.

The role of guilt in the development of post-traumatic stress disorder: A systematic review.

BACKGROUND: Post-traumatic stress disorder (PTSD) can be a debilitating condition associated with a myriad of emotions. Guilt is an important associated feature of PTSD that has received far less recognition than other symptoms often associated with fear and intense threat. The nature of the relationship between guilt and PTSD remains elusive and requires further clarification. The aim of the current paper was to review the extant literature regarding the link between guilt and PTSD. METHOD: A systematic database search of PsycINFO, Medline, Embase and Web of Science identified articles that enabled examination of the guilt-PTSD relationship. A total of 27 articles met inclusion criteria for this review. RESULTS: There were cross-sectional relationships between guilt and PTSD symptomology with evidence of associations between PTSD symptoms and cognitions related to perceived wrong doing and self-blame. However, the direction of association between guilt and PTSD is unclear and possibly confounded by overlapping constructs such as shame. LIMITATIONS: The review is constrained by the absence of longitudinal and experimental research and studies, which control for potential confounding variables. The reliability and validity of measures of guilt and PTSD is also not consistently reported. CONCLUSION: This review outlines four competing models of the guilt-PTSD relationship and examines existing evidence linking the two constructs. The current literature is too preliminary to offer any strong support for one model over the other. However, in critically appraising existing studies, this review helps to inform the design of future studies investigating the association between guilt and PTSD.