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Background Immunotherapy has revolutionized clinical outcomes for patients suffering from lung cancer, yet relatively few patients sustain long-term durable responses. Recent studies have demonstrated that the tumor immune microenvironment fosters tumorous heterogeneity and mediates both disease progression and response to immune checkpoint inhibitors (ICI). As such, there is an unmet need to elucidate the spatially defined single-cell landscape of the lung cancer microenvironment to understand the mechanisms of disease progression and identify biomarkers of response to ICI.Methods Here, in this study, we applied imaging mass cytometry to characterize the tumor and immunological landscape of immunotherapy response in non-small cell lung cancer by describing activated cell states, cellular interactions and neighborhoods associated with improved efficacy. We functionally validated our findings using preclinical mouse models of cancer treated with anti-programmed cell death protein-1 (PD-1) immune checkpoint blockade.Results We resolved 114,524 single cells in 27 patients treated with ICI, enabling spatial resolution of immune lineages and activation states with distinct clinical outcomes. We demonstrated that CXCL13 expression is associated with ICI efficacy in patients, and that recombinant CXCL13 potentiates anti-PD-1 response in vivo in association with increased antigen experienced T cell subsets and reduced CCR2+ monocytes.Discussion Our results provide a high-resolution molecular resource and illustrate the importance of major immune lineages as well as their functional substates in understanding the role of the tumor immune microenvironment in response to ICIs.

The hypothesis of chaotic population dynamics was proposed in ecology by Robert May in the mid-1970s. At that time the idea was controversial, and it remains a fascinating and unsettled issue today. We report the results of a 20-year laboratory research programme that continued in the tradition of the pioneering ecologist Thomas Park using the Tribolium flour beetle model. We present biological evidence of complex population dynamics – including bifurcations, chaos, saddle nodes, phase switching, resonance effects, and multiple attractors – by using a low-dimensional difference equation model for Tribolium together with carefully designed, conducted, and statistically analysed experiments. The model, parameterized with data, also explains the results of historical Tribolium experiments, such as the classical competition studies of Thomas Park and his colleagues. Our research programme has inspired other studies using the Tribolium mathematical and laboratory model. This work was conducted by a multidisciplinary team, which included Jim Cushing. [ABSTRACT FROM AUTHOR]

Abstract Using multistable mechanical metamaterials to develop deployable structures, electrical devices, and mechanical memories raises two unanswered questions. First, can mechanical instability be programmed to design sensors and memory devices? Second, how can mechanical properties be tuned at the post‐fabrication stage via external stimuli? Answering these questions requires a thorough understanding of the snapping sequences and variations of the elastic energy in multistable metamaterials. The mechanics of deformation sequences and continuous force/energy–displacement curves are comprehensively unveiled here. A 1D array, that is chain, of bistable cells is studied to explore instability‐induced energy release and snapping sequences under one external mechanical stimulus. This method offers an insight into the programmability of multistable chains, which is exploited to fabricate a mechanical sensor/memory with sampling (analog to digital‐A/D) and data reconstruction (digital to analog‐D/A) functionalities operating based on the correlation between the deformation sequence and the mechanical input. The findings offer a new paradigm for developing programmable high‐capacity read–write mechanical memories regardless of thei size scale. Furthermore, exotic mechanical properties can be tuned by harnessing the attained programmability of multistable chains. In this respect, a transversely multistable mechanical metamaterial with tensegrity‐like bistable cells is designed to showcase the tunability of chirality.

Available literature demonstrates that methadone is prone to moderate postmortem redistribution, but subject to high interindividual variability in the central to peripheral blood concentration ratios (C/P). In this case series, 10 cases of chronic methadone users displaying C/P < 1 (range 0.26–0.82) are described. Femoral, cardiac and ante-mortem blood concentrations of methadone and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) are reported for all cases, as well as sex, age, case history, results of the pathological investigation, other toxicological findings and cause and manner of death. EDDP blood concentrations, similar in both central and peripheral blood, as well as antemortem blood concentration results in Case 4, demonstrate that this atypical C/P < 1 finding is attributable to postmortem changes and not analytical or pre-analytical artifacts. Case 4 is a particularly instructive example, with femoral blood concentration (966 ng/mL) approximately twice as high as cardiac blood (499 ng/mL) and ante-mortem blood (418 ng/mL, collected 38 min prior to death)—clearly demonstrating that cardiac blood methadone concentration is more representative of the antemortem blood concentration in this case. In Case 4 and four others, toxicological interpretation based on femoral blood concentration alone would have been misleading. Based on these results and evidence from the literature, it is hypothesized that methadone bioaccumulates in the tissues of chronic users and redistributes from thigh tissues into femoral blood, increasing the concentration postmortem. This case series highlights how femoral blood is not always preserved from postmortem changes and that the analysis of multiple blood sources is necessary to avoid a misleading toxicological interpretation—particularly for cases of chronic methadone users. [ABSTRACT FROM AUTHOR]

Bile acids, which are synthesized from cholesterol by the liver, are chemically transformed along the intestinal tract by the gut microbiota, and the products of these transformations signal through host receptors, affecting overall host health. These transformations include bile acid deconjugation, oxidation, and 7α-dehydroxylation. An understanding of the biogeography of bile acid transformations in the gut is critical because deconjugation is a prerequisite for 7α-dehydroxylation and because most gut microorganisms harbor bile acid transformation capacity. Here, we used a coupled metabolomic and metaproteomic approach to probe in vivo activity of the gut microbial community in a gnotobiotic mouse model. Results revealed the involvement of Clostridium scindens in 7α-dehydroxylation, of the genera Muribaculum and Bacteroides in deconjugation, and of six additional organisms in oxidation (the genera Clostridium, Muribaculum, Bacteroides, Bifidobacterium, Acutalibacter, and Akkermansia). Furthermore, the bile acid profile in mice with a more complex microbiota, a dysbiosed microbiota, or no microbiota was considered. For instance, conventional mice harbor a large diversity of bile acids, but treatment with an antibiotic such as clindamycin results in the complete inhibition of 7α-dehydroxylation, underscoring the strong inhibition of organisms that are capable of carrying out this process by this compound. Finally, a comparison of the hepatic bile acid pool size as a function of microbiota revealed that a reduced microbiota affects host signaling but not necessarily bile acid synthesis. In this study, bile acid transformations were mapped to the associated active microorganisms, offering a systematic characterization of the relationship between microbiota and bile acid composition.