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Background The identification and assessment of sentinel lymph nodes (SLNs) in breast cancer is important for optimised patient management. The aim of this study was to develop an interactive 3D breast SLN atlas and to perform statistical analyses of lymphatic drainage patterns and tumour prevalence. Methods A total of 861 early-stage breast cancer patients who underwent preoperative lymphoscintigraphy and SPECT/CT were included. Lymphatic drainage and tumour prevalence statistics were computed using Bayesian inference, non-parametric bootstrapping, and regression techniques. Image registration of SPECT/CT to a reference patient CT was carried out on 350 patients, and SLN positions transformed relative to the reference CT. The reference CT was segmented to visualise bones and muscles, and SLN distributions compared with the European Society for Therapeutic Radiology and Oncology (ESTRO) clinical target volumes (CTVs). The SLN atlas and statistical analyses were integrated into a graphical user interface (GUI). Results Direct lymphatic drainage to the axilla level I (anterior) node field was most common (77.2%), followed by the internal mammary node field (30.4%). Tumour prevalence was highest in the upper outer breast quadrant (22.9%) followed by the retroareolar region (12.8%). The 3D atlas had 765 SLNs from 335 patients, with 33.3–66.7% of axillary SLNs and 25.4% of internal mammary SLNs covered by ESTRO CTVs. Conclusion The interactive 3D atlas effectively displays breast SLN distribution and statistics for a large patient cohort. The atlas is freely available to download and is a valuable educational resource that could be used in future to guide treatment.

An agent has access to multiple information sources, each modeled as a Brownian motion whose drift provides information about a different component of an unknown Gaussian state. Information is acquired continuously—where the agent chooses both which sources to sample from, and also how to allocate attention across them—until an endogenously chosen time, at which point a decision is taken. We demonstrate conditions on the agent’s prior belief under which it is possible to exactly characterize the optimal information acquisition strategy. We then apply this characterization to derive new results regarding: (1) endogenous information acquisition for binary choice, (2) the dynamic consequences of attention manipulation, and (3) strategic information provision by biased news sources.

Although morphologic progression coupled with expression of specific molecular markers has been characterized along the esophageal squamous differentiation gradient, the molecular heterogeneity within cell types along this trajectory has yet to be classified at the single cell level. To address this knowledge gap, we perform single cell RNA-sequencing of 44,679 murine esophageal epithelial, to identify 11 distinct cell populations as well as pathways alterations along the basal-superficial axis and in each individual population. We evaluate the impact of aging upon esophageal epithelial cell populations and demonstrate age-associated mitochondrial dysfunction. We compare single cell transcriptomic profiles in 3D murine organoids and human esophageal biopsies with that of murine esophageal epithelium. Finally, we employ pseudotemporal trajectory analysis to develop a working model of cell fate determination in murine esophageal epithelium. These studies provide comprehensive molecular perspective on the cellular heterogeneity of murine esophageal epithelium in the context of homeostasis and aging. The level of cellular diversity in the esophageal epithelium has yet to be classified at the single cell level. Here the authors analyze the transcriptome of 44,679 murine esophageal keratinocytes to identify an unexpected level of cellular heterogeneity.

Ageing is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death 1 . Despite rapid advances over recent years, many of the molecular and cellular processes that underlie the progressive loss of healthy physiology are poorly understood 2 . To gain a better insight into these processes, here we generate a single-cell transcriptomic atlas across the lifespan of Mus musculus that includes data from 23 tissues and organs. We found cell-specific changes occurring across multiple cell types and organs, as well as age-related changes in the cellular composition of different organs. Using single-cell transcriptomic data, we assessed cell-type-specific manifestations of different hallmarks of ageing—such as senescence 3 , genomic instability 4 and changes in the immune system 2 . This transcriptomic atlas—which we denote Tabula Muris Senis , or ‘Mouse Ageing Cell Atlas’—provides molecular information about how the most important hallmarks of ageing are reflected in a broad range of tissues and cell types. A single-cell transcriptomic atlas across the lifespan of the mouse, denoted Tabula Muris Senis , provides molecular information about the hallmarks of ageing in a range of tissues and cell types.

Ageing is the single greatest cause of disease and death worldwide, and understanding the associated processes could vastly improve quality of life. Although major categories of ageing damage have been identified—such as altered intercellular communication, loss of proteostasis and eroded mitochondrial function 1 —these deleterious processes interact with extraordinary complexity within and between organs, and a comprehensive, whole-organism analysis of ageing dynamics has been lacking. Here we performed bulk RNA sequencing of 17 organs and plasma proteomics at 10 ages across the lifespan of Mus musculus , and integrated these findings with data from the accompanying Tabula Muris Senis 2 —or ‘Mouse Ageing Cell Atlas’—which follows on from the original Tabula Muris 3 . We reveal linear and nonlinear shifts in gene expression during ageing, with the associated genes clustered in consistent trajectory groups with coherent biological functions—including extracellular matrix regulation, unfolded protein binding, mitochondrial function, and inflammatory and immune response. Notably, these gene sets show similar expression across tissues, differing only in the amplitude and the age of onset of expression. Widespread activation of immune cells is especially pronounced, and is first detectable in white adipose depots during middle age. Single-cell RNA sequencing confirms the accumulation of T cells and B cells in adipose tissue—including plasma cells that express immunoglobulin J—which also accrue concurrently across diverse organs. Finally, we show how gene expression shifts in distinct tissues are highly correlated with corresponding protein levels in plasma, thus potentially contributing to the ageing of the systemic circulation. Together, these data demonstrate a similar yet asynchronous inter- and intra-organ progression of ageing, providing a foundation from which to track systemic sources of declining health at old age. Bulk RNA sequencing of organs and plasma proteomics at different ages across the mouse lifespan is integrated with data from the Tabula Muris Senis , a transcriptomic atlas of ageing mouse tissues, to describe organ-specific changes in gene expression during ageing.

The ability to slow or reverse biological ageing would have major implications for mitigating disease risk and maintaining vitality 1 . Although an increasing number of interventions show promise for rejuvenation 2 , their effectiveness on disparate cell types across the body and the molecular pathways susceptible to rejuvenation remain largely unexplored. Here we performed single-cell RNA sequencing on 20 organs to reveal cell-type-specific responses to young and aged blood in heterochronic parabiosis. Adipose mesenchymal stromal cells, haematopoietic stem cells and hepatocytes are among those cell types that are especially responsive. On the pathway level, young blood invokes new gene sets in addition to reversing established ageing patterns, with the global rescue of genes encoding electron transport chain subunits pinpointing a prominent role of mitochondrial function in parabiosis-mediated rejuvenation. We observed an almost universal loss of gene expression with age that is largely mimicked by parabiosis: aged blood reduces global gene expression, and young blood restores it in select cell types. Together, these data lay the groundwork for a systemic understanding of the interplay between blood-borne factors and cellular integrity. A transcriptomics study demonstrates cell-type-specific responses to differentially aged blood and shows young blood to have restorative and rejuvenating effects that may be invoked through enhanced mitochondrial function.

Background Pangolins are the only mammals that have overlapping scales covering most of their bodies, and they play a crucial role in the ecosystem, biological research, and human health and disease. Previous studies indicated pangolin scale might provide an important mechanical defense to themselves. The origin and exact functions of this unique trait remain a mystery. Using a multi-omics analysis approach, we report a novel functional explanation for how mammalian scales can provide host–pathogen defense. Results Our data suggest that pangolin scales have a sophisticated structure that could potentially trap pathogens. We identified numerous proteins and metabolites exhibiting antimicrobial activity, which could suggest a role for scales in pathogen defense. Notably, we found evidence suggesting the presence of exosomes derived from diverse cellular origins, including mesenchymal stem cells, immune cells, and keratinocytes. This observation suggests a complex interplay where various cell types may contribute to the release of exosomes and antimicrobial compounds at the interface between scales and viable tissue. These findings indicate that pangolin scales may serve as a multifaceted defense system, potentially contributing to innate immunity. Comparisons with human nail and hair revealed pangolin-specific proteins that were enriched in functions relating to sensing, immune responses, neutrophil degranulation, and stress responses. We demonstrated the antimicrobial activity of key pangolin scale components on pathogenic bacteria by antimicrobial assays. Conclusions This study identifies a potential role of pangolin scales and implicates scales, as possible determinants of pathogen defense due to their structure and contents. We indicate for the first time the presence of exosomes in pangolin scales and propose the new functions of scales and their mechanisms. This new mechanism could have implications for multiple fields, including providing interesting new research directions and important insights that can be useful for synthesizing and implementing new biomimetic antimicrobial approaches.

Choroideremia is a rare X-linked recessive retinal disorder characterized by progressive vision loss caused by retinal degeneration resulting from mutations in the CHM gene, which encodes Rab escort protein 1 (REP-1). In humans and mice, the Rab escort protein (REP) family consists of two members, REP-1 and REP-2, with REP-2 hypothesized to compensate for REP-1 deficiency in tissues outside the eye in choroideremia. In this study, we conducted a systematic mutational analysis of the mouse orthologs of REP-1 and REP-2. Blood analyses revealed metabolic abnormalities in the mutant mice deficient for REP-1, resembling the systemic metabolic disturbances observed in individuals with choroideremia, such as altered lipid and hemoglobin metabolism. We also observed an elevation in systemic inflammatory biomarkers in these mutant mice. Interestingly, these systemic abnormalities emerged before retinal degeneration became detectable in REP-1-deficient mice. Transcriptomic analysis of retinas isolated from REP-1 deficient mice revealed enrichment of proinflammatory signaling pathways. These results suggest important similarities between choroideremia and some forms of retinitis pigmentosa. While engineered loss of REP-2 alone caused no detectable phenotypic changes, dual deficiency in REP-1 and REP-2 resulted in lethality under both in vivo and in vitro conditions. Our findings offer novel insights into REPs and deepen our understanding of choroideremia, which may contribute to the development of new treatments for this genetic condition.

The continental shelves of the Arctic Ocean and surrounding seas contain large stocks of organic matter (OM) and methane (CH 4 ), representing a potential ecosystem feedback to climate change not included in international climate agreements. We performed a structured expert assessment with 25 permafrost researchers to combine quantitative estimates of the stocks and sensitivity of organic carbon in the subsea permafrost domain (i.e. unglaciated portions of the continental shelves exposed during the last glacial period). Experts estimated that the subsea permafrost domain contains ∼560 gigatons carbon (GtC; 170–740, 90% confidence interval) in OM and 45 GtC (10–110) in CH 4 . Current fluxes of CH 4 and carbon dioxide (CO 2 ) to the water column were estimated at 18 (2–34) and 38 (13–110) megatons C yr −1 , respectively. Under Representative Concentration Pathway (RCP) RCP8.5, the subsea permafrost domain could release 43 Gt CO 2 -equivalent (CO 2 e) by 2100 (14–110) and 190 Gt CO 2 e by 2300 (45–590), with ∼30% fewer emissions under RCP2.6. The range of uncertainty demonstrates a serious knowledge gap but provides initial estimates of the magnitude and timing of the subsea permafrost climate feedback.

Mitochondria from different types of cancer show bioenergetics and dysfunction that favor cell proliferation. The mechanistic understanding of estrogen in cervical cancer is poorly understood. Therefore, the objective of this study was to determine how 17β-estradiol (E2) affects mitochondrial function and the Warburg effect in SiHa, HeLa and C33A cervical cancer cells. Mitochondrial compromise was evaluated measuring changes in the membrane permeability by immunofluorescence, calcium concentration, redox status, iron and ferritin reserves. Glucose consumption and lactic acid assays were used to detect the metabolic activity. Results were confirmed at molecular level by analysis of the differential gene expression using RNA sequencing. E2 modified the mitochondrial permeability and produced an alteration in the calcium signaling pathway. In HeLa and SiHa, there was a significant decrease in nitric oxide levels and lipid peroxidation, and an increase in glucose consumption and lactic acid levels when stimulated with E2. Intracellular iron or ferritin reserves were not affected by the E2 treatment. Genes differentially modulated by E2 were involved in the mitochondrial electron transport chain, oxidative phosphorylation system, glycolysis, pentose phosphate pathway and the regulation of metabolic signaling pathways. Herein, we provide evidence for a primary effect of estrogen on mitochondrial function and the Warburg effect, favoring the metabolic adaptation of the cervical cancer cell lines and their survival.