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Most metastatic cancers remain incurable due to the emergence of apoptosis-resistant clones, fuelled by intratumour heterogeneity and tumour evolution. To improve treatment, therapies should not only kill cancer cells but also activate the immune system against the tumour to eliminate any residual cancer cells that survive treatment. While current cancer therapies rely heavily on apoptosis — a largely immunologically silent form of cell death — there is growing interest in harnessing immunogenic forms of cell death such as necroptosis. Unlike apoptosis, necroptosis generates second messengers that act on immune cells in the tumour microenvironment, alerting them of danger. This lytic form of cell death optimizes the provision of antigens and adjuvanticity for immune cells, potentially boosting anticancer treatment approaches by combining cellular suicide and immune response approaches. In this Review, we discuss the mechanisms of necroptosis and how it activates antigen-presenting cells, drives cross-priming of CD8 + T cells and induces antitumour immune responses. We also examine the opportunities and potential drawbacks of such strategies for exposing cancer cells to immunological attacks. In this Review, Meier et al. discuss the molecular mechanisms of necroptosis, delineate how this form of immunogenic cell death activates antitumour immune responses and explore the opportunities and limitations of targeting necroptosis for anticancer therapy.

[...]open-access publishing has been linked to higher citation rates, often receiving more media coverage and more downloads, all contributing to increased visibility and a wider reach and impact of the research.1 Open science can enhance the quality of research through rigorous prepublication and postpublication peer review and open discussion.2 The COVID-19 pandemic has underscored the benefits of these open science principles: accelerating research efforts, avoiding ‘research waste’ and improveing transparency and credibility.3 This study of Cobey et al reports on a survey exploring open science practices among international cardiology researchers sheds light on crucial insights.4 While there is a general awareness of open science, there exists a notable gap especially in training and implementation. Defining and reducing barriers for open science, including improved training, is essential as also stated by the recent UNESCO recommendations and should be a collaborative approach involving funders, research institutions and journals to create a supportive environment.5 Open Heart is committed to playing a role in this endeavour by fostering a culture of openness and collaboration within the cardiology community. At Open Heart, we strongly encourage that data underlying a research paper be made publicly available, and all research articles must contain a ‘data availability statement’.

Open data encourages public scrutiny and further data analysis and is a catalyst for innovation and scientific advancement. The COVID-19 pandemic has once more highlighted the importance of a robust peer-review system to avoid delays in publication of potentially life-saving new research findings, while at the same time guaranteeing validity. [...]this is how I personally ended up in my role as editor of this journal: I started doing peer reviews for the BMJ, actively engaged with its editorial team, became associate editor for Heart, also for the BMJ, and ended up helping to start this journal, Open Heart, as funding editor-in-chief.

Intracellular potassium (K + ) homeostasis is fundamental to cell viability. In addition to channels, K + levels are maintained by various ion transporters. One major family is the proton-driven K + efflux transporters, which in gram-negative bacteria is important for detoxification and in plants is critical for efficient photosynthesis and growth. Despite their importance, the structure and molecular basis for K + -selectivity is poorly understood. Here, we report ~3.1 Å resolution cryo-EM structures of the Escherichia coli glutathione (GSH)-gated K + efflux transporter KefC in complex with AMP, AMP/GSH and an ion-binding variant. KefC forms a homodimer similar to the inward-facing conformation of Na + /H + antiporter NapA. By structural assignment of a coordinated K + ion, MD simulations, and SSM-based electrophysiology, we demonstrate how ion-binding in KefC is adapted for binding a dehydrated K + ion. KefC harbors C-terminal regulator of K + conductance (RCK) domains, as present in some bacterial K + -ion channels. The domain-swapped helices in the RCK domains bind AMP and GSH and they inhibit transport by directly interacting with the ion-transporter module. Taken together, we propose that KefC is activated by detachment of the RCK domains and that ion selectivity exploits the biophysical properties likewise adapted by K + -ion-channels. Intracellular potassium (K+) homeostasis is achieved by activity of both ion channels and transporters. Here, the authors report structures of E. coli glutathione (GSH)-gated K+ efflux transporter KefC with bound K+ and conclude that the ion-binding site is adapted for binding a dehydrated ion.

The NLRP3 inflammasome responds to infection and tissue damage, and rapidly escalates the intensity of inflammation by activating interleukin (IL)-1β, IL-18 and cell death by pyroptosis. How the NLRP3 inflammasome is negatively regulated is poorly understood. Here we show that NLRP3 inflammasome activation is suppressed by sumoylation. NLRP3 is sumoylated by the SUMO E3-ligase MAPL, and stimulation-dependent NLRP3 desumoylation by the SUMO-specific proteases SENP6 and SENP7 promotes NLRP3 activation. Defective NLRP3 sumoylation, either by NLRP3 mutation of SUMO acceptor lysines or depletion of MAPL, results in enhanced caspase-1 activation and IL-1β release. Conversely, depletion of SENP7 suppresses NLRP3-dependent ASC oligomerisation, caspase-1 activation and IL-1β release. These data indicate that sumoylation of NLRP3 restrains inflammasome activation, and identify SUMO proteases as potential drug targets for the treatment of inflammatory diseases. The NLRP3 inflammasome is an important component of inflammatory responses, but how it is negatively regulated is still unclear. Here the authors show that post-translational modification of NLRP3 by sumoylation suppresses inflammasome activity, and that desumoylation of NLRP3 by the SENP6 and SENP7 proteases promotes NLRP3 activation.

Cell competition is an emerging principle that eliminates suboptimal or potentially dangerous cells. For ‘unfit’ cells to be detected, their competitive status needs to be compared to the collective fitness of cells within a tissue. Here we report that the NMDA receptor controls cell competition of epithelial cells and Myc supercompetitors in the Drosophila wing disc. While clonal depletion of the NMDA receptor subunit NR2 results in their rapid elimination via the TNF/Eiger>JNK signalling pathway, local over-expression of NR2 causes NR2 cells to acquire supercompetitor-like behaviour that enables them to overtake the tissue through clonal expansion that causes, but also relies on, the killing of surrounding cells. Consistently, NR2 is utilised by Myc clones to provide them with supercompetitor status. Mechanistically, we find that the JNK>PDK signalling axis in ‘loser’ cells reprograms their metabolism, driving them to produce and transfer lactate to winners. Preventing lactate transfer from losers to winners abrogates NMDAR-mediated cell competition. Our findings demonstrate a functional repurposing of NMDAR in the surveillance of tissue fitness. Cell competition among epithelial cells allows removal of unfit or dangerous cells. Here, the authors show that the NMDA receptor is an important determinant of cell fitness in the Drosophila wing, also in the context of Myc super-competitor cells, with “loser” cells contributing metabolitic fuel to “winner” cells.

The strict exchange of Na + for H + ions across cell membranes is a reaction carried out in almost every cell. Na + /H + exchangers that perform this task are physiological homodimers, and whilst the ion transporting domain is highly conserved, their dimerization differs. The Na + /H + exchanger NhaA from Escherichia coli has a weak dimerization interface mediated by a β-hairpin domain and with dimer retention dependent on cardiolipin. Similarly, organellar Na + /H + exchangers NHE6, NHE7 and NHE9 also contain β-hairpin domains and recent analysis of Equus caballus NHE9 indicated PIP 2 lipids could bind at the dimer interface. However, structural validation of the predicted lipid-mediated oligomerization has been lacking. Here, we report cryo-EM structures of E. coli NhaA and E. caballus NHE9 in complex with cardiolipin and phosphatidylinositol-3,5-bisphosphate PI(3,5)P 2 lipids binding at their respective dimer interfaces. We further show how the endosomal specific PI(3,5)P 2 lipid stabilizes the NHE9 homodimer and enhances transport activity. Indeed, we show that NHE9 is active in endosomes, but not at the plasma membrane where the PI(3,5)P 2 lipid is absent. Thus, specific lipids can regulate Na + /H + exchange activity by stabilizing dimerization in response to either cell specific cues or upon trafficking to their correct membrane location. Na+ /H+ exchangers regulate intracellular pH, sodium levels, and cell volume. Cryo-EM structures reveal lipid coordination at the dimer interfaces of NhaA with cardiolipin and endosomal NHE9 with PI(3,5)P2. These findings demonstrate how specific lipids can regulate ion-exchange activity by stabilizing dimerization with physiological ramifications.

The strict exchange of protons for sodium ions across cell membranes by Na +/ H + exchangers is a fundamental mechanism for cell homeostasis. At active pH, Na + /H + exchange can be modelled as competition between H + and Na + to an ion-binding site, harbouring either one or two aspartic-acid residues. Nevertheless, extensive analysis on the model Na + /H + antiporter NhaA from Escherichia coli , has shown that residues on the cytoplasmic surface, termed the pH sensor, shifts the pH at which NhaA becomes active. It was unclear how to incorporate the pH senor model into an alternating-access mechanism based on the NhaA structure at inactive pH 4. Here, we report the crystal structure of NhaA at active pH 6.5, and to an improved resolution of 2.2 Å. We show that at pH 6.5, residues in the pH sensor rearrange to form new salt-bridge interactions involving key histidine residues that widen the inward-facing cavity. What we now refer to as a pH gate, triggers a conformational change that enables water and Na + to access the ion-binding site, as supported by molecular dynamics (MD) simulations. Our work highlights a unique, channel-like switch prior to substrate translocation in a secondary-active transporter. By determining the crystal structure of the Na + /H + antiporter NhaA at active pH, the authors show how substrate accessibility to the ion-binding site can be controlled by pH sensitive switch located on the cytoplasmic surface.

The strict exchange of Na for H ions across cell membranes is a reaction carried out in almost every cell. Na /H exchangers that perform this task are physiological homodimers, and whilst the ion transporting domain is highly conserved, their dimerization differs. The Na /H exchanger NhaA from Escherichia coli has a weak dimerization interface mediated by a β-hairpin domain and with dimer retention dependent on cardiolipin. Similarly, organellar Na /H exchangers NHE6, NHE7 and NHE9 also contain β-hairpin domains and recent analysis of Equus caballus NHE9 indicated PIP lipids could bind at the dimer interface. However, structural validation of the predicted lipid-mediated oligomerization has been lacking. Here, we report cryo-EM structures of E. coli NhaA and E. caballus NHE9 in complex with cardiolipin and phosphatidylinositol-3,5-bisphosphate PI(3,5)P lipids binding at their respective dimer interfaces. We further show how the endosomal specific PI(3,5)P lipid stabilizes the NHE9 homodimer and enhances transport activity. Indeed, we show that NHE9 is active in endosomes, but not at the plasma membrane where the PI(3,5)P lipid is absent. Thus, specific lipids can regulate Na /H exchange activity by stabilizing dimerization in response to either cell specific cues or upon trafficking to their correct membrane location.

Background and Objectives: Ventral stabilization of thoracolumbar spine fractures can be achieved using different interbody reconstruction techniques, including titanium cages, vertebral body replacements (VBR), and autologous pelvic bone grafts (APBG). Although all approaches aim to restore anterior column stability and alignment, comparative data on long-term patient-reported outcomes remain limited. The objective of this study was to compare long-term patient-reported wellbeing following ventral stabilization using these three techniques. Materials and Methods: A retrospective, non-randomized single-center cohort study with prospective follow-up was analyzed. Treatment allocation was indication-based. Ninety-one patients treated between 2008 and 2018 underwent ventral stabilization using cage implantation (n = 12), vertebral body replacement (n = 45), or autologous pelvic bone grafting (n = 34). Clinical outcome was assessed at least 12 months postoperatively using a modified Visual Analog Scale Spine Score (VAS-Spine). Statistical analysis included linear and ordinal regression adjusted for age and sex. Potential baseline differences between groups were considered in the interpretation of the results. Results: Sixty-three patients (mean age 52 ± 15 years; 41% female) completed follow-up. The mean VAS-Spine score was lowest after cage implantation (2.7 ± 3.6), followed by VBR (3.9 ± 2.8) and APBG (4.9 ± 1.8; p* = 0.021). The observed difference between cage and APBG approached the minimal clinically important difference reported for VAS-based measures. Patients treated with cage implantation reported less pain during rest and activity and fewer limitations in daily life. No significant differences were observed regarding age or sex. Conclusions: In this observational cohort, cage implantation was associated with more favorable patient-reported outcomes compared with VBR and APBG. Autologous pelvic bone grafting was associated with worse patient-reported outcomes, potentially related to donor-site morbidity. Given the non-randomized design and potential confounding, these findings should be interpreted as associative and hypothesis-generating.