Ligand dependent switch from RXR homo- to RXR-NURR1 heterodimerization

Retinoid X receptors (RXRs) play key roles in many physiological processes in both the periphery and central nervous system. In addition, RXRs form heterodimers with other nuclear receptors to exert their physiological effects. The nuclear receptor related 1 protein (NURR1) is particularly interesting because of its role in promoting differentiation and survival of dopamine neurons. However, only a small number of RXR-heterodimer selective modulators are available, with limited chemical diversity. This work describes the synthesis, biochemical evaluation, and structural elucidation of a novel series of RXR ligands with strongly biased interactions with RXRα-NURR1 heterodimers. Targeted modifications to the small molecule biaryl scaffold caused local RXRα side-chain disturbances and displacement of secondary structural elements upon ligand binding. This resulted in the repositioning of protein helices in the heterodimer interface of RXRα, alterations in homo- versus heterodimer formation, and modulation of activation function 2 (AF2). The data provide a rationale for the design of RXR ligands consisting of a highly conserved hydrophilic region, strongly contributing to the ligand affinity, and a variable hydrophobic region, which efficiently probes the effects of structural changes at the level of the ligand on co-regulator recruitment or the RXRα-NURR1 dimerization interface.</p

Towards Arctic Research Upholding Indigenous Peoples’ Rights : Recommendations for ICARP IV, the International Conference on Arctic Research Planning

A decolonial approach is needed to fulfil IASC’s (International Conference on Arctic Research Planning) commitment to recognizing that Traditional Knowledge, Indigenous Knowledge and academic scientific knowledge are co-equal and complementary knowledge systems that all can and should inform its work (website ICARP IV, 2023). This document summarizes key recommendations for actions regarding five themes: 1. Indigenous Peoples’ right to self-determination as a prerequisite for high-quality Arctic research 2. Ethics, methods and methodology as key for decolonial research 3. Indigenous-led research in design and practice 4. Indigenous Peoples’ co-equal participation in Arctic research funding structures and decision-making for securing decolonial Arctic research in practice 5. Funding for Co-Creative and Indigenous-Led Arctic ResearchA decolonial approach is needed to fulfil IASC’s (International Conference on Arctic Research Planning) commitment to recognizing that Traditional Knowledge, Indigenous Knowledge and academic scientific knowledge are co-equal and complementary knowledge systems that all can and should inform its work (website ICARP IV, 2023). This document summarizes key recommendations for actions regarding five themes: 1. Indigenous Peoples’ right to self-determination as a prerequisite for high-quality Arctic research 2. Ethics, methods and methodology as key for decolonial research 3. Indigenous-led research in design and practice 4. Indigenous Peoples’ co-equal participation in Arctic research funding structures and decision-making for securing decolonial Arctic research in practice 5. Funding for Co-Creative and Indigenous-Led Arctic Researc

Improving the relationships between Indigenous rights holders and researchers in the Arctic: an invitation for change in funding and collaboration

Truly transdisciplinary approaches are needed to tackle the complex problems that the Arctic is facing at the moment. Collaboration between Indigenous rights holders and researchers through co-creative research approaches can result in high-quality research outcomes, but crucially also address colonial legacies and power imbalances, enhance mutual trust, and respect the rights of Indigenous Peoples. However, to be successful, collaborative research projects have specific requirements regarding research designs, timeframes, and dissemination of results, which often do not fit into the frameworks of academic calendars and funding guidelines. Funding agencies in particular play an important role in enabling (or disabling) meaningful collaboration between Indigenous rights holders and researchers. There is an urgent need to re-think existing funding-structures. This article will propose a new paradigm for the financing of Arctic research, which centres around the inclusion of Indigenous partners, researchers, and institutions from the initial planning stages of funding programmes to the final stages of research projects. These findings and recommendations have been contextualized based on critical reflections of the co-authors, a group of Indigenous and non-Indigenous partners, who have practiced their own collaborative work process, the challenges encountered, and lessons learned

MYD88 mutations identify a molecular subgroup of diffuse large B-cell lymphoma with an unfavorable prognosis

The 2016 World Health Organization classification defines diffuse large B-cell lymphoma (DLBCL) subtypes based on Epstein-Barr virus (EBV) infection and oncogenic rearrangements of MYC/BCL2/BCL6 as drivers of lymphomagenesis. A subset of DLBCL, however, is characterized by activating mutations in MYD88/CD79B. We investigated whether MYD88/CD79B mutations could improve the classification and prognostication of DLBCL. In 250 primary DLBCL, MYD88/CD79B mutations were identified by allele-specific polymerase chain reaction or next-generationsequencing, MYC/BCL2/BCL6 rearrangements were analyzed by fluorescence in situ hybridization, and EBV was studied by EBV-encoded RNA in situ hybridization. Associations of molecular features with clinicopathologic characteristics, outcome, and prognosis according to the International Prognostic Index (IPI) were investigated. MYD88 and CD79B mutations were identified in 29.6% and 12.3%, MYC, BCL2, and BCL6 rearrangements in 10.6%, 13.6%, and 20.3%, and EBV in 11.7% of DLBCL, respectively. Prominent mutual exclusivity between EBV positivity, rearrangements, and MYD88/CD79B mutations established the value of molecular markers for the recognition of biologically distinct DLBCL subtypes. MYD88-mutated DLBCL had a significantly inferior 5-year overall survival than wild-type MYD88 DLBCL (log-rank; P=0.019). DLBCL without any of the studied aberrations had superior overall survival compared to cases carrying .1 aberrancy (log-rank; P=0.010). MYD88 mutations retained their adverse prognostic impact upon adjustment for other genetic and clinical variables by multivariable analysis and improved the prognostic performance of the IPI. This study demonstrates the clinical utility of defining MYD88-mutated DLBCL as a distinct molecular subtype with adverse prognosis. Our data call for sequence analysis of MYD88 in routine diagnostics of DLBCL to optimize classification and prognostication, and to guide the development of improved treatment strategies

Predictive value of neurological examination for early cortical responses to somatosensory evoked potentials in patients with postanoxic coma

Bilateral absence of cortical N20 responses of median nerve somatosensory evoked potentials (SEP) predicts poor neurological outcome in postanoxic coma after cardiopulmonary resuscitation (CPR). Although SEP is easy to perform and available in most hospitals, it is worthwhile to know how neurological signs are associated with SEP results. The aim of this study was to investigate whether specific clinical neurological signs are associated with either an absent or a present median nerve SEP in patients after CPR. Data from the previously published multicenter prospective cohort study PROPAC (prognosis in postanoxic coma, 2000–2003) were used. Neurological examination, consisting of Glasgow Coma Score (GCS) and brain stem reflexes, and SEP were performed 24, 48, and 72 h after CPR. Positive predictive values for predicting absent and present SEP, as well as diagnostic accuracy were calculated. Data of 407 patients were included. Of the 781 SEPs performed, N20 s were present in 401, bilaterally absent in 299, and 81 SEPs were technically undeterminable. The highest positive predictive values (0.63–0.91) for an absent SEP were found for absent pupillary light responses. The highest positive predictive values (0.71–0.83) for a present SEP were found for motor scores of withdrawal to painful stimuli or better. Multivariate analyses showed a fair diagnostic accuracy (0.78) for neurological examination in predicting an absent or present SEP at 48 or 72 h after CPR. This study shows that neurological examination cannot reliably predict absent or present cortical N20 responses in median nerve SEPs in patients after CPR

Shaping Arctic’s Tomorrow through Indigenous Knowledge Engagement and Knowledge Co-Production

This perspective presents a statement of the 10th International Congress of Arctic Social Sciences Indigenous Knowledge and knowledge co-production panel and discussion group, 20 July 2021. The statement is designed to serve as a characterization of the state-of-the-art and guidance for further advancement of Indigenous Knowledge and knowledge co-production in the Arctic. It identifies existing challenges and provides specific recommendations for researchers, Indigenous communities, and funding agencies on meaningful recognition and engagement of Indigenous Knowledge systems