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The immune system is integral to cardiovascular health and disease. Targeting inflammation ameliorates adverse cardiovascular outcomes. Atherosclerosis, a major underlying cause of cardiovascular disease (CVD), is conceptualised as a lipid-driven inflammation where macrophages play a non-redundant role. However, evidence emerging so far from single cell atlases suggests a dichotomy between lipid associated and inflammatory macrophage states. Here, we present an inclusive reference atlas of human intraplaque immune cell communities. Combining scRNASeq of human surgical carotid endarterectomies in a discovery cohort with bulk RNASeq and immunohistochemistry in a validation cohort (the Carotid Plaque Imaging Project-CPIP), we reveal the existence of PLIN2 hi /TREM1 hi macrophages as a toll-like receptor-dependent inflammatory lipid-associated macrophage state linked to cerebrovascular events. Our study shifts the current paradigm of lipid-driven inflammation by providing biological evidence for a pathogenic macrophage transition to an inflammatory lipid-associated phenotype and for its targeting as a new treatment strategy for CVD., Competing Interests: Competing Interests Statement All authors report no conflict of interest. A.E has received consultancy fees from and/or served on the advisory boards of Novo Nordisk, Sanofi and Amgen but this has not had any relationship with the current study or affected the design/outcome of the study. The remaining authors have no conflicts of interest.

IFNγ is an immune mediator with concomitant pro- and anti-tumor functions. Here, we provide evidence that IFNγ directly acts on intra-tumoral CD8 T cells to restrict anti-tumor responses. We report that expression of the IFNγ receptor β chain (IFNγR2) in CD8 T cells negatively correlates with clinical responsiveness to checkpoint blockade in metastatic melanoma patients, suggesting that the loss of sensitivity to IFNγ contributes to successful antitumor immunity. Indeed, specific deletion of IFNγR in CD8 T cells promotes tumor control in a mouse model of melanoma. Chronic IFNγ inhibits the maintenance, clonal diversity and proliferation of stem-like T cells. This leads to decreased generation of T cells with intermediate expression of exhaustion markers, previously associated with beneficial anti-tumor responses. This study provides evidence of a negative feedback loop whereby IFNγ depletes stem-like T cells to restrict anti-tumor immunity. Targeting this pathway might represent an alternative strategy to enhance T cell-based therapies., (© 2023. The Author(s).)

More than 40% of individuals will develop osteoarthritis (OA) during their lifetime, yet there are currently no licensed disease-modifying treatments for this disabling condition. Common polymorphic variants in ALDH1A2 , which encodes the key enzyme for synthesis of all-trans retinoic acid (atRA), are associated with severe hand OA. Here, we sought to elucidate the biological significance of this association. We first confirmed that ALDH1A2 risk variants were associated with hand OA in the U.K. Biobank. Articular cartilage was acquired from 33 individuals with hand OA at the time of routine hand OA surgery. After stratification by genotype, RNA sequencing was performed. A reciprocal relationship between ALDH1A2 mRNA and inflammatory genes was observed. Articular cartilage injury up-regulated similar inflammatory genes by a process that we have previously termed mechanoflammation, which we believe is a primary driver of OA. Cartilage injury was also associated with a concomitant drop in atRA-inducible genes, which were used as a surrogate measure of cellular atRA concentration. Both responses to injury were reversed using talarozole, a retinoic acid metabolism blocking agent (RAMBA). Suppression of mechanoflammation by talarozole was mediated by a peroxisome proliferator-activated receptor gamma (PPARγ)-dependent mechanism. Talarozole was able to suppress mechano-inflammatory genes in articular cartilage in vivo 6 hours after mouse knee joint destabilization and reduced cartilage degradation and osteophyte formation after 26 days. These data show that boosting atRA suppresses mechanoflammation in the articular cartilage in vitro and in vivo and identifies RAMBAs as potential disease-modifying drugs for OA.

Exposure to particulate matter (PM) from ambient air pollution is a well-known risk factor for many lung diseases, but the mechanism(s) for this is not completely understood. Bronchial epithelial cells, which line the airway of the respiratory tract, undergo genome-wide level changes in gene expression and DNA methylation particularly when exposed to fine (<2.5 µm) PM (PM 2.5 ). Although some of these changes have been reported in other studies, a comparison of how different concentrations and duration of exposure affect both the gene transcriptome and DNA methylome has not been done. Here, we exposed BEAS-2B, a bronchial epithelial cell line, to different concentrations of PM 2.5 , and compared how single or repeated doses of PM 2.5 affect both the transcriptome and methylome of cells. Widespread changes in gene expression occurred after cells were exposed to a single treatment of high-concentration (30 µg/cm 2 ) PM 2.5 for 24 h. These genes were enriched in pathways regulating cytokine-cytokine interactions, Mitogen-Activated Protein Kinase (MAPK) signaling, PI3K-Akt signaling, IL6, and P53. DNA methylomic analysis showed that nearly half of the differentially expressed genes were found to also have DNA methylation changes, with just a slightly greater trend toward overall hypomethylation across the genome. Cells exposed to a lower concentration (1 µg/cm 2 ) of PM 2.5 demonstrated a comparable, but more attenuated change in gene expression compared to cells exposed to higher concentrations. There were also many genes affected by lower concentrations of PM 2.5 , but not higher concentrations. Additionally, repeated exposure to PM 2.5 (1 µg/cm 2 ) for seven days resulted in transcriptomic and DNA methylomic changes that were distinct from cells treated with PM 2.5 for only one day. Compared to single exposure, repeated exposure to PM 2.5 caused a more notable degree of hypomethylation across the genome, though certain genes and regions demonstrated increased DNA methylation. The overall increase in hypomethylation, especially with repeated exposure to PM 2.5 , was associated with an increase in expression of ten-eleven translocation enzymes. These data demonstrate how variations in concentration and duration of PM 2.5 exposure induce distinct differences in the transcriptomic and DNA methylomic profile of bronchial epithelial cells, which may have important implications in the development of both acute and chronic lung disease., (© The Author(s) 2021. Published by Oxford University Press.)

An important comorbidity of chronic inflammation is anemia, which may be related to dysregulated activity of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM). Among HSPCs, we found that the receptor for IL-33, ST2, is expressed preferentially and highly on erythroid progenitors. Induction of inflammatory spondyloarthritis in mice increased IL-33 in BM plasma, and IL-33 was required for inflammation-dependent suppression of erythropoiesis in BM. Conversely, administration of IL-33 in healthy mice suppressed erythropoiesis, decreased hemoglobin expression, and caused anemia. Using purified erythroid progenitors in vitro, we show that IL-33 directly inhibited terminal maturation. This effect was dependent on NF-κB activation and associated with altered signaling events downstream of the erythropoietin receptor. Accordingly, IL-33 also suppressed erythropoietin-accelerated erythropoiesis in vivo. These results reveal a role for IL-33 in pathogenesis of anemia during inflammatory disease and define a new target for its treatment., Competing Interests: Disclosures: F. Powrie reported personal fees from GSK, grants from Janssen, personal fees from Genentech, and personal fees from Kintai Therapeutics outside the submitted work. No other disclosures were reported., (© 2020 Swann et al.)

Background: Human papillomavirus (HPV) oncogenes E6, E7, and shorter isoforms of E6 (E6*) are known carcinogenic factors in head and neck squamous cell carcinoma (HNSCC). Little is known regarding E6* functions., Methods: We analyzed RNA-seq data from 68 HNSCC HPV type 16-positive tumors to determine host genes and pathways associated with E6+E7 expression (E6E7) or the percent of full-length E6 (E6%FL). Influence scores of E6E7 and E6%FL were used to test for associations with clinical variables., Results: For E6E7, we recapitulated all major known affected pathways and revealed additional pathways. E6%FL was found to affect mitochondrial processes, and E6%FL influence score was significantly associated with overall survival and tumor size., Conclusions: HPV E6E7 and E6* result in extensive, dose-dependent compensatory effects and dysregulation of key cancer pathways. The switch from E6 to E6* promotes oxidative phosphorylation, larger tumor size, and worse prognosis, potentially serving as a prognostic factor for HPV-positive HNSCC., (© 2020 Wiley Periodicals, Inc.)

The incidence of human papillomavirus (HPV)-related oropharynx cancer has steadily increased over the past two decades and now represents a majority of oropharyngeal cancer cases. Integration of the HPV genome into the host genome is a common event during carcinogenesis that has clinically relevant effects if the viral early genes are transcribed. Understanding the impact of HPV integration on clinical outcomes of head and neck squamous cell carcinoma (HNSCC) is critical for implementing deescalated treatment approaches for HPV + HNSCC patients. RNA sequencing (RNA-seq) data from HNSCC tumors ( n = 84) were used to identify and characterize expressed integration events, which were overrepresented near known head and neck, lung, and urogenital cancer genes. Five genes were recurrent, including CD274 (PD-L1) A significant number of genes detected to have integration events were found to interact with Tp63, ETS, and/or FOX1A. Patients with no detected integration had better survival than integration-positive and HPV - patients. Furthermore, integration-negative tumors were characterized by strongly heightened signatures for immune cells, including CD4 + , CD3 + , regulatory, CD8 + T cells, NK cells, and B cells, compared with integration-positive tumors. Finally, genes with elevated expression in integration-negative specimens were strongly enriched with immune-related gene ontology terms, while upregulated genes in integration-positive tumors were enriched for keratinization, RNA metabolism, and translation. Implications: These findings demonstrate the clinical relevancy of expressed HPV integration, which is characterized by a change in immune response and/or aberrant expression of the integration-harboring cancer-related genes, and suggest strong natural selection for tumor cells with expressed integration events in key carcinogenic genes. Mol Cancer Res; 16(1); 90-102. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Epidemiologic studies and studies in rodents point to potential risks from developmental exposure to BPA on cardiometabolic diseases. Furthermore, it is becoming increasingly evident that the manifestation and severity of adverse outcomes is the result of interaction between developmental insults and the prevailing environment. Consistent with this premise, recent studies in sheep found prenatal BPA treatment prevented the adverse effects of postnatal obesity in inducing hypertension. The gene networks underlying these complex interactions are not known. mRNA-seq of myocardium was performed on four groups of four female sheep to assess the effects of prenatal BPA exposure, postnatal overfeeding and their interaction on gene transcription, pathway perturbations and functional effects. The effects of prenatal exposure to BPA, postnatal overfeeding, and prenatal BPA with postnatal overfeeding all resulted in transcriptional changes (85-141 significant differentially expressed genes). Although the effects of prenatal BPA and postnatal overfeeding did not involve dysregulation of many of the same genes, they affected a remarkably similar set of biological pathways. Furthermore, an additive or synergistic effect was not found in the combined treatment group, but rather prenatal BPA treatment led to a partial reversal of the effects of overfeeding alone. Many genes previously known to be affected by BPA and involved in obesity, hypertension, or heart disease were altered following these treatments, and AP-1, EGR1, and EGFR were key hubs affected by BPA and/or overfeeding. Environ. Mol. Mutagen. 58:4-18, 2017. © 2016 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Purpose: There is substantial heterogeneity within human papillomavirus (HPV)-associated head and neck cancer (HNC) tumors that predispose them to different outcomes; however, the molecular heterogeneity in this subgroup is poorly characterized due to various historical reasons., Experimental Design: We performed unsupervised gene expression clustering on deeply annotated (transcriptome and genome) HPV(+) HNC samples from two cohorts (84 total primary tumors), including 18 HPV(-) HNC samples, to discover subtypes and characterize the differences between subgroups in terms of their HPV characteristics, pathway activity, whole-genome somatic copy number alterations, and mutation frequencies., Results: We identified two distinct HPV(+) subtypes (namely HPV-KRT and HPV-IMU). HPV-KRT is characterized by elevated expression of genes in keratinocyte differentiation and oxidation-reduction process, whereas HPV-IMU has strong immune response and mesenchymal differentiation. The differences in expression are likely connected to the differences in HPV characteristics and genomic changes. HPV-KRT has more genic viral integration, lower E2/E4/E5 expression levels, and higher ratio of spliced to full-length HPV oncogene E6 than HPV-IMU; the subgroups also show differences in copy number alterations and mutations, in particular the loss of chr16q in HPV-IMU and gain of chr3q and PIK3CA mutation in HPV-KRT., Conclusions: Our characterization of two subtypes of HPV(+) HNC tumors provides valuable molecular level information that point to two main carcinogenic paths. Together, these results shed light on stratifications of the HPV(+) HNCs and will help to guide personalized care for HPV(+) HNC patients. Clin Cancer Res; 22(18); 4735-45. ©2016 AACR., Competing Interests: The authors declare there are no potential conflicts of interest., (©2016 American Association for Cancer Research.)

This paper reports the results of replicative analysis of associations of 15 SNPs in a region of 14 genes previously identified in genome-wide association studies (GWAS) with early-onset schizophrenia in Kazakhs. An association of early-onset schizophrenia with genetic markers in three genes (VRK2, KCNB2, and CPVL) was found. An association of rs2312147 in the VRK2 gene with schizophrenia was also previously reported in the Chinese population, so this marker may be considered as possibly race-specific. Two groups consisting of four and six genes demonstrating intergenic epistatic interactions were revealed by multifactor dimensionality reduction methods. The gene ontologies of 14 studied genes were reduced to variants of one molecular function (peptidase activity) and one biological process (positive regulation of biosynthesis processes). Bioinformatic analysis of the protein-protein interactions of products of the genes under study demonstrates that the products of six out of 14 genes may be involved in a single interrelated network, the major connecting link of which is represented by their ubiquitination by the UBC protein.

Co-existence of bronchial asthma (BA) and tuberculosis (TB) is extremely uncommon (dystropic). We assume that this is caused by the interplay between genes involved into specific pathophysiological pathways that arrest simultaneous manifestation of BA and TB. Identification of common and specific genes may be important to determine the molecular genetic mechanisms leading to rare co-occurrence of these diseases and may contribute to the identification of susceptibility genes for each of these dystropic diseases. To address the issue, we propose a new methodological strategy that is based on reconstruction of associative networks that represent molecular relationships between proteins/genes associated with BA and TB, thus facilitating a better understanding of the biological context of antagonistic relationships between the diseases. The results of our study revealed a number of proteins/genes important for the development of both BA and TB.

Demographic and clinical genetic parameters used for simulation modeling of the prevalence of spinocerebellar ataxia type 1 (SCA1) in Yakut populations are described. Demographic parameters of simulated populations and the clinical genetic characteristics of carriers of the SCA1 mutant allele in them have been compared with actual data on Abyisky and Ust-Aldansky uluses of the Republic of Sakha (Yakutia). The results of a series of simulation experiments (without migration or spontaneous mutagenesis) agree with the conclusion that the high prevalence of rate of spinocerebellar ataxia type 1 in Yakut populations may be maintained because of their specific demographic structure. Prediction of the disease prevalence has shown that it will take about 1290 years for natural selection to eliminate the mutation from the population. If medical genetic counseling (MGC) is offered to 1% of the carriers of the mutation, this period will be reduced to 200 years.

Rural and urban settlements of the Republic of Sakha (Yakutia) are characterized by intense marriage migrations: both indigenous residents of different uluses (districts) of the republic (7-30%) and migrants from outside Yakutia (7-29%) contract marriages in five administrative centers analyzed in this respect. All the populations studied are characterized by a wide geographic range of the birthplaces of persons contracted marriages there (from 14 to 24 uluses of Yakutia), without any predominant migration flow from one district to another. The proportion of homolocal marriages among indigenous ethnic groups (Evenks, Evens, and Yukagirs) is as high as 75-100%; this proportion among Yakuts varies from 26 to 68%; heterolocal marriages are more characteristic of Russian immigrants (41-95%). Positive assortative marriages among persons with the same birthplaces have been found in all populations except for Momsky ulus.

A simulation model has been developed for predicting the distribution of trinucleotide repeat expansion diseases in human populations. The interface of the software used to run this model presents the options for simulating natural reproduction of a population, with the population demographic parameters taken into account, and for simulating the appearance of a dynamic mutation in populations, transmission of the mutant gene from parents to offspring, and the effect of the phenotypic expression of the disease (the patients' life expectancy and birthrate) on the transmission of the mutant allele in the patients' families and its accumulation in the population.

Marriage structure has been analyzed in the populations of the administrative centers of five uluses of the Republic of Sakha (Yakutia). The populations studied differ from one another with respect to ethnic composition, namely in the ratio between the indigenous and immigrant populations (the indigenous populations are larger in three uluses), in the proportions of representatives of indigenous ethnic groups among men and women contracting marriages, and in the frequencies of monoethnic and interethnic marriages. Positive assortative marriage among persons of the same ethnic group has been demonstrated. The total inbreeding estimated by isonymy (F(it)) varies from 0 to 0.007576.

The distributions of surnames have been studied in 12 rural ethnic territorial groups of Sakha Republic (Yakutia). The populations studied are characterized by considerable accumulation of individual surnames, the surname spectra of representative of different ethnic groups living in the same area substantially overlapping. The random isonymy, migration index, surname diversity, and the surname distribution redundancy index display geographic and ethnic differences. The isonymy relationship coefficients calculated for representatives of individual ethnic groups (Yakuts, Evens, and Russians) and for total populations of the settlements studied are determined by the geographic distances between the compared populations and the intensity of migrations.

Migration and gametic structure have been analyzed in rural population of Sakha Republic (Yakutia). The populations studied differ from one another in the migration rate and direction, which are determined by the socioeconomic development of the regions and ethnic composition of settlements. A high rate of long-distance migrations and a low rate of migrations within uluses (districts) are characteristic of regions with well-developed industry and transportation and are more characteristic of immigrant than indigenous populations. In rural regions, migrations within uluses are more prevalent. The gametic structure of the youngest age group does not always correspond to the migration activity of previous generations. The migration effectiveness values (the correspondence of migration flows to the gametic structure depending on the geographic origin of the gametes) are different for men and women.

The genetic demographic structure of 12 rural populations from eight uluses of Sakha Republic (Yakutia) has been analyzed. The ethnic, sex, and age composition of the population and the reproductive parameters of women that have completed and have not completed the reproductive period are reported. Crow's indices have been estimated in representatives of three indigenous ethnic groups (Yakuts, Evens, and Evenks).