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Abstract Iron-sulfur (FeS) protein biogenesis in eukaryotes begins with the de novo assembly of [2Fe-2S] clusters by the mitochondrial core iron-sulfur cluster assembly (ISC) complex. This complex comprises the scaffold protein ISCU2, the cysteine desulfurase subcomplex NFS1-ISD11-ACP1, the allosteric activator frataxin (FXN) and the electron donor ferredoxin-2 (FDX2). The structural interaction of FDX2 with the complex remains unclear. Here, we present cryo-EM structures of the human FDX2-bound core ISC complex showing that FDX2 and FXN compete for overlapping binding sites. FDX2 binds in either a ‘distal’ conformation, where its helix F interacts electrostatically with an arginine patch of NFS1, or a ‘proximal’ conformation, where this interaction tightens and the FDX2-specific C terminus binds to NFS1, facilitating the movement of the [2Fe-2S] cluster of FDX2 closer to the ISCU2 FeS cluster assembly site for rapid electron transfer. Structure-based mutational studies verify the contact areas of FDX2 within the core ISC complex.

Abstract Acid sphingomyelinase (ASM) inhibitors are widely used for the treatment of post-stroke depression. They promote neurological recovery in animal stroke models via neurorestorative effects. In a previous study, we found that antidepressants including amitriptyline, fluoxetine, and desipramine increase cerebral angiogenesis post-ischemia/reperfusion (I/R) in an ASM-dependent way. To elucidate the underlying mechanisms, we investigated the effects of the functional ASM inhibitor amitriptyline in two models of I/R injury, that is, in human cerebral microvascular endothelial hCMEC/D3 cells exposed to oxygen-glucose deprivation and in mice exposed to middle cerebral artery occlusion (MCAO). In addition to our earlier studies, we now show that amitriptyline increased mitochondrial reactive oxygen species (ROS) formation in hCMEC/D3 cells and increased ROS formation in the vascular compartment of MCAO mice. ROS formation was instrumental for amitriptyline’s angiogenic effects. ROS formation did not result in excessive endothelial injury. Instead, amitriptyline induced a profound metabolic reprogramming of endothelial cells that comprised reduced endothelial proliferation, reduced mitochondrial energy metabolism, reduced endoplasmic reticulum stress, increased autophagy/mitophagy, stimulation of antioxidant responses and inhibition of apoptotic cell death. Specifically, the antioxidant heme oxygenase-1, which was upregulated by amitriptyline, mediated amitriptyline’s angiogenic effects. Thus, heme oxygenase-1 knockdown severely compromised angiogenesis and abolished amitriptyline’s angiogenic responses. Our data demonstrate that ASM inhibition reregulates a complex network of metabolic and mitochondrial responses post-I/R that contribute to cerebral angiogenesis without compromising endothelial survival.

BackgroundIncreasing pressure on limited intensive care capacities often requires a subjective assessment of a patient's discharge readiness in the absence of established Admission, Discharge, and Transfer (ADT) guidelines. To avoid suboptimal care transitions, it is important to define clear guidelines for the admission and discharge of intensive care patients and to optimize transfer processes between the intensive care unit (ICU) and lower care levels. To achieve these goals, structured insights into usual ICU discharge and transfer practices are essential. This study aimed to generate these insights by focusing on involved stakeholders, established processes, discharge criteria and tools, relevant performance metrics, and current barriers to a timely and safe discharge.MethodIn 2022, a structured, web-based, anonymous cross-sectional survey was conducted, aimed at practicing ICU physicians, nurses, and bed coordinators. The survey consisted of 29 questions (open, closed, multiple choice, and scales) that were divided into thematic blocks. The study was supported by several national and international societies for intensive care medicine and nursing.ResultsA total of 219 participants from 40 countries (105 from Germany) participated in the survey. An overload of acute care resources with ~90% capacity utilization in the ICU and the general ward (GW) leads to not only premature but also delayed patient transfers due to a lack of available ward and intermediate care (IMC) beds. After multidisciplinary rounds within the intensive care team, the ICU clinician on duty usually makes the final transfer decision, while one-third of the panel coordinates discharge decisions across departmental boundaries. By the end of the COVID-19 pandemic, half of the hospitals had implemented ADT policies. Among these hospitals, nearly one-third of the hospitals had specific transfer criteria established, consisting primarily of vital signs and laboratory data, patient status and autonomy, and organization-specific criteria. Liaison nurses were less common but were ranked right after the required IMC capacities to bridge the care gap between the ICU and normal wards. In this study, 80% of the participants suggested that transfer planning would be easier if there was good transparency regarding the capacity utilization of lower care levels, a standardized transfer process, and improved interdisciplinary communication.ConclusionTo improve care transitions, transfer processes should be managed proactively across departments, and efforts should be made to identify and address care gaps.

Abstract Background The intravenous delivery of adult neural precursor cells (NPC) has shown promising results in enabling cerebroprotection, brain tissue remodeling, and neurological recovery in young, healthy stroke mice. However, the translation of cell-based therapies to clinical settings has encountered challenges. It remained unclear if adult NPCs could induce brain tissue remodeling and recovery in mice with hyperlipidemia, a prevalent vascular risk factor in stroke patients. Methods Male mice on a normal (regular) diet or on cholesterol-rich Western diet were exposed to 30 min intraluminal middle cerebral artery occlusion (MCAO). Vehicle or 106 NPCs were intravenously administered immediately after reperfusion, at 3 day and 7 day post-MCAO. Neurological recovery was evaluated using the Clark score, Rotarod and tight rope tests over up to 56 days. Histochemistry and light sheet microscopy were used to examine ischemic injury and brain tissue remodeling. Immunological responses in peripheral blood and brain were analyzed through flow cytometry. Results NPC administration reduced infarct volume, blood–brain barrier permeability and the brain infiltration of neutrophils, monocytes, T cells and NK cells in the acute stroke phase in both normolipidemic and hyperlipidemic mice, but increased brain hemorrhage formation and neutrophil, monocyte and CD4+ and CD8+ T cell counts and activation in the blood of hyperlipidemic mice. While neurological deficits in hyperlipidemic mice were reduced by NPCs at 3 day post-MCAO, NPCs did not improve neurological deficits at later timepoints. Besides, NPCs did not influence microglia/macrophage abundance and activation (assessed by morphology analysis), astroglial scar formation, microvascular length or branching point density (evaluated using light sheet microscopy), long-term neuronal survival or brain atrophy in hyperlipidemic mice. Conclusions Intravenously administered NPCs did not have persistent effects on post-ischemic neurological recovery and brain remodeling in hyperlipidemic mice. These findings highlight the necessity of rigorous investigations in vascular risk factor models to fully assess the long-term restorative effects of cell-based therapies. Without comprehensive studies in such models, the clinical potential of cell-based therapies cannot be definitely determined.

Pundits and academics alike are increasingly concerned about the health of democracy worldwide. Much of this concern is tied to the rise of populism, a global phenomenon presenting challenges to both long-established and relatively young democracies. Political science has been at the forefront of this debate, and thanks to a growing—but not universal—consensus on the ideational definition of populism, our understanding of the subject has deepened considerably. This symposium maps key debates on the complex and often ambivalent relationship between populism and democracy. In this concluding piece, we build on the arguments presented throughout the symposium and related academic discussions to outline two paths for future research on the populism and democracy nexus: a top-down and a bottom-up perspective. [ABSTRACT FROM AUTHOR]

A cryo-electron microscopy reconstruction of a stressosome complex from a Gram-negative bacterium, Vibrio vulnificus, reveals variations in subunit composition and symmetry, which could serve to adjust the activation threshold in the response to low levels of oxygen and starvation.

Cryo-EM structures of the stress-sensing complex in Listeria innocua reveal conformational changes that initiate the signaling response to environmental stress.

The measurement of quality indicators supports quality improvement initiatives. The German Interdisciplinary Society of Intensive Care Medicine (DIVI) has published quality indicators for intensive care medicine for the fourth time now. After a scheduled evaluation after three years, changes in several indicators were made. Other indicators were not changed or only minimally. The focus remained strongly on relevant treatment processes like management of analgesia and sedation, mechanical ventilation and weaning, and infections in the ICU. Another focus was communication inside the ICU. The number of 1ndicators remained the same. The development method was more structured and transparency was increased by adding new features like evidence levels or author contribution and potential conflicts of interest. These quality indicators should be used in the peer review in intensive care, a method endorsed by the DIVI. Other forms of measurement and evaluation are also reasonable, for example in quality management. This fourth edition of the quality indicators will be updated in the future to reflect the recently published recommendations on the structure of intensive care units by the DIVI.

COVID-19 shocked the world and provided a particular challenge for populist radical right (PRR) forces. We lay out three research questions that this special issue addresses through case studies of the PRR in government in Brazil, Hungary, Turkey and the US and in opposition in France, Italy, Germany and Spain: (1) How have PRR actors responded to the pandemic? (2) How have PRR actors framed the politics of the pandemic? and (3) What have been the effects of the pandemic on the popularity of the PRR? We explain the case selection of this special issue and summarize the main findings of the eight case studies, which show that the pandemic did not severely damage the PRR and that they had very different responses to the challenge. This reinforces the idea that the PRR is not ephemeral but is rather the by-product of structural transformations of contemporary societies and is here for the foreseeable future. [ABSTRACT FROM AUTHOR]

Summary: Although mice mostly communicate in the ultrasonic range, they also emit audible calls. We demonstrate that mice selectively bred for high anxiety-related behavior (HAB) have a high disposition for emitting sonic calls when caught by the tail. The vocalization was unrelated to pain but sensitive to anxiolytics. As revealed by manganese-enhanced MRI, HAB mice displayed an increased tonic activity of the periaqueductal gray (PAG). Selective inhibition of the dorsolateral PAG not only reduced anxiety-like behavior but also completely abolished sonic vocalization. Calls were emitted at a fundamental frequency of 3.8 kHz, which falls into the hearing range of numerous predators. Indeed, playback of sonic vocalization attracted rats if associated with a stimulus mouse. If played back to HAB mice, sonic calls were repellent in the absence of a conspecific but attractive in their presence. Our data demonstrate that sonic vocalization attracts both predators and conspecifics depending on the context.

The rise of populism as a global phenomenon has captured the attention of scholars and raised concerns about its impact on democracy. Thanks to a growing academic consensus around an ideational definition of populism, one can observe the generation of important cumulative knowledge on the relationship between populism and democracy. Political science has been at the forefront of this development, and this symposium seeks to both offer state-of-the art information on this topic and discuss blind spots that future studies should try to address. [ABSTRACT FROM AUTHOR]

Interviews for faculty positions in psychology often include a teaching demonstration or research talk, but there is little empirical data about what makes these job talks successful. Psychology faculty (N = 303) described the job talks required at 4-year institutions and the attributes of a successful job talk. For both teaching demonstrations and research talks, being accurate and knowledgeable was of highest importance, but being practiced, open, and engaging were also important. However, significant differences between institutions showed that baccalaureate institutions emphasize teaching skills during job talks and doctoral institutions emphasize research skills. The results confirm that a polished job talk is crucial, but they also illustrate that successful job talks must fit the teaching and research mission of the institution.

Although the populist radical right (PRR) has become a global phenomenon, most studies of it focus on Europe. Moreover, extant research has centred on analysing those who support rather than reject the PRR. To address this twofold research gap, we rely on novel public opinion data to examine those who both 'love' and 'hate' the PRR in contemporary Chile. We demonstrate not only that those in favour of the Chilean PRR are a homogeneous constituency with similar characteristics to their European brethren (e.g., xenophobic attitudes) but also that those at odds with the Chilean PRR make up a relatively large and heterogeneous constituency. In summary, this contribution seeks to broaden comparative studies on the PRR and to show the relevance of studying support as well as rejection of the PRR, particularly in countries with runoff elections; since then, large segments of the electorate vote for the lesser evil. [ABSTRACT FROM AUTHOR]

This article offers an analysis of the evolution of the Chilean right from the transition to democracy to the present day. It aims to show that programmatic moderation has not only allowed the right to become more competitive in electoral terms, but has also orphaned a sector of the electorate and, therefore, made it highly probable that this political faction will split into two poles: one liberal-progressive and one populist-conservative. Methodology: The research involved a descriptive analysis of data from the World Values Survey, revealing the evolution of Chilean public opinion toward issues normally defended by the right, and of the “Manifesto Project,” in order to trace the variation over time of the positions defended by the Chilean right in their electoral campaigns. Conclusions: This article concludes that the great future challenge of the Chilean center-right will be how to handle internal tensions that, if not adequately channeled, can unleash a political fragmentation that gives rise to a period of greater electoral uncertainty. Originality: This article seeks to fill the gap that exists in the academic literature on the evolution of the post-transition Chilean right. At the same time, it posits that a space has opened for new types of government coalitions in Chile, either between radical populist forces and conventional parties or between conventional parties that historically have been reluctant to establish electoral alliances.