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Summary: Bats host a range of disease-causing viruses without displaying clinical symptoms. The mechanisms behind this are a continuous source of interest. Here, we studied the antiviral response in the Egyptian fruit bat and Kuhl’s pipistrelle, representing two subordinal clades. We profiled the antiviral response in fibroblasts using RNA sequencing and compared bat with primate and rodent responses. Both bats upregulate similar genes; however, a subset of these genes is transcriptionally divergent between them. These divergent genes also evolve rapidly in sequence, have specific promoter architectures, and are associated with programs underlying tolerance and resistance. Finally, we characterized antiviral genes that expanded in bats, with duplicates diverging in sequence and expression.Our study reveals a largely conserved antiviral program across bats and points to a set of genes that rapidly evolve through multiple mechanisms. These can contribute to bat adaptation to viral infection and provide directions to understanding the mechanisms behind it.

Polycomb repressive complexes modify histones but it is unclear how changes in chromatin states alter kinetics of transcription. Here, the authors use single-cell RNAseq and ChIPseq to find that actively transcribed genes with Polycomb marks have greater cell-to-cell variation in expression.

T helper 2 (Th2) cells regulate helminth infections, allergic disorders, tumor immunity, and pregnancy by secreting various cytokines. It is likely that there are undiscovered Th2 signaling molecules. Although steroids are known to be immunoregulators, de novo steroid production from immune cells has not been previously characterized. Here, we demonstrate production of the steroid pregnenolone by Th2 cells in vitro and in vivo in a helminth infection model. Single-cell RNA sequencing and quantitative PCR analysis suggest that pregnenolone synthesis in Th2 cells is related to immunosuppression. In support of this, we show that pregnenolone inhibits Th cell proliferation and B cell immunoglobulin class switching. We also show that steroidogenic Th2 cells inhibit Th cell proliferation in a Cyp11a1 enzyme-dependent manner. We propose pregnenolone as a “lymphosteroid,” a steroid produced by lymphocytes. We speculate that this de novo steroid production may be an intrinsic phenomenon of Th2-mediated immune responses to actively restore immune homeostasis.

Nature Communications 6: Article number: 8687 (2015); Published: 22 October 2015; Updated: 11 January 2016. The original version of this Article contained an error in the spelling of the author Tomislav Ilicic, which was incorrectly given as Tomislav Illicic. This has now been corrected in both the PDF and HTML versions of the Article.

Abstract Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of cardiometabolic syndrome, which often also includes obesity, diabetes, and dyslipidemia. It is rapidly becoming the most prevalent liver disease worldwide. A sizable minority of NAFLD patients develop nonalcoholic steatohepatitis (NASH), which is characterized by inflammatory changes that can lead to progressive liver damage, cirrhosis, and hepatocellular carcinoma. Recent studies have shown that in addition to genetic predisposition and diet, the gut microbiota affects hepatic carbohydrate and lipid metabolism as well as influences the balance between pro‐inflammatory and anti‐inflammatory effectors in the liver, thereby impacting NAFLD and its progression to NASH. In this review, we will explore the impact of gut microbiota and microbiota‐derived compounds on the development and progression of NAFLD and NASH, and the unexplored factors related to potential microbiome contributions to this common liver disease.

Carotenoids are very effectively delivered by albumin to adipocytes. The uptake of carotenoids to the cells occurs in the form of self-aggregates that localize in the vicinity of the adipocyte membrane, as shown by high spatial resolution Raman spectroscopy. The binding of carotenoids to albumin and the mechanism of their transport were elucidated with the help of chiroptical spectroscopies, in tandem with molecular docking and molecular dynamics simulations. In particular, apart from the recognized high affinity pocket of albumin that binds a carotenoid monomer in domain I, we have identified a hydrophobic periphery area in domain IIIB that loosely bounds the self-aggregated carotenoid in aqueous media and enables its easy detachment in hydrophobic environments. This explains the effectiveness of albumins as nanocarriers of carotenoids to adipocytes in vitro .

Amyloid fibrils are complex protein structures with multilayered chiral architecture, that are known to self-propagate. The replication of the mother seed structure by daughter fibrils is known as conformational or templated memory. Using vibrational circular dichroism (VCD), electronic circular dichroism (ECD), transmission electron microscopy (TEM), and cryo-electron microscopy (cryo-EM) we have shown that environmental factors (here agitation) can be a competing force against the templated growth of human lysozyme fibrils. In the cross-seeding experiment non-agitated daughters preserved the structure of agitated mothers, whereas agitated daughters did not always exhibit the same characteristics as their non-agitated mothers. This pattern was reflected on various levels of fibril architecture (secondary structure, protofilament handedness, morphology), demonstrating that the structural indeterminism originates from deeper levels of the fibril structure. This observation may contribute to a better understanding of the processes behind fibril formation., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Agnieszka Kaczor reports financial support was provided by National Science Centre Poland., (Copyright © 2023. Published by Elsevier B.V.)

Amyloid fibrils form remarkable, multi-layered chiral supramolecular architectures. The proximity of interacting oscillators in the chiral fibril supramolecules is responsible for the unusual sensitivity of vibrational circular dichroism (VCD) for fibril formation. Surprisingly, up to now, such characteristics have not been shown for ROA, although it displays the same vibrational markers of fibrils as VCD, including the amide I band. Here, we report an exceptionally large enhancement of the ROA signal detected for mature amyloid fibrils and their prefibrillar states. Remarkably, the same ROA signal has been obtained for fibrils of homologous lysozymes and the dissimilar protein, insulin, indicating a possible common enhanced ROA spectrum, analogous to that for VCD for all amyloid fibrils investigated to date. The ROA signal is observed at earlier stages of fibril formation than VCD and provides access to a considerably broader range of vibrations. Further studies are necessary to verify the applicability of ROA for the analysis of amyloid fibrils.

Immunotherapies that target programmed cell death protein 1 (PD-1) and its ligand PD-L1 as well as cytotoxic T-lymphocyte-associated protein 4 (CTLA4) have shown impressive clinical outcomes for multiple tumours. However, only a subset of patients achieves durable responses, suggesting that the mechanisms of the immune checkpoint pathways are not completely understood. Here, we report that PD-L1 translocates from the plasma membrane into the nucleus through interactions with components of the endocytosis and nucleocytoplasmic transport pathways, regulated by p300-mediated acetylation and HDAC2-dependent deacetylation of PD-L1. Moreover, PD-L1 deficiency leads to compromised expression of multiple immune-response-related genes. Genetically or pharmacologically modulating PD-L1 acetylation blocks its nuclear translocation, reprograms the expression of immune-response-related genes and, as a consequence, enhances the anti-tumour response to PD-1 blockade. Thus, our results reveal an acetylation-dependent regulation of PD-L1 nuclear localization that governs immune-response gene expression, and thereby advocate targeting PD-L1 translocation to enhance the efficacy of PD-1/PD-L1 blockade.

The cyclin-dependent kinase 1 (Cdk1) drives cell division. To uncover additional functions of Cdk1, we generated knockin mice expressing an analog-sensitive version of Cdk1 in place of wild-type Cdk1. In our study, we focused on embryonic stem cells (ESCs), because this cell type displays particularly high Cdk1 activity. We found that in ESCs, a large fraction of Cdk1 substrates is localized on chromatin. Cdk1 phosphorylates many proteins involved in epigenetic regulation, including writers and erasers of all major histone marks. Consistent with these findings, inhibition of Cdk1 altered histone-modification status of ESCs. High levels of Cdk1 in ESCs phosphorylate and partially inactivate Dot1l, the H3K79 methyltransferase responsible for placing activating marks on gene bodies. Decrease of Cdk1 activity during ESC differentiation de-represses Dot1l, thereby allowing coordinated expression of differentiation genes. These analyses indicate that Cdk1 functions to maintain the epigenetic identity of ESCs., Competing Interests: Declaration of Interests W.M. is currently an employee of Cedilla Therapeutics. B.A. is a shareholder of Syros Pharmaceuticals. R.A.Y. is a founder and shareholder of Syros Pharmaceuticals, Camp4 Therapeutics, Omega Therapeutics, and Dewpoint Therapeutics. P.S. has been a consultant at Novartis, Genovis, Guidepoint, The Planning Shop, ORIC Pharmaceuticals, and Exo Therapeutics, and his laboratory receives research funding from Novartis. In situ visualization of kinase substrates has been patented (P.S. and W.M., WO2018/035296A1)., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Cyclins, cyclin-dependent kinases and other components of the core cell cycle machinery drive cell division. Growing evidence indicates that this machinery operates in a distinct fashion in some mammalian stem cell types, such as pluripotent embryonic stem cells. In this Review, we discuss our current knowledge of how cell cycle proteins mechanistically link cell proliferation, pluripotency and cell fate specification. We focus on embryonic stem cells, induced pluripotent stem cells and embryonic neural stem/progenitor cells.