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After recognizing its ligand lipopolysaccharide, Toll-like receptor 4 (TLR4) recruits adaptor proteins to the cell membrane, thereby initiating downstream signaling and triggering inflammation. Whether this recruitment of adaptor proteins is dependent solely on protein-protein interactions is unknown. Here, we report that the sphingolipid sphinganine physically interacts with the adaptor proteins MyD88 and TIRAP and promotes MyD88 recruitment in macrophages. Myeloid cell-specific deficiency in serine palmitoyltransferase long chain base subunit 2 , which encodes the key enzyme catalyzing sphingolipid biosynthesis, decreases the membrane recruitment of MyD88 and inhibits inflammatory responses in in vitro bone marrow-derived macrophage and in vivo sepsis models. In a melanoma mouse model, s erine palmitoyltransferase long chain base subunit 2 deficiency decreases anti-tumor myeloid cell responses and increases tumor growth. Therefore, sphinganine biosynthesis is required for the initiation of TLR4 signal transduction and serves as a checkpoint for macrophage pattern recognition in sepsis and melanoma mouse models. The interaction of Toll-like receptor 4 (TLR4) results in recruitment of proteinacious adapter molecules to the cell membrane. Here Hering and colleagues show that sphinganine recruits adaptor protein MyD88 to TLR4 in the macrophage membrane and the absence of sphinganine in murine models disrupts TLR4 driven inflammation.

Patient-derived organoids resemble the biology of tissues and tumors, enabling ex vivo modeling of human diseases. They have heterogeneous morphologies with unclear biological causes and relationship to treatment response. Here, we use high-throughput, image-based profiling to quantify phenotypes of over 5 million individual colorectal cancer organoids after treatment with >500 small molecules. Integration of data using multi-omics modeling identifies axes of morphological variation across organoids: Organoid size is linked to IGF1 receptor signaling, and cystic vs. solid organoid architecture is associated with LGR5 + stemness. Treatment-induced organoid morphology reflects organoid viability, drug mechanism of action, and is biologically interpretable. Inhibition of MEK leads to cystic reorganization of organoids and increases expression of LGR5 , while inhibition of mTOR induces IGF1 receptor signaling. In conclusion, we identify shared axes of variation for colorectal cancer organoid morphology, their underlying biological mechanisms, and pharmacological interventions with the ability to move organoids along them. The heterogeneity underlying cancer organoid phenotypes is not yet well understood. Here, the authors develop an imaging analysis assay for high throughput phenotypic screening of colorectal organoids that allows to define specific morphological changes that occur following different drug treatments.

Background Essential phospholipids (EPL) have hepatoprotective effects across many liver diseases/conditions. The impact of EPL on hepatocyte function in vitro was investigated. Methods Effects of noncytotoxic concentrations of EPL (0.1 and 0.25 mg/ml), and its constituents, polyenylphosphatidylcholine (PPC) and phosphatidylinositol (PI) (both at 0.1 and 1 mg/ml), on membrane fluidity, apoptosis and extracellular transport versus controls were investigated in human hepatocyte cell lines (HepG2, HepaRG, steatotic HepaRG).  Results Significantly increased membrane fluidity occurred with all 3 phospholipids (PLs) in HepG2 cultures, and with PI (1 mg/ml) in steatotic HepaRG cells. Significantly decreased tamoxifen-induced apoptosis was observed in HepG2 cells with EPL, PPC and PI. Breast cancer resistance protein (BCRP) activity was significantly increased by EPL and PI in HepG2 cells. Multidrug resistance-associated protein 2 (MRP-2) activity was unaffected by any PL in HepG2 cells, and significantly increased by EPL, PI and PPC (1 mg/ml) in HepaRG cells, and by PI (1 mg/ml) in steatotic HepaRG cells. Bile salt export protein (BSEP) activity in HepG2 cells and steatotic HepaRG cells was significantly increased by EPL (0.25 mg/ml), and PPC (both concentrations), but not by PI. The PLs had no effects on HepaRG cell BSEP activity. P-glycoprotein (P-GP) activity was significantly increased by all compounds in HepG2 cells. PI (1 mg/ml) significantly increased P-GP activity in HepaRG and steatotic HepaRG cells. Conclusions EPL, PPC, and PI increased hepatocyte membrane fluidity, decreased apoptosis and increased hepatocellular export, all of which may improve liver function. These in-vitro investigations provide valuable insights into the mechanism of action of EPL.

Abstract “Pig butchering” represents a sophisticated form of cyber-enabled social engineering that combines elements of romance and investment scams. Although existing literature focuses on victims’ experiences, there is a lack of understanding regarding how scammers are trained to implement these strategies. To this end, we analysed a unique data source, scam manuals (i.e. documents guiding scam operations), to uncover the psychological and communication theories that inform their use. Our findings reveal that scammers systematically exploit interpersonal communication, relationship, and motivational tactics to gain victims’ trust and commitment, and to manipulate their self-growth needs. We propose a unified stage model that maps and links psychological and communication theories across the scam stages. We discuss how our model contributes to the broader cybersecurity literature by informing the design of more targeted prevention and intervention strategies that address the human vulnerabilities exploited in advanced cyber-enabled crime.

Tissue macrophages are crucial for organ development and homeostasis, yet the developmental routes leading to tissue macrophages remain controversial. By combining unbiased Polylox barcoding with computational inference, we comprehensively mapped tissue macrophage ontogeny in mice from gastrulation to adult organs. Our data reveal a lineage tree of all tissue macrophages. This tree originates from a pan-hematopoietic progenitor at embryonic day (E)6.5 and branches, via oligolineage progenitors (E7.5-E9.5), into organ-specific macrophage lineages by E10.5. Barcode analysis in embryonic tissues and adult organ fragments suggests that local macrophage colonies, formed by organ-specific progenitors, persist into adulthood. Indeed, spatial fate mapping with Polytope barcoding detects local Kupffer cell colonies of the size predicted by the lineage tree model. Our findings uncover the origin of tissue-resident macrophages from a lineage tree, and show how holistic barcoding can comprehensively map complex cellular lineage specification.Competing Interest StatementThe authors have declared no competing interest.

Tracing the fate of individual cells and their progeny remains a challenging task. While imaging-based fate-mapping provides spatial information, it generally lacks complexity due to limited label diversity, resulting in diminished capture of comprehensive lineages and fate maps. Here, we introduce ′Polytope′, an epitope barcoding system capable of generating up to 512 unique color codes. Comprising nine epitope tag cassettes flanked by loxP sites, Polytope allows random excision via Cre recombinase, creating unique color codes detectable through multiplexed imaging. Using an engineered Polytope mouse, we traced the fate of hundreds of clones across tissues in vivo, from embryonic development until adulthood. Together, Polytope enables high-resolution imaging-based fate-mapping through endogenous epitope barcoding, comprehensively capturing the spatial organization of complex clonal dynamics in situ.Competing Interest StatementThe authors have declared no competing interest.

Patient derived organoids resemble the biology of tissues and tumors, enabling ex vivo modeling of human diseases from primary patient samples. Organoids can be used as models for drug discovery and are being explored to guide clinical decision making. Patient derived organoids can have heterogeneous morphologies with unclear biological causes and relationship to treatment response. Here, we used high-throughput, image-based profiling to quantify phenotypes of over 5 million individual colorectal cancer organoids after treatment with more than 500 small molecules. Integration of data using a joint multi-omics modelling framework identified organoid size and cystic vs. solid organoid architecture as axes of morphological variation across organoids. Mechanistically, we found that organoid size was linked to IGF1 receptor signaling, while a cystic organoid architecture was associated with an LGR5+ stemness program. Treatment-induced organoid morphology reflected organoid viability, drug mechanism of action, and was biologically interpretable using joint modelling. Inhibition of MEK led to cystic reorganization of organoids and increased expression of LGR5, while inhibition of mTOR induced IGF1 receptor signaling. In conclusion, we identified shared axes of variation for colorectal cancer organoid morphology, their underlying biological mechanisms, and pharmacological interventions with the ability to move organoids along them. Image-based profiling of patient derived organoids coupled with multi-omics integration facilitates drug discovery by linking drug responses with underlying biological mechanisms. Competing Interest Statement The authors declare no competing interests. M.B. and M.E. received a research grant within the Merck Heidelberg Innovation Program, which did not support this study. Footnotes * Updated several figures and new analysis was added to the new version of the manuscript. Supplemental files were updated.

The newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a pandemic respiratory disease. Moreover, thromboembolic events throughout the body, including in the CNS, have been described. Given the neurological symptoms observed in a large majority of individuals with COVID-19, SARS-CoV-2 penetrance of the CNS is likely. By various means, we demonstrate the presence of SARS-CoV-2 RNA and protein in anatomically distinct regions of the nasopharynx and brain. Furthermore, we describe the morphological changes associated with infection such as thromboembolic ischemic infarction of the CNS and present evidence of SARS-CoV-2 neurotropism. SARS-CoV-2 can enter the nervous system by crossing the neural–mucosal interface in olfactory mucosa, exploiting the close vicinity of olfactory mucosal, endothelial and nervous tissue, including delicate olfactory and sensory nerve endings. Subsequently, SARS-CoV-2 appears to follow neuroanatomical structures, penetrating defined neuroanatomical areas including the primary respiratory and cardiovascular control center in the medulla oblongata. The authors demonstrate the presence of SARS-CoV-2 in the nasopharynx and brain, suggesting that the virus is present in the CNS and may enter through the olfactory mucosa, exploiting the close vicinity of olfactory mucosal, endothelial and nervous tissue.

A crisis can be described as subjective experience that threatens and overwhelms a person's ability to handle a specific situation. In dealing with crises some people are looking for support from professionals. The \"professional relationship\" between people experiencing a crisis and professionals plays an important role in the successful management of a crisis which has been widely researched in many contexts. However, regarding outpatient services (e. g. crisis resolution home treatment teams), yet empirical evidence remains limited. We aim to explore descriptions of supportive professional relationships during outpatient crisis interventions in empirical literature. Accordingly, a scoping review was conducted to identify types of evidence, map the key concepts, and point out research gaps. MEDLINE, PsycINFO, CINAHL and Social Science Citation Index were searched for studies reporting empirical data on the professional relationship between people experiencing a crisis (18+) and professionals (e. g. social workers, psychiatrists) during a crisis intervention, defined as a short-term, face-to-face, low threshold, time-limited, outpatient, and voluntary intervention to cope with crises. Studies were excluded if they were published before 2007, in languages other than English and German, and if they couldn't be accessed. Included studies were summarized, compared, and synthesized using qualitative content analyses. 3.741 records were identified, of which 8 met the eligibility criteria. Only one study directly focused on the relationship; the others addressed varied aspects. Two studies explored the perspectives of service users, five focused on those of the professionals and one study examined both. The empirical literature was categorized into three main themes: strategies used to develop a supportive professional relationship, factors influencing the relationship and the nature of these relationships. The results reveal a gap in understanding the nature of supportive professional relationships from the service users' perspective, as well as how professionals construct these relationships.