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More than 100 missense mutations in presenilin 1 and 2 are associated with early‐onset dominant Alzheimer disease. These proteins span the membrane several times and are ostensibly the catalytic component of the γ‐secretase complex, which is responsible for producing the amyloid β‐peptide (Aβ) that deposits in the Alzheimer brain. A common outcome of Alzheimer‐associated presenilin mutations is an increase in the ratio of the more aggregation‐prone 42‐residue form of Aβ to the 40‐residue variant, which is often referred to as a presenilin ‘gain of function’. An apparent paradox is that most of these mutant presenilins have reduced proteolytic efficiency, which forms part of the counter argument that presenilin ‘loss of function’ can cause the neuronal dysfunction and death that lead to the disease. In this review, a unifying hypothesis is presented that puts forward a biochemical mechanism by which slower less‐efficient forms of the protease can result in a greater proportion of 42‐residue Aβ.

Clinical analysis of blood is the most widespread diagnostic procedure in medicine, and blood biomarkers are used to categorize patients and to support treatment decisions. However, existing biomarkers are far from comprehensive and often lack specificity and new ones are being developed at a very slow rate. As described in this review, mass spectrometry (MS)‐based proteomics has become a powerful technology in biological research and it is now poised to allow the characterization of the plasma proteome in great depth. Previous “triangular strategies” aimed at discovering single biomarker candidates in small cohorts, followed by classical immunoassays in much larger validation cohorts. We propose a “rectangular” plasma proteome profiling strategy, in which the proteome patterns of large cohorts are correlated with their phenotypes in health and disease. Translating such concepts into clinical practice will require restructuring several aspects of diagnostic decision‐making, and we discuss some first steps in this direction. Graphical Abstract The performance of mass spectrometry (MS)‐based proteomics has reached a sensitivity and dynamic range that makes it suitable for biomarker studies. This Review discusses plasma proteome profiling strategies and how they can be translated into clinical practice.

Sepsis has been identified by the World Health Organization (WHO) as a global health priority. There has been a tremendous effort to decipher underlying mechanisms responsible for organ failure and death, and to develop new treatments. Despite saving thousands of animals over the last three decades in multiple preclinical studies, no new effective drug has emerged that has clearly improved patient outcomes. In the present review, we analyze the reasons for this failure, focusing on the inclusion of inappropriate patients and the use of irrelevant animal models. We advocate against repeating the same mistakes and propose changes to the research paradigm. We discuss the long‐term consequences of surviving sepsis and, finally, list some putative approaches—both old and new—that could help save lives and improve survivorship. Graphical Abstract This review recapitulates our knowledge on sepsis and its long‐term consequences, the lack of therapeutic advances in the last decades, and proposes new approaches to improve sepsis survival.

Cytosolic double‐stranded DNA (dsDNA) is a danger signal that is tightly monitored and sensed by nucleic acid‐sensing pattern recognition receptors. We study the inflammatory cascade on dsDNA recognition and investigate the neuroprotective effect of cyclic GMP‐AMP (cGAMP) synthase (cGAS) antagonist A151 and its mechanisms of neuroprotection in a mouse model of experimental stroke. Here, we found that cerebral ischemia promoted the release of dsDNA into the cytosol, where it initiated inflammatory responses by activating the cGAS. A151 effectively reduced the expression of cGAS, absent in melanoma 2 (AIM2) inflammasome, and pyroptosis‐related molecules, including caspase‐1, gasdermin D, IL‐1β, and IL‐18. Furthermore, mice treated with A151 showed a dampened immune response to stroke, with reduced counts of neutrophils, microglia, and microglial production of IL‐6 and TNF‐α after MCAO. Moreover, A151 administration significantly reduced infarct volume, attenuated neurodeficits, and diminished cell death. Notably, the protective effect of A151 was blocked in a microglia‐specific cGAS knockout mouse. These findings offer unique perspectives on stroke pathogenesis and indicate that inhibition of cGAS could attenuate brain inflammatory burden, representing a potential therapeutic opportunity for stroke. Synopsis Inflammation is involved in the progression of ischemic brain injury. This study focuses on the inflammatory cascade on double‐strand DNA (dsDNA) recognition and highlights the possibility of inhibiting dsDNA‐sensing cyclic GMP‐AMP synthase (cGAS) for treatment of ischemic stroke. The release of dsDNA from necrotic tissue during brain infarction triggers an innate inflammatory cascade. A synthetic oligonucleotide A151 that antagonizes cGAS regulates the microglial immune response and pyroptosis after ischemic stroke. Inhibition of cGAS leads to a decline in neutrophil infiltration into the brain. Suppression of the dsDNA‐sensing cGAS pathway reduces ischemic brain injury via mitigating neuroinflammation. Graphical Abstract Inflammation is involved in the progression of ischemic brain injury. This study focuses on the inflammatory cascade on double‐strand DNA (dsDNA) recognition and highlights the possibility of inhibiting dsDNA‐sensing cyclic GMP‐AMP synthase (cGAS) for treatment of ischemic stroke.

A better understanding of the molecular mechanisms underlying disease is key for expediting the development of novel therapeutic interventions. Disease mechanisms are often mediated by interactions between proteins. Insights into the physical rewiring of protein–protein interactions in response to mutations, pathological conditions, or pathogen infection can advance our understanding of disease etiology, progression, and pathogenesis and can lead to the identification of potential druggable targets. Advances in quantitative mass spectrometry (MS)‐based approaches have allowed unbiased mapping of these disease‐mediated changes in protein–protein interactions on a global scale. Here, we review MS techniques that have been instrumental for the identification of protein–protein interactions at a system‐level, and we discuss the challenges associated with these methodologies as well as novel MS advancements that aim to address these challenges. An overview of examples from diverse disease contexts illustrates the potential of MS‐based protein–protein interaction mapping approaches for revealing disease mechanisms, pinpointing new therapeutic targets, and eventually moving toward personalized applications. Graphical Abstract This Review discusses mass spectrometry techniques that have been instrumental for identifying protein‐protein interactions. Examples from diverse disease contexts illustrate the potential of these approaches for revealing disease mechanisms and therapeutic targets.

Sarcomas are heterogeneous and clinically challenging soft tissue and bone cancers. Although constituting only 1% of all human malignancies, sarcomas represent the second most common type of solid tumors in children and adolescents and comprise an important group of secondary malignancies. More than 100 histological subtypes have been characterized to date, and many more are being discovered due to molecular profiling. Owing to their mostly aggressive biological behavior, relative rarity, and occurrence at virtually every anatomical site, many sarcoma subtypes are in particular difficult‐to‐treat categories. Current multimodal treatment concepts combine surgery, polychemotherapy (with/without local hyperthermia), irradiation, immunotherapy, and/or targeted therapeutics. Recent scientific advancements have enabled a more precise molecular characterization of sarcoma subtypes and revealed novel therapeutic targets and prognostic/predictive biomarkers. This review aims at providing a comprehensive overview of the latest advances in the molecular biology of sarcomas and their effects on clinical oncology; it is meant for a broad readership ranging from novices to experts in the field of sarcoma. Graphical Abstract Sarcomas are heterogeneous and clinically challenging soft tissue and bone cancers. The current article comprehensively reviews recent advances in the molecular characterization of sarcoma subtypes, and describes novel therapeutic targets and biomarkers in this field.

Propagation of tau pathology is linked with progressive neurodegeneration, but the mechanism underlying trans‐synaptic spread of tau is unknown. We show that stimulation of neuronal activity, or AMPA receptor activation, induces tau release from healthy, mature cortical neurons. Notably, phosphorylation of extracellular tau appears reduced in comparison with intracellular tau. We also find that AMPA‐induced release of tau is calcium‐dependent. Blocking pre‐synaptic vesicle release by tetanus toxin and inhibiting neuronal activity with tetrodotoxin both significantly impair AMPA‐mediated tau release. Tau secretion is therefore a regulatable process, dysregulation of which could lead to the spread of tau pathology in disease. This report provides evidence that stimulation of neuronal activity, or AMPA receptor activation, induces tau release from cortical neurons via a calcium‐dependent mechanism. Dysregulation of this process could lead to the spread of tau pathology in disease.

Non‐alcoholic fatty liver disease (NAFLD) affects 25% of the population and can progress to cirrhosis with limited treatment options. As the liver secretes most of the blood plasma proteins, liver disease may affect the plasma proteome. Plasma proteome profiling of 48 patients with and without cirrhosis or NAFLD revealed six statistically significantly changing proteins (ALDOB, APOM, LGALS3BP, PIGR, VTN, and AFM), two of which are already linked to liver disease. Polymeric immunoglobulin receptor (PIGR) was significantly elevated in both cohorts by 170% in NAFLD and 298% in cirrhosis and was further validated in mouse models. Furthermore, a global correlation map of clinical and proteomic data strongly associated DPP4, ANPEP, TGFBI, PIGR, and APOE with NAFLD and cirrhosis. The prominent diabetic drug target DPP4 is an aminopeptidase like ANPEP, ENPEP, and LAP3, all of which are up‐regulated in the human or mouse data. Furthermore, ANPEP and TGFBI have potential roles in extracellular matrix remodeling in fibrosis. Thus, plasma proteome profiling can identify potential biomarkers and drug targets in liver disease. Synopsis Applying Plasma Proteome Profiling to liver disease in different human cohorts associated PIGR and ALDOB and other proteins to non‐alcoholic fatty liver disease. Potential biomarkers were validated in a mouse model. Plasma proteome profiling augmented by Boxcar acquisition identified potential biomarkers of human liver diseases. PIGR and ALDOB are associated with NAFLD, among other novel proteins. DPP4, ANPEP, PIGR, APOE, and TGFBI highly correlate with AST, ALT, GGT and ALP. A mouse NAFLD model recapitulated many of the changes seen in humans. Graphical Abstract Applying Plasma Proteome Profiling to liver disease in different human cohorts associated PIGR and ALDOB and other proteins to non‐alcoholic fatty liver disease. Potential biomarkers were validated in a mouse model.

In this study, we develop a simple assay to identify mitophagy inducers on the basis of the use of fluorescently tagged mitochondria that undergo a colour change on lysosomal delivery. Using this assay, we identify iron chelators as a family of compounds that generate a strong mitophagy response. Iron chelation-induced mitophagy requires that cells undergo glycolysis, but does not require PINK1 stabilization or Parkin activation, and occurs in primary human fibroblasts as well as those isolated from a Parkinson's patient with Parkin mutations. Thus, we have identified and characterized a mitophagy pathway, the induction of which could prove beneficial as a potential therapy for several neurodegenerative diseases in which mitochondrial clearance is advantageous.

Lgr5 marks adult stem cells in multiple adult organs and is a receptor for the Wnt‐agonistic R‐spondins (RSPOs). Intestinal, stomach and liver Lgr5 + stem cells grow in 3D cultures to form ever‐expanding organoids, which resemble the tissues of origin. Wnt signalling is inactive and Lgr5 is not expressed under physiological conditions in the adult pancreas. However, we now report that the Wnt pathway is robustly activated upon injury by partial duct ligation (PDL), concomitant with the appearance of Lgr5 expression in regenerating pancreatic ducts. In vitro , duct fragments from mouse pancreas initiate Lgr5 expression in RSPO1‐based cultures, and develop into budding cyst‐like structures (organoids) that expand five‐fold weekly for >40 weeks. Single isolated duct cells can also be cultured into pancreatic organoids, containing Lgr5 stem/progenitor cells that can be clonally expanded. Clonal pancreas organoids can be induced to differentiate into duct as well as endocrine cells upon transplantation, thus proving their bi‐potentiality. The establishment of conditions for long‐term culture and expansion of adult, bi‐potent pancreas progenitors may facilitate novel and tailored therapeutic approaches.