Multiplexed imaging of human tuberculosis granulomas uncovers immunoregulatory features conserved across tissue and blood

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis that is distinctly characterized by granuloma formation within infected tissues. Granulomas are dynamic and organized immune cell aggregates that limit dissemination, but can also hinder bacterial clearance. Consequently, outcome in TB is influenced by how granuloma structure and composition shift the balance between these two functions. To date, our understanding of what factors drive granuloma function in humans is limited. With this in mind, we used Multiplexed Ion Beam Imaging by Time-of-Flight (MIBI-TOF) to profile 37 proteins in tissues from thirteen patients with active TB disease from the U.S. and South Africa. With this dataset, we constructed a comprehensive tissue atlas where the lineage, functional state, and spatial distribution of 19 unique cell subsets were mapped onto eight phenotypically-distinct granuloma microenvironments. This work revealed an immunosuppressed microenvironment specific to TB granulomas with spatially coordinated co-expression of IDO1 and PD-L1 by myeloid cells and proliferating regulatory T cells. Interestingly, this microenvironment lacked markers consistent with T-cell activation, supporting a myeloid-mediated mechanism of immune suppression. We observed similar trends in gene expression of immunoregulatory proteins in a confirmatory transcriptomic analysis of peripheral blood collected from over 1500 individuals with latent or active TB infection and healthy controls across 29 cohorts spanning 14 countries. Notably, PD-L1 gene expression was found to correlate with TB progression and treatment response, supporting its potential use as a blood-based biomarker. Taken together, this study serves as a framework for leveraging independent cohorts and complementary methodologies to understand how local and systemic immune responses are linked in human health and disease

Multiplexed imaging of human tuberculosis granulomas uncovers immunoregulatory features conserved across tissue and blood

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis that is distinctly characterized by granuloma formation within infected tissues. Granulomas are dynamic and organized immune cell aggregates that limit dissemination, but can also hinder bacterial clearance. Consequently, outcome in TB is influenced by how granuloma structure and composition shift the balance between these two functions. To date, our understanding of what factors drive granuloma function in humans is limited. With this in mind, we used Multiplexed Ion Beam Imaging by Time-of-Flight (MIBI-TOF) to profile 37 proteins in tissues from thirteen patients with active TB disease from the U.S. and South Africa. With this dataset, we constructed a comprehensive tissue atlas where the lineage, functional state, and spatial distribution of 19 unique cell subsets were mapped onto eight phenotypically-distinct granuloma microenvironments. This work revealed an immunosuppressed microenvironment specific to TB granulomas with spatially coordinated co-expression of IDO1 and PD-L1 by myeloid cells and proliferating regulatory T cells. Interestingly, this microenvironment lacked markers consistent with T-cell activation, supporting a myeloid-mediated mechanism of immune suppression. We observed similar trends in gene expression of immunoregulatory proteins in a confirmatory transcriptomic analysis of peripheral blood collected from over 1500 individuals with latent or active TB infection and healthy controls across 29 cohorts spanning 14 countries. Notably, PD-L1 gene expression was found to correlate with TB progression and treatment response, supporting its potential use as a blood-based biomarker. Taken together, this study serves as a framework for leveraging independent cohorts and complementary methodologies to understand how local and systemic immune responses are linked in human health and disease

Shallow non-inversion tillage in organic farming maintains crop yields and increases soil C stocks: a meta-analysis

Reduced tillage is increasingly promoted to improve sustainability and productivity of agricultural systems. Nonetheless, adoption of reduced tillage by organic farmers has been slow due to concerns about nutrient supply, soil structure, and weeds that may limit yields. Here, we compiled the results from both published and unpublished research comparing deep or shallow inversion tillage, with various categories of reduced tillage under organic management. Shallow refers to less than 25 cm. We found that (1) division of reduced tillage practices into different classes with varying degrees of intensity allowed us to assess the trade-offs between reductions in tillage intensity, crop yields, weed incidence, and soil C stocks. (2) Reducing tillage intensity in organic systems reduced crop yields by an average of 7.6 % relative to deep inversion tillage with no significant reduction in yield relative to shallow inversion tillage. (3) Among the different classes of reduced tillage practice, shallow non-inversion tillage resulted in non-significant reductions in yield relative to deep inversion; whereas deep non-inversion tillage resulted in the largest yield reduction, of 11.6 %. (4) Using inversion tillage to only a shallow depth resulted in minimal reductions in yield, of 5.5 %, but significantly higher soil C stocks and better weed control. This finding suggests that this is a good option for organic farmers wanting to improve soil quality while minimizing impacts on yields. (5) Weeds were consistently higher, by about 50 %, when tillage intensity was reduced, although this did not always result in reduced yields

The Atlantic salmon genome provides insights into rediploidization

The whole-genome duplication 80 million years ago of the common ancestor of salmonids (salmonid-specific fourth vertebrate whole-genome duplication, Ss4R) provides unique opportunities to learn about the evolutionary fate of a duplicated vertebrate genome in 70 extant lineages. Here we present a high-quality genome assembly for Atlantic salmon (Salmo salar), and show that large genomic reorganizations, coinciding with bursts of transposon-mediated repeat expansions, were crucial for the post-Ss4R rediploidization process. Comparisons of duplicate gene expression patterns across a wide range of tissues with orthologous genes from a pre-Ss4R outgroup unexpectedly demonstrate far more instances of neofunctionalization than subfunctionalization. Surprisingly, we find that genes that were retained as duplicates after the teleost-specific whole-genome duplication 320 million years ago were not more likely to be retained after the Ss4R, and that the duplicate retention was not influenced to a great extent by the nature of the predicted protein interactions of the gene products. Finally, we demonstrate that the Atlantic salmon assembly can serve as a reference sequence for the study of other salmonids for a range of purposes.publishedVersio

Multiplexed imaging reveals an IFN-γ-driven inflammatory state in nivolumab-associated gastritis

Immune checkpoint blockade using PD-1 inhibition is an effective approach for treating a wide variety of cancer subtypes. While lower gastrointestinal (GI) side effects are more common, upper gastrointestinal adverse events are rarely reported. Here, we present a case of nivolumab-associated autoimmune gastritis. To elucidate the immunology underlying this condition, we leverage multiplexed ion beam imaging by time-of-flight (MIBI-TOF) to identify the presence and proportion of infiltrating immune cells from a single section of biopsy specimen. Using MIBI-TOF, we analyze formalin-fixed, paraffin-embedded human gastric tissue with 28 labels simultaneously. Our analyses reveal a gastritis characterized by severe mucosal injury, interferon gamma (IFN-γ)-producing gastric epithelial cells, and mixed inflammation that includes CD8 and CD4 T cell infiltrates with reduced expression of granzyme B and FOXP3, respectively. Here, we provide a comprehensive multiplexed histopathological mapping of gastric tissue, which identifies IFN-γ-producing epithelial cells as possible contributors to the nivolumab-associated gastritis

Space‐time NURBS‐enhanced finite elements for free‐surface flows in 2D

The accuracy of numerical simulations of free‐surface flows depends strongly on the computation of geometric quantities like normal vectors and curvatures. This geometrical information is additional to the actual degrees of freedom and usually requires a much finer discretization of the computational domain than the flow solution itself. Therefore, the utilization of a numerical method, which uses standard functions to discretize the unknown function in combination with an enhanced geometry representation is a natural step to improve the simulation efficiency. An example of such method is the NURBS‐enhanced finite element method (NEFEM), recently proposed by Sevilla et al. The current paper discusses the extension of the spatial NEFEM to space‐time methods and investigates the application of space‐time NURBS‐enhanced elements to free‐surface flows. Derived is also a kinematic rule for the NURBS motion in time, which is able to preserve mass conservation over time. Numerical examples show the ability of the space‐time NEFEM to account for both pressure discontinuities and surface tension effects and compute smooth free‐surface forms. For these examples, the advantages of the NEFEM compared with the classical FEM are shown.&nbsp