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Lysine methylation on histone tails impacts genome regulation and cell fate determination in many developmental processes. Apicomplexa intracellular parasites cause major diseases and they have developed complex life cycles with fine-tuned differentiation events. Yet, apicomplexa genomes have few transcription factors and little is known about their epigenetic control systems. Tick-borne Theileria apicomplexa species have relatively small, compact genomes and a remarkable ability to transform leucocytes in their bovine hosts. Here we report enriched H3 lysine 18 monomethylation (H3K18me1) on the gene bodies of repressed genes in Theileria macroschizonts. Differentiation to merozoites (merogony) leads to decreased H3K18me1 in parasite nuclei. Pharmacological manipulation of H3K18 acetylation or methylation impacted parasite differentiation and expression of stage-specific genes. Finally, we identify a parasite SET-domain methyltransferase (TaSETup1) that can methylate H3K18 and represses gene expression. Thus, H3K18me1 emerges as an important epigenetic mark which controls gene expression and stage differentiation in Theileria parasites. Post-translational modifications (PTM) of histones are important for epigenetic regulation in mammals. Here, Cheeseman et al. report dynamic changes in H3K18 PTM during the differentiation stages of Theileria parasites and they identify a SET-domain methyltransferase (TaSETup1) as the relevant enzyme promoting this modification.

Skeletal muscle fibers are large syncytia but it is currently unknown whether gene expression is coordinately regulated in their numerous nuclei. Here we show by snRNA-seq and snATAC-seq that slow, fast, myotendinous and neuromuscular junction myonuclei each have different transcriptional programs, associated with distinct chromatin states and combinations of transcription factors. In adult mice, identified myofiber types predominantly express either a slow or one of the three fast isoforms of Myosin heavy chain (MYH) proteins, while a small number of hybrid fibers can express more than one MYH. By snRNA-seq and FISH, we show that the majority of myonuclei within a myofiber are synchronized, coordinately expressing only one fast Myh isoform with a preferential panel of muscle-specific genes. Importantly, this coordination of expression occurs early during post-natal development and depends on innervation. These findings highlight a previously undefined mechanism of coordination of gene expression in a syncytium. Whether skeletal muscle fibre gene expression is coordinated as a whole in different nuclei in the fibre is unclear. Here, the authors use single nucleus RNAseq and ATACseq to show the transcriptome heterogeneity of muscle nuclei in the adult mouse fibre, with correlations between the two datasets.

Immune system dysfunction is paramount in coronavirus disease 2019 (COVID-19) severity and fatality rate. Mucosal-associated invariant T (MAIT) cells are innate-like T cells involved in mucosal immunity and protection against viral infections. Here, we studied the immune cell landscape, with emphasis on MAIT cells, in cohorts totaling 208 patients with various stages of disease. MAIT cell frequency is strongly reduced in blood. They display a strong activated and cytotoxic phenotype that is more pronounced in lungs. Blood MAIT cell alterations positively correlate with the activation of other innate cells, proinflammatory cytokines, notably interleukin (IL)-18, and with the severity and mortality of severe acute respiratory syndrome coronavirus 2 infection. We also identified a monocyte/macrophage interferon (IFN)-α–IL-18 cytokine shift and the ability of infected macrophages to induce the cytotoxicity of MAIT cells in an MR1-dependent manner. Together, our results suggest that altered MAIT cell functions due to IFN-α–IL-18 imbalance contribute to disease severity, and their therapeutic manipulation may prevent deleterious inflammation in COVID-19 aggravation. Severe COVID-19 is characterized by hyperinflammation, and there is a need for accurate predictive biomarkers of progression. Lehuen et al. demonstrate that patients with severe COVID-19 show a dramatic loss of MAIT cells, and those that do remain are in a highly activated state.

Toxoplasma gondii is a cyst-forming apicomplexan parasite of virtually all warm-blooded species, with all true cats (Felidae) as definitive hosts. It is the etiologic agent of toxoplasmosis, a disease causing substantial public health burden worldwide. Few intercontinental clonal lineages represent the large majority of isolates worldwide. Little is known about the evolutionary forces driving the success of these lineages, the timing and the mechanisms of their global dispersal. In this study, we analyse a set of 156 genomes and we provide estimates of T. gondii mutation rate and generation time. We elucidate how the evolution of T. gondii populations is intimately linked to the major events that have punctuated the recent history of cats. We show that a unique haplotype, whose length represents only 0.16% of the whole T. gondii genome, is common to all intercontinental lineages and hybrid populations derived from these lineages. This haplotype has accompanied wildcats ( Felis silvestris ) during their emergence from the wild to domestic settlements, their dispersal in the Old World, and their expansion in the last five centuries to the Americas. The selection of this haplotype is most parsimoniously explained by its role in sexual reproduction of T. gondii in domestic cats. Toxoplasma gondii can infect all warm-blooded animals, with felidae being the definitive hosts. Despite this broad host range, most clinical and animal isolates belong to few clonal lineages. Here, Galal et al. perform whole-genome sequencing of isolates from distinct geographical regions and estimate T. gondii mutation rate and generation time. They find that recent waves of migration disseminated the parasite from Old to New World and identify a unique haplotype that likely accompanied the global expansion of cats and is today common to all intercontinental lineages and hybrid populations.

This study showed that there were mutations in ARMC5, a putative tumor-suppressor gene, in a substantial proportion of patients with corticotropin-independent macronodular adrenal hyperplasia, a finding that may be helpful in the diagnosis and management of this disease. Corticotropin-independent macronodular adrenal hyperplasia can lead to excess cortisol secretion and Cushing's syndrome. 1 , 2 Adrenocortical nodules in corticotropin-independent macronodular adrenal hyperplasia are, by definition, larger than 10 mm in diameter and frequently reach 30 to 40 mm in diameter. The condition is typically diagnosed in patients with Cushing's syndrome who are between 40 and 60 years of age and who have suppressed levels of circulating corticotropin. Tumor growth and cortisol dysregulation appear to progress slowly in cases of corticotropin-independent macronodular adrenal hyperplasia, and the diagnosis is often made only after several years or decades of disease progression. 3 Milder forms are . . .

Background The 18-gene tumor inflammation signature (TIS) is a clinical research assay that enriches for clinical benefit to immune checkpoint blockade. We evaluated its ability to predict clinical benefit of immunotherapy in cancer patients treated with PD-1 checkpoint inhibitors in routine clinical care. Methods The CERTIM cohort is a prospective cohort which includes patients receiving immune checkpoint inhibitors in Cochin University hospital. RNA extracted from 58 archival formalin fixed paraffin embedded tumor blocks (including 38 lung cancers, 5 melanomas, 10 renal carcinomas, 4 urothelial carcinomas and 1 colon carcinoma) was hybridized to a beta version of the NanoString ® PanCancer IO360™ CodeSet using nCounter ® technology. Gene expression signatures were correlated with tumor responses (by RECIST criteria) and overall survival. PD-L1 immunostaining on tumor cells was assessed in 37 non-small cell lung cancer (NSCLC) samples and tumor mutational burden (TMB) measured by whole exome sequencing in 19 of these. Results TIS scores were significantly associated with complete or partial response to anti-PD-1 treatment in the whole cohort (odds ratio = 2.64, 95% CI [1.4; 6.0], p  = 0.008), as well as in the NSCLC population (odds ratio = 3.27, 95% CI [1.2; 11.6], p  = 0.03). Patients whose tumor had a high TIS score (upper tertile) showed prolonged overall survival compared to patients whose tumor had lower TIS scores, both in the whole cohort (hazard ratio = 0.37, 95% CI [0.18, 0.76], p  = 0.005) and in the NSCLC population (hazard ratio = 0.36, 95% CI [0.14, 0.90], p  = 0.02). In the latter, the TIS score was independent from either PD-L1 staining on tumor cells (spearman coefficient 0.2) and TMB (spearman coefficient − 0.2). Conclusions These results indicate that validated gene expression assay measuring the level of tumor microenvironment inflammation such as TIS, are accurate and independent predictive biomarkers and can be easily implemented in the clinical practice.

Intestinal epithelium has the capacity to self-renew and generate differentiated cells through the existence of two types of epithelial stem cells: active crypt base columnar cells (CBCs) and quiescent +4 cells. The behaviors of these cells are regulated both by intrinsic programs and by extrinsic signals sent by neighboring cells, which define the niche. It is clear that the ß-catenin pathway acts as an essential intrinsic signal for the maintenance and proliferation of CBC, and it was recently proposed that Paneth cells provide a crucial niche by secreting Wingless/lnt (Wnt) ligands. Here, we examined the effect of disrupting the intestinal stem cell niche by inducible deletion of the transcription factor Mathi (Atohl), an essential driver of secretory cell differentiation. We found that complete loss of Paneth cells attributable to Mathi deficiency did not perturb the crypt architecture and allowed the maintenance and proliferation of CBCs. Indeed, Mathi-deficient crypt cells tolerated in vivo Paneth cell loss and maintained active ß-catenin signaling but could not grow ex vivo without exogenous Wnt, implying that, in vivo, underlying mucosal cells act as potential niche. Upon irradiation, Mathi-deficient crypt cells regenerated and CBCs continued cycling. Finally, CBC stem cells deficient in adenomatous polyposis coli (Ape) and Math1 were able to promote intestinal tumorigenesis. We conclude that in vivo, Mathi -deficient crypts counteract the absence of Paneth cell-derived Wnts and prevent CBC stem cell exhaustion.

This review of the literature examines diseases and pathogen characteristics on military vessels, in order to improve the success of missions on a boat. Our aim is to understand the spread of disease, aiming to maximize biological resilience and hopefully eliminate outbreaks. Keyword research was conducted from various sources of information, including scientific publications, theses, public health organization websites, and clinical trials. A synthesis of bacterial, viral, fungal, and parasitosis characteristics was established, and a risk prioritization index was defined, based on contagiousness (basic reproduction number (R0)) and clinical severity. For instance, COVID-19 was assessed as moderately contagious, with critical severity, and Influenza A H1N1 as having a minor level of contagiousness with critical severity, resulting in a level two out of three risk prioritization index. This approach demonstrates that while diseases have numerous characteristics, a method for classifying them by isolating specific criteria and prioritizing them could be proposed. In conclusion, further work is needed to analyze onboard operator activities and develop simulation models related to pathogen characteristics.

Foxo family transcription factors are critically involved in multiple processes, such as metabolism, quiescence, cell survival and cell differentiation. Although continuous, high activity of Foxo transcription factors extends the life span of some species, the involvement of Foxo proteins in mammalian aging remains to be determined. Here, we show that Foxo1 is down-regulated with age in mouse T cells. This down-regulation of Foxo1 in T cells may contribute to the disruption of naive T-cell homeostasis with age, leading to an increase in the number of memory T cells. Foxo1 down-regulation is also associated with the up-regulation of co-inhibitory receptors by memory T cells and exhaustion in aged mice. Using adoptive transfer experiments, we show that the age-dependent down-regulation of Foxo1 in T cells is mediated by T-cell-extrinsic cues, including type 1 interferons. Taken together, our data suggest that type 1 interferon-induced Foxo1 down-regulation is likely to contribute significantly to T-cell dysfunction in aged mice. Although continuous activity of Foxo transcription factors substantially increase the life span of species such as Hydra vulgaris , these proteins have never been implicated in mammalian aging. In this study, the authors demonstrate that, with age, Foxo1 is down-regulated in mouse T lymphocytes and associated with exhaustion.

Radiotherapy represents a major curative treatment for prostate cancer (PCa), but some patients will develop radioresistance (RR) and relapse. The underlying mechanisms remain poorly understood, and miRNAs might be key players in the acquisition and maintenance of RR. Through their encapsulation in small extracellular vesicles (EVs), they can also be relevant biomarkers of radiation response. Using next-generation sequencing, we found that miR-200c-3p was downregulated in PCa RR cells and in their small EVs due to a gain of methylation on its promoter during RR acquisition. We next showed that its exogenous overexpression restores the radiosensitivity of RR cells by delaying DNA repair through the targeting of HP1α. Interestingly, we also observed downregulation of miR-200c-3p expression by DNA methylation in radiation-resistant lung and breast cancer cell lines. In summary, our study demonstrates that the downregulation of miR-200c-3p expression in PCa cells and in their small EVs could help distinguish radioresistant from sensitive tumor cells. This miRNA targets HP1α to delay DNA repair and promote cell death.