Ionic modulation of immune checkpoint proteins

Despite extensive basic and clinical research on immune checkpoint regulatory pathways, little is known about the effects of the ionic tumour microenvironment on immune checkpoint expression and function. We screened effects of ion channel modulating compounds on indoleamine-2',3'-dioxygenase (IDO1) activity. Here, we describe a mechanistic link between Na+/K+ ATPase inhibition by cardiac glycosides and activity of IDO1, a well-characterized immune checkpoint. IDO1 catalyses the rate-limitig step of tryptophan catabolim and inhibits the immune response to the tumour by local depletion of tryptophan, an amino acid essential for anabolic functions in cancer and T cells

Brain-Wide Correspondence of Neuronal Epigenomics and Distant Projections

Single-cell analyses parse the brain’s billions of neurons into thousands of ‘cell-type’ clusters residing in different brain structures1. Many cell types mediate their functions through targeted long-distance projections allowing interactions between specific cell types. Here we used epi-retro-seq2 to link single-cell epigenomes and cell types to long-distance projections for 33,034 neurons dissected from 32 different regions projecting to 24 different targets (225 source-to-target combinations) across the whole mouse brain. We highlight uses of these data for interrogating principles relating projection types to transcriptomics and epigenomics, and for addressing hypotheses about cell types and connections related to genetics. We provide an overall synthesis with 926 statistical comparisons of discriminability of neurons projecting to each target for every source. We integrate this dataset into the larger BRAIN Initiative Cell Census Network atlas, composed of millions of neurons, to link projection cell types to consensus clusters. Integration with spatial transcriptomics further assigns projection-enriched clusters to smaller source regions than the original dissections. We exemplify this by presenting in-depth analyses of projection neurons from the hypothalamus, thalamus, hindbrain, amygdala and midbrain to provide insights into properties of those cell types, including differentially expressed genes, their associated cis-regulatory elements and transcription-factor-binding motifs, and neurotransmitter use

Beyond ΛCDM:problems, solutions, and the road ahead

97 pages, 8 figuresInternational audienceDespite its continued observational successes, there is a persistent (and growing) interest in extending cosmology beyond the standard model, $\Lambda$CDM. This is motivated by a range of apparently serious theoretical issues, involving such questions as the cosmological constant problem, the particle nature of dark matter, the validity of general relativity on large scales, the existence of anomalies in the CMB and on small scales, and the predictivity and testability of the inflationary paradigm. In this paper, we summarize the current status of $\Lambda$CDM as a physical theory, and review investigations into possible alternatives along a number of different lines, with a particular focus on highlighting the most promising directions. While the fundamental problems are proving reluctant to yield, the study of alternative cosmologies has led to considerable progress, with much more to come if hopes about forthcoming high-precision observations and new theoretical ideas are fulfilled

Pluralismo religioso, educación y ciudadanía Religious pluralism, education and citizenship

Este artículo describe las formas peculiares que adquiere el cambio religioso, tanto a nivel de las adhesiones a nuevos movimientos religiosos como en las creencias religiosas en Chile. Este trabajo analiza la manera en que el factor educacional interviene en las tendencias hacia la pluralización religiosa. También se exploran las posibles consecuencias que puedan tener las manifestaciones concretas del cambio religioso en la cultura política de Chile.<br>This article describes the peculiar forms taken by religious change in Chile. It considers the adhesion to new religious movements and beliefs as well as education and its interference on the multiplication of religious institutions. It also pictures the concrete manifestations of religious change and their consequences for political culture

Brain-wide correspondence of neuronal epigenomics and distant projections.

Single-cell analyses parse the brains billions of neurons into thousands of cell-type clusters residing in different brain structures1. Many cell types mediate their functions through targeted long-distance projections allowing interactions between specific cell types. Here we used epi-retro-seq2 to link single-cell epigenomes and cell types to long-distance projections for 33,034 neurons dissected from 32 different regions projecting to 24 different targets (225 source-to-target combinations) across the whole mouse brain. We highlight uses of these data for interrogating principles relating projection types to transcriptomics and epigenomics, and for addressing hypotheses about cell types and connections related to genetics. We provide an overall synthesis with 926 statistical comparisons of discriminability of neurons projecting to each target for every source. We integrate this dataset into the larger BRAIN Initiative Cell Census Network atlas, composed of millions of neurons, to link projection cell types to consensus clusters. Integration with spatial transcriptomics further assigns projection-enriched clusters to smaller source regions than the original dissections. We exemplify this by presenting in-depth analyses of projection neurons from the hypothalamus, thalamus, hindbrain, amygdala and midbrain to provide insights into properties of those cell types, including differentially expressed genes, their associated cis-regulatory elements and transcription-factor-binding motifs, and neurotransmitter use