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\"She lived in a savage world in an uncivilized age - a world ruled by men and governed by the sword. The[y] called her... Red Sonja - for her flame red hair, and for the smoldering fire of her pride, which gave her sword-arm a strength that few men could match, and none had ever defeated. This collection contains a variety of issues from the original Marvel Comics series 'The Savage Sword of Conan,' as well as Sonja Tales from 'Kull and the Barbarians,' with each page re-mastered for this volume. Also included is a gallery of pin-ups by Frank Thorne, Howard Chaykin, and more. These tales are where it all began, and set the stage for the current Red Sonja series from Dynamite Entertainment\"--back cover.

Targeting subunits of BAF/PBAF chromatin remodeling complexes has been proposed as an approach to exploit cancer vulnerabilities. Here, we develop proteolysis targeting chimera (PROTAC) degraders of the BAF ATPase subunits SMARCA2 and SMARCA4 using a bromodomain ligand and recruitment of the E3 ubiquitin ligase VHL. High-resolution ternary complex crystal structures and biophysical investigation guided rational and efficient optimization toward ACBI1, a potent and cooperative degrader of SMARCA2, SMARCA4 and PBRM1. ACBI1 induced anti-proliferative effects and cell death caused by SMARCA2 depletion in SMARCA4 mutant cancer cells, and in acute myeloid leukemia cells dependent on SMARCA4 ATPase activity. These findings exemplify a successful biophysics- and structure-based PROTAC design approach to degrade high profile drug targets, and pave the way toward new therapeutics for the treatment of tumors sensitive to the loss of BAF complex ATPases. A structure-based design allows the development of a potent PROTAC to degrade BAF ATPase subunits SMARCA2 and SMARCA4 via recruitment of E3 ubiquitin ligase VHL and induce cancer cell death.

Targeted protein degradation offers an alternative modality to classical inhibition and holds the promise of addressing previously undruggable targets to provide novel therapeutic options for patients. Heterobifunctional molecules co-recruit a target protein and an E3 ligase, resulting in ubiquitylation and proteosome-dependent degradation of the target. In the clinic, the oral route of administration is the option of choice but has only been achieved so far by CRBN- recruiting bifunctional degrader molecules. We aimed to achieve orally bioavailable molecules that selectively degrade the BAF Chromatin Remodelling complex ATPase SMARCA2 over its closely related paralogue SMARCA4, to allow in vivo evaluation of the synthetic lethality concept of SMARCA2 dependency in SMARCA4-deficient cancers. Here we outline structure- and property-guided approaches that led to orally bioavailable VHL-recruiting degraders. Our tool compound, ACBI2, shows selective degradation of SMARCA2 over SMARCA4 in ex vivo human whole blood assays and in vivo efficacy in SMARCA4-deficient cancer models. This study demonstrates the feasibility for broadening the E3 ligase and physicochemical space that can be utilised for achieving oral efficacy with bifunctional molecules. Protein degraders are an emerging drug modality; however, their properties lie beyond typical drug-like space. Here the authors report optimisation via structure-based exit vector and linker design towards the VHL-recruiting PROTAC ACBI2, an orally bioavailable and selective degrader of SMARCA2.

PEAK pseudokinases regulate cell migration, invasion and proliferation by recruiting key signaling proteins to the cytoskeleton. Despite lacking catalytic activity, alteration in their expression level is associated with several aggressive cancers. Here, we elucidate the molecular details of key PEAK signaling interactions with the adapter proteins CrkII and Grb2 and the scaffold protein 14-3-3. Our findings rationalize why the dimerization of PEAK proteins has a crucial function in signal transduction and provide biophysical and structural data to unravel binding specificity within the PEAK interactome. We identify a conserved high affinity 14-3-3 motif on PEAK3 and demonstrate its role as a molecular switch to regulate CrkII binding and signaling via Grb2. Together, our studies provide a detailed structural snapshot of PEAK interaction networks and further elucidate how PEAK proteins, especially PEAK3, act as dynamic scaffolds that exploit adapter proteins to control signal transduction in cell growth/motility and cancer. The PEAK family of pseudokinases are key hubs in cellular signalling, including cell motility and cancer. Here, the authors characterise how PEAK proteins interact with the adapter proteins CrkII and Grb2 and regulatory scaffold protein 14-3-3, to achieve functional signalling assemblies.

Posttraumatic stress disorder (PTSD) is a significant public health issue. Yet, there are limited treatment options and no data to suggest which treatment will work for whom. We tested the efficacy of virtual reality exposure (VRE) or prolonged imaginal exposure (PE), augmented with D-cycloserine (DCS) for combat-related PTSD. As an exploratory aim, we examined whether brain-derived neurotrophic factor (BDNF) and fatty acid amide hydrolase (FAAH) moderated treatment response. Military personnel with PTSD ( n  = 192) were recruited into a multisite double-blind randomized controlled trial to receive nine weeks of VRE or PE, with DCS or placebo. Primary outcome was the improvement in symptom severity. Randomization was stratified by comorbid depression (MDD) and site. Participants in both VRE and PE showed similar meaningful clinical improvement with no difference between the treatment groups. A significant interaction ( p  = 0.45) suggested VRE was more effective for depressed participants (CAPS difference M = 3.51 [95% CI 1.17–5.86], p  = 0.004, ES = 0.14) while PE was more effective for nondepressed participants (M = −8.87 [95% CI −11.33 to −6.40], p  < 0.001, ES = −0.44). The main effect of DCS vs. placebo was not significant. Augmentation by MDD interaction ( p  = 0.073) suggested that depressed participants improved more on placebo (M = −8.43 [95% CI −10.98 to −5.88], p  < 0.001, ES = −0.42); DCS and placebo were equally effective for nondepressed participants. There was an apparent moderating effect of BDNF Val66Met polymorphism on DCS augmentation (ES = 0.67). Met66 allele carriers improved more on DCS (ES = −0.25). FAAH 385 A carriers improved more than non-carriers (ES = 0.33), particularly those with MDD (ES = 0.62). This study provides a step toward precision therapeutics for PTSD by demonstrating that comorbid MDD and genetic markers may help guide treatment selection. ClinicalTrials.gov Identifier: NCT01352637.

Targeted protein degradation using proteolysis-targeting chimeras (PROTACs) offers a promising strategy to eliminate previously undruggable proteins. PROTACs are bifunctional molecules that link a target protein with an E3 ubiquitin ligase, enabling the formation of a ternary complex that promotes ubiquitination and subsequent proteasomal degradation. Although many ternary complex structures are available, understanding how structural features relate to PROTAC function remains challenging due to the dynamic nature of these complexes. Here we show that the interface between the target protein SMARCA2 and the E3 ligase VHL is conformationally flexible and stabilized by interactions involving disordered loops. Using molecular dynamics simulations and X-ray crystallography of SMARCA2–VHL complexes bound to five different PROTACs, we find that interfacial residues often adopt energetically suboptimal, or ‘frustrated,’ configurations. We further show that the degree of frustration correlates with experimentally measured cooperativity for a set of 11 PROTACs. These findings suggest that quantifying interface frustration provides a rational, structure-based approach to guiding PROTAC design. PROTACs induce degradation by bridging a target protein and E3 ubiquitin ligase. Here, authors show that protein interface frustration correlates with cooperativity, offering a structural metric to prioritize PROTAC candidates prior to synthesis.

Subconcussive blast exposure has been shown to alter neurological functioning. However, the extent to which neurological dysfunction persists after blast exposure is unknown. This longitudinal study examined the potential short- and long-term effects of repeated subconcussive blast exposure on neuromotor performance from heavy weapons training in military personnel. A total of 214 participants were assessed; 137 were exposed to repeated subconcussive blasts and 77 were not exposed to blasts (controls). Participants completed a short stepping-in-place task while an Android smartphone app placed on their thigh recorded movement kinematics. We showed acute suppression of neuromotor variability 6 h after subconcussive blast exposure, followed by a rebound to levels not different from baseline at the 72 h, 2-week, and 3-month post-tests. It is postulated that this suppression of neuromotor variability results from a reduction in the functional degrees of freedom from the subconcussive neurological insult. It is important to note that this change in behavior is short-lived, with a return to pre-blast exposure movement kinematics within 72 h.

Background Research has been criticised for its extractive nature, often neglecting to reciprocate benefits to the communities involved. Addressing this, Patient and Public Involvement and Engagement (PPIE) has emerged as a crucial approach, engaging community members as research partners rather than subjects of research. However, it is important that PPIE is carried out in a meaningful way to avoid tokenism and extraction from communities. This paper reflects on the learning from the PPIE approach of the CommonHealth Assets (CHA) project, which partnered with 14 community-led organisations (CLOs) across the UK to evaluate their impact on health and wellbeing in their communities. Main body The CHA Lived Experience Panel (LEP), comprised of around 13 individuals from the project-partnered CLOs, played a pivotal role in informing and influencing the research process to enhance the relevance and impact of the CHA project. Following community engagement resources, we aimed to create a supportive and inclusive environment for meaningful PPIE. Through the evaluation of the CHA LEP, this paper reports on its successes and limitations to offer recommendations on creating the conditions for meaningful and effective PPIE in community-based public health research. From our evaluation, we found that adequately resourcing PPIE is crucial to its success. PPIE activities require a dedicated facilitator with expertise in working with diverse stakeholders to advocate for the sustained integration of PPIE into the research team, and to support contributors in their engagement. Being adaptive and responsive in your approach, utilising continuous evaluation and accountability in the process is also key. For contributors to have a meaningful impact, they must be engaged from the funding application stage and throughout the early stages of the project. Contributors must work closely with members of the research team at all levels, with researchers committing to facilitating authentic involvement of contributors, accessing training to work with diverse communication needs where required. Conclusion Our findings demonstrate that meaningful and effective PPIE requires a strong, sustained commitment to valuing and integrating patient/public perspectives in research. We add to the knowledge base in this area by offering a practical example of implementing PPIE in community-based research settings. Plain English summary This paper sets out ways to achieve meaningful Patient and Public Involvement and Engagement (PPIE) in community-based research. PPIE is a way for communities to influence the design, delivery and outputs of research. PPIE improves research by making sure it is relevant and impactful. It is a way to ensure that research takes account of community expertise. To work well, PPIE must be a genuine collaboration that values lived experience alongside academic knowledge. Based on learning from the CommonHealth Assets (CHA) project, we make recommendations about the conditions needed for meaningful and effective participation. Building trust and balancing power dynamics between the research team and the PPIE panel are key. We recommend a dedicated, skilled PPIE facilitator to support the panel. In our project there were limited opportunities for PPIE at the funding application stages, which meant limited impact on the study design. More time for the senior team and researchers to work with the LEP would have strengthened our approach.

Background Subconcussive blast exposure during military training has been the subject of both anecdotal concerns and reports in the medical literature, but prior studies have often been small and have used inconsistent methods. Methods This paper presents the methodology employed in INVestigating traIning assoCiated blasT pAthology (INVICTA) to assess a wide range of aspects of brain function, including immediate and delayed recall, gait and balance, audiologic and oculomotor function, cerebral blood flow, brain electrical activity and neuroimaging and blood biomarkers. Results A number of the methods employed in INVICTA are relatively easy to reproducibly utilize, and can be completed efficiently, while other measures require greater technical expertise, take longer to complete, or may have logistical challenges. Conclusions This presentation of methods used to assess the impact of blast exposure on the brain is intended to facilitate greater uniformity of data collection in this setting, which would enable comparison between different types of blast exposure and environmental circumstances, as well as to facilitate meta-analyses and syntheses across studies.

Traumatic brain injury (TBI) affects millions of Americans each year and has been shown to disproportionately impact those subject to greater disparities in health. Female sex is one factor that has been associated with disparities in health outcomes, including in TBI, but sex differences in biomarker levels and behavioral outcomes after TBI are underexplored. This study included participants with both blunt and blast TBI with majority rating their TBI as mild. Time since injury was 5.4 (2.0, 15.5) years for females and 6.8 (2.4, 11.3) years for males. The aim of this cross sectional study is to investigate the relationship between postconcussive, depression, and post-traumatic stress disorder (PTSD) symptoms, as well as health related quality of life (HRQOL), and the levels of glial fibrillary acidic protein (GFAP), total tau (t-tau), neurofilament light chain (NfL), and ubiquitin C-terminal hydrolase-L1 (UCH-L1). Behavioral outcomes were evaluated with the Neurobehavioral Symptom Inventory (NSI), Patient Health Questionnaire-9 (PHQ-9), PTSD Checklist- Civilian Version (PCL-C), short form (SF)-36, and plasma levels of total tau, GFAP, NfL, and UCHL-1 measured with the Simoa-HDX. We observed that females had significantly higher levels of GFAP and tau ( ps < 0.05), and higher PHQ-9 scores, NSI total scores, NSI- vestibular, NSI-somatosensory, NSI-affective sub-scale scores ( ps < 0.05)), than males. In addition, females had lower scores in HRQOL outcomes of role limitations due to emotional problems, vitality, emotional well-being, social functioning, and pain compared to males ( ps < 0.05). Correlation analysis showed positive associations between levels of tau and the NSI-total and NSI-cognitive sub-scale scores ( ps < 0.05) in females. No significant associations were found for NfL or GFAP with NSI scores. For female participants, negative correlations were observed between tau and NfL concentrations and the SF-36 physical function subscale ( ps < 0.05), as well as tau and the social function subscale ( p < 0.001), while GFAP levels positively correlated with role limitations due to emotional problems ( p = 0.004). No significant associations were observed in males. Our findings suggest that sex differences exist in TBI-related behavioral outcomes, as well as levels of biomarkers associated with brain injury, and that the relationship between biomarker levels and behavioral outcomes is more evident in females than males. Future studies are warranted to corroborate these results, and to determine the implications for prognosis and treatment. The identification of candidate TBI biomarkers may lead to development of individualized treatment guidelines.