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Recent research has identified the mechanistic Target of Rapamycin Complex 2 (mTORC2) as a conserved direct effector of Ras proteins. While previous studies suggested the involvement of the Switch I (SWI) effector domain of Ras in binding mTORC2 components, the regulation of the Ras-mTORC2 pathway is not entirely understood. In Dictyostelium, mTORC2 is selectively activated by the Ras protein RasC, and the RasC-mTORC2 pathway then mediates chemotaxis to cAMP and cellular aggregation by regulating the actin cytoskeleton and promoting cAMP signal relay. Here, we investigated the role of specific residues in RasC's SWI, C-terminal allosteric domain, and hypervariable region (HVR) related to mTORC2 activation. Interestingly, our results suggest that RasC SWI residue A31, which was previously implicated in RasC-mediated aggregation, regulates RasC's specific activation by the Aimless RasGEF. On the other hand, our investigation identified a crucial role for RasC SWI residue T36, with secondary contributions from E38 and allosteric domain residues. Finally, we found that conserved basic residues and the adjacent prenylation site in the HVR, which are crucial for RasC's membrane localization, are essential for RasC-mTORC2 pathway activation by allowing for both RasC's own cAMP-induced activation and its subsequent activation of mTORC2. Therefore, our findings revealed new determinants of RasC-mTORC2 pathway specificity in Dictyostelium, contributing to a deeper understanding of Ras signaling regulation in eukaryotic cells., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Prostate cancer is the most common non-cutaneous cancer among men in the UK, causing significant health and economic burdens. Diagnosis and risk prognostication can be challenging due to the genetic and clinical heterogeneity of prostate cancer as well as uncertainties in our knowledge of the underlying biology and natural history of disease development. Urinary extracellular vesicles (EVs) are microscopic, lipid bilayer defined particles released by cells that carry a variety of molecular cargoes including nucleic acids, proteins and other molecules. Urine is a plentiful source of prostate-derived EVs. In this narrative review, we summarise the evidence on the function of urinary EVs and their applications in the evolving field of prostate cancer diagnostics and active surveillance. EVs are implicated in the development of all hallmarks of prostate cancer, and this knowledge has been applied to the development of multiple diagnostic tests, which are largely based on RNA and miRNA. Common gene probes included in multi-probe tests include PCA3 and ERG , and the miRNAs miR-21 and miR-141. The next decade will likely bring further improvements in the diagnostic accuracy of biomarkers as well as insights into molecular biological mechanisms of action that can be translated into opportunities in precision uro-oncology.

Ras and Rap small GTPases of the Ras superfamily act as molecular switches to control diverse cellular processes as part of different signaling pathways. Dictyostelium expresses several Ras and Rap proteins, and their study has and continues to greatly contribute to our understanding of their role in eukaryote biology. To study the activity of Ras and Rap proteins in Dictyostelium, several assays based on their interaction with the Ras binding domain of known eukaryotic Ras/Rap effectors have been developed and proved extremely useful to study their regulation and cellular roles. Here, we describe methods to assess Ras/Rap activity biochemically using a pull-down assay and through live-cell imaging using fluorescent reporters., (© 2024. The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

There is increasing interest in how student engagement can be enhanced in medical schools: not just engagement with learning but with broader academic practices such as curriculum development, research, organisational leadership, and community involvement. To foster evidence-based practice, it is important to understand how institutions from diverse sociocultural contexts achieve excellence in student engagement.We analysed 11 successful applications for an international award in student engagement and interviewed nine key informants from five medical schools across four continents, characterising how and why student engagement was fostered at these institutions.Document analysis revealed considerable consensus on the core practices of student engagement, as well as innovative and creative practices often in response to local strengths and challenges. The interviews uncovered the importance of an authentic partnership culture between students and faculty which sustained mutually beneficial enhancements across multiple domains. Faculty promoted, welcomed, and acted on student inputs, and students reported greater willingness to participate if they could see the benefits. These combined to create self-perpetuating virtuous cycles of academic endeavour. Successful strategies included having participatory values actively reinforced by senior leadership, engagement activities that are driven by both students and staff, and focusing on strategies with reciprocal benefits for all stakeholders.

Background: Anxiety disorders are common and can be debilitating. In addition, various barriers exist that can hinder access to adequate care. Coaching that is grounded in evidence-based interventions and delivered via synchronous (ie, live) text-based messaging could potentially increase the reach of mental health services among populations who select this modality instead of other services (eg, face-to-face coaching and psychotherapy). In addition, the delivery of live messaging coaching within a blended care model has the potential to combine the benefits of coaching with those of evidence-based digital mental health tools., Objective: This real-world study evaluates the anxiety and satisfaction outcomes of live messaging coaching blended with digital tools (ie, digital exercises and activities)., Methods: This was a retrospective cohort study of 121 adults with moderate levels of anxiety symptoms at the beginning of coaching (Generalized Anxiety Disorder-7 [GAD-7] scores: range 8-14). Participants received an employer-offered blended messaging coaching (BMC) program, and those who opted to receive all live coaching sessions via text-based messaging were included. Anxiety symptom severity was regularly measured by using the GAD-7 scale. Using growth curve models, the change in GAD-7 scores over the course of BMC was evaluated, as were the effects of text-based coaching sessions on GAD-7 scores. The proportion of participants that had a reliable improvement in anxiety symptom severity (GAD-7 score reduction of ≥4) or subclinical symptom severity (GAD-7 score of <8) at the end of care was also estimated. Participants also self-reported their likelihood of recommending their live messaging coach to someone with similar needs., Results: At baseline, the average GAD-7 score was 9.88 (SD 1.80). Anxiety symptom severity significantly decreased with each week in the BMC program (week: b=-1.04; P<.001), and the rate of decline in anxiety symptom severity decreased over time (week 2 : b=0.06; P<.001). Each live messaging coaching session was associated with significantly lower anxiety symptom severity during the week of the coaching session (b=-1.56; P<.001) and the week immediately following the session (b=-1.03; P<.001). Overall, 86% (104/121) of participants had subclinical symptom severity or a reliable reduction in anxiety symptom severity by the end of care. Further, 33.1% (40/121) of participants reported coaching satisfaction levels; of the 40 participants in this subset, 37 (92.5%) were likely or extremely likely to recommend their live messaging coach., Conclusions: BMC that provides coaching sessions via live messaging can be beneficial for adults with moderate symptoms of anxiety who qualify for and self-select this care modality. Large-scale studies with longer follow-ups are needed., (©Jocelynn T Owusu, Pam Wang, Robert E Wickham, Sarah F Smith, Jennifer L Lee, Connie Chen, Anita Lungu. Originally published in JMIR Formative Research (https://formative.jmir.org), 01.02.2023.)

Background: Stockholm syndrome or traumatic bonding (Painter & Dutton, Patterns of emotional bonding in battered women: Traumatic bonding. International Journal of Women's Studies , 8 (4), 363-375, 1985) has been used in mainstream culture, legal, and some clinical settings to describe a hypothetical phenomenon of trauma survivors developing powerful emotional attachments to their abuser. It has frequently been used to explain the reported 'positive bond' between some kidnap victims and their captor's, although scarce empirical research has supported this assertion. It has been used in various situations where interpersonal violence and mind control are reported and where clear power differentials exist, such as in child sexual abuse, intimate partner violence, human trafficking, and hostage situation scenarios. Objective: We propose replacing Stockholm syndrome with 'appeasement,' a term that can be explained through a biopsychological model (i.e. Polyvagal Theory) to describe how survivors may appear emotionally connected with their perpetrators to effectively adapt to life-threatening situations by calming the perpetrator. Conclusion: We believe the term appeasement will demystify the reported survivor experiences and will, in the eyes of the public, victims, and survivors, provide a science-based explanation for their narratives of survival that may initially appear to be contradictory. By understanding the potent reflexive neurobiological survival mechanisms embedded in appeasement, individuals and families can operationalise their survival from a perspective that supports resilience, a healthy long-term recovery, and normalises their coping responses as survival techniques.

Background: Cognitive models propose that behavioural responses to voices maintain distress by preventing disconfirmation of negative beliefs about voices. We used Experience Sampling Methodology (ESM) to examine the hypothesized maintenance role of behavioural responses during daily life., Method: Thirty-one outpatients with frequent voices completed a smartphone-based ESM questionnaire 10 times a day over 9 days, assessing voice-related distress; resistance and compliance responses to voices; voice characteristics (intensity and negative content); appraisals of voice dominance, uncontrollability and intrusiveness., Results: In line with predictions, behavioural responses were associated with voice appraisals (dominance and uncontrollability), but not voice characteristics. Greater resistance and compliance were reported in moments of increased voice distress, but these associations did not persist after controlling for concurrent voice appraisals and characteristics. Voice distress was predicted by appraisals, and, unexpectedly, also by voice characteristics. As predicted, compliance and resistance were related to increases in distress at subsequent timepoints, whilst antecedent voice appraisals and characteristics had no such effect. Compliance, but not resistance, additionally predicted subsequent increases in voice uncontrollability. In both cases, the reverse models showed no association, indicating directional effects of responses on subsequent distress, and of compliance on uncontrollability appraisals., Conclusions: These results provide support for the cognitive model by suggesting that momentary behavioural and emotional responses to voices are associated with concurrent negative voice appraisals. Findings suggest that behavioural responses may be driven by voice appraisals, rather than directly by distress, and may in turn maintain voice appraisals and associated distress during the course of daily life.

The required adjustments precipitated by the coronavirus disease 2019 crisis have been challenging, but also represent a critical opportunity for the evolution and potential disruptive and constructive change of medical education. Given that the format of medical education is not fixed, but malleable and in fact must be adaptable to societal needs through ongoing reflexivity, we find ourselves in a potentially transformative learning phase for the field. An Association for Medical Education in Europe ASPIRE Academy group of 18 medical educators from seven countries was formed to consider this opportunity, and identified critical questions for collective reflection on current medical education practices and assumptions, with the attendant challenge to envision the future of medical education. This was achieved through online discussion as well as asynchronous collective reflections by group members. Four major themes and related conclusions arose from this conversation: Why we teach: the humanitarian mission of medicine should be reinforced; what we teach: disaster management, social accountability and embracing an environment of complexity and uncertainty should be the core; how we teach: open pathways to lean medical education and learning by developing learners embedded in a community context; and whom we teach: those willing to take professional responsibility. These collective reflections provide neither fully matured digests of the challenges of our field, nor comprehensive solutions; rather they are offered as a starting point for medical schools to consider as we seek to harness the learning opportunities stimulated by the pandemic.