The specialized cytokine secretion profiles of T helper (TH) cells are the basis for a focused and efficient immune response. On the twentieth anniversary of the first descriptions of the cytokine ...signals that promote the differentiation of interleukin-9 (IL-9)-secreting T cells, this Review focuses on the extracellular signals and the transcription factors that promote the development of what we now term TH9 cells, which are characterized by the production of this cytokine. We summarize our current understanding of the contribution of TH9 cells to both effective immunity and immunopathological disease, and we propose that TH9 cells could be targeted for the treatment of allergic and autoimmune disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
The gastrointestinal tract is a site of high immune challenge, as it must maintain a delicate balance between tolerating luminal contents and generating an immune response toward pathogens. CD4
T ...cells are key in mediating the host protective and homeostatic responses. Yet, CD4
T cells are also known to be the main drivers of inflammatory bowel disease (IBD) when this balance is perturbed. Many subsets of CD4
T cells have been identified as players in perpetuating chronic intestinal inflammation. Over the last few decades, understanding of how each subset of Th cells plays a role has dramatically increased. Simultaneously, this has allowed development of therapeutic innovation targeting specific molecules rather than broad immunosuppressive agents. Here, we review the emerging evidence of how each subset functions in promoting and sustaining the chronic inflammation that characterizes IBD.
Abstract
Background
The largest West African monkeypox outbreak began September 2017, in Nigeria. Four individuals traveling from Nigeria to the United Kingdom (n = 2), Israel (n = 1), and Singapore ...(n = 1) became the first human monkeypox cases exported from Africa, and a related nosocomial transmission event in the United Kingdom became the first confirmed human-to-human monkeypox transmission event outside of Africa.
Methods
Epidemiological and molecular data for exported and Nigerian cases were analyzed jointly to better understand the exportations in the temporal and geographic context of the outbreak.
Results
Isolates from all travelers and a Bayelsa case shared a most recent common ancestor and traveled to Bayelsa, Delta, or Rivers states. Genetic variation for this cluster was lower than would be expected from a random sampling of genomes from this outbreak, but data did not support direct links between travelers.
Conclusions
Monophyly of exportation cases and the Bayelsa sample, along with the intermediate levels of genetic variation, suggest a small pool of related isolates is the likely source for the exported infections. This may be the result of the level of genetic variation present in monkeypox isolates circulating within the contiguous region of Bayelsa, Delta, and Rivers states, or another more restricted, yet unidentified source pool.
Molecular and epidemiological data from multiple human monkeypox exportations from Nigeria show no direct linkage between travelers; however, limited genetic variation among sequenced viruses point to a possible common source pool or independently acquired infections within a small geographic area.
An Outbreak of Covid-19 on an Aircraft Carrier Kasper, Matthew R; Geibe, Jesse R; Sears, Christine L ...
The New England journal of medicine,
12/2020, Letnik:
383, Številka:
25
Journal Article
Recenzirano
Odprti dostop
In March of 2020, a sailor on the U.S.S.
Theodore Roosevelt
was identified as having SARS-CoV-2 infection. Over the next several weeks, 1271 crew members (27% of the crew) tested positive, the ...majority of whom (77%) had no symptoms at the time of laboratory diagnosis. Twenty-three crew members were hospitalized, and 1 died.
The molecular mechanisms that regulate the rapid transcriptional changes that occur during cytotoxic T lymphocyte (CTL) proliferation and differentiation in response to infection are poorly ...understood. We have utilized ChIP-seq to assess histone H3 methylation dynamics within naive, effector, and memory virus-specific T cells isolated directly ex vivo after influenza A virus infection. Our results show that within naive T cells, codeposition of the permissive H3K4me3 and repressive H3K27me3 modifications is a signature of gene loci associated with gene transcription, replication, and cellular differentiation. Upon differentiation into effector and/or memory CTLs, the majority of these gene loci lose repressive H3K27me3 while retaining the permissive H3K4me3 modification. In contrast, immune-related effector gene promoters within naive T cells lacked the permissive H3K4me3 modification, with acquisition of this modification occurring upon differentiation into effector/memory CTLs. Thus, coordinate transcriptional regulation of CTL genes with related functions is achieved via distinct epigenetic mechanisms.
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•Specific H3K4me3 and H3K27me3 patterns identify functionally related CTL genes•Many CTL-specific transcription factors are bivalent for H3K4me3 and H3K27me3•Bivalent loci largely resolve to a permissive signature rapidly after activation•H3K4me2 identifies a subset of rapidly transcribed immune-specific gene loci
It is unclear how changes in genome-wide histone methylation status regulate distinct transcriptional signatures observed in naive, effector, and memory virus-specific cytotoxic lymphocytes. Russ et al. identify key epigenetic signatures that delineate distinct transcriptional programs that underpin CD8+ T cell differentiation during infection.
Lung cancer is the leading cause of cancer-related deaths in the world, and non-small-cell lung cancer (NSCLC) accounts for 80% of cases.
MicroRNA-21 (
miR-21) expression is increased and predicts ...poor survival in NSCLC. Although miR-21 function has been studied in vitro with cancer cell lines, the role of miR-21 in tumor development in vivo is unknown. We utilize transgenic mice with loss-of-function and gain-of-function
miR-21 alleles combined with a model of NSCLC to determine the role of miR-21 in lung cancer. We show that overexpression of
miR-21 enhances tumorigenesis and that genetic deletion of
miR-21 partially protects against tumor formation. MiR-21 drives tumorigenesis through inhibition of negative regulators of the Ras/MEK/ERK pathway and inhibition of apoptosis.
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► miR-21 overexpression promotes tumorigenesis in a mouse model of NSCLC ► miR-21 deletion suppresses tumorigenesis in a mouse model of NSCLC ► miR-21 targets multiple suppressors of Ras signaling enhancing proliferation ► miR-21 suppresses apoptosis by targeting proapoptotic genes enhancing survival
The BET proteins are major transcriptional regulators and have emerged as new drug targets, but their functional distinction has remained elusive. In this study, we report that the BET family members ...Brd2 and Brd4 exert distinct genomic functions at genes whose transcription they co-regulate during mouse T helper 17 (Th17) cell differentiation. Brd2 is associated with the chromatin insulator CTCF and the cohesin complex to support cis-regulatory enhancer assembly for gene transcriptional activation. In this context, Brd2 binds the transcription factor Stat3 in an acetylation-sensitive manner and facilitates Stat3 recruitment to active enhancers occupied with transcription factors Irf4 and Batf. In parallel, Brd4 temporally controls RNA polymerase II (Pol II) processivity during transcription elongation through cyclin T1 and Cdk9 recruitment and Pol II Ser2 phosphorylation. Collectively, our study uncovers both separate and interdependent Brd2 and Brd4 functions in potentiating the genetic program required for Th17 cell development and adaptive immunity.
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•Brd2 and Brd4 have distinct genomic occupancy in Th17 cells•Brd2 interacts with the CTCF-cohesin complex and the Stat3-Irf4-Batf complex•Brd2-BD2 recruits Stat3 to chromatin through interaction with Stat3-K87ac•Brd2 and Brd4 coordinate functionally to regulate gene transcription in chromatin
Cheung et al. uncover both separate and interdependent Brd2 and Brd4 genomic functions in potentiating the genetic program required for Th17 cell development and adaptive immunity. Brd2 interacts with the transcription factor Stat3 and the chromatin insulator CTCF-cohesin complex to support enhancer assembly, whereas Brd4 temporally controls RNA polymerase II for transcription elongation.
In several areas of the macaque brain, neurons fire during delayed-response tasks at a rate determined by the value of the reward expected at the end of the trial. The activity of these neurons might ...be related to the value of the expected reward or to the degree of motivation induced by expectation of the reward. We describe results indicating that the nature of reward-dependent activity varies across areas. Neuronal activity in orbitofrontal cortex represents the value of the expected reward, whereas neuronal activity in premotor cortex reflects the degree of motivation.
In September, 2017, human monkeypox re-emerged in Nigeria, 39 years after the last reported case. We aimed to describe the clinical and epidemiological features of the 2017–18 human monkeypox ...outbreak in Nigeria.
We reviewed the epidemiological and clinical characteristics of cases of human monkeypox that occurred between Sept 22, 2017, and Sept 16, 2018. Data were collected with a standardised case investigation form, with a case definition of human monkeypox that was based on previously established guidelines. Diagnosis was confirmed by viral identification with real-time PCR and by detection of positive anti-orthopoxvirus IgM antibodies. Whole-genome sequencing was done for seven cases. Haplotype analysis results, genetic distance data, and epidemiological data were used to infer a likely series of events for potential human-to-human transmission of the west African clade of monkeypox virus.
122 confirmed or probable cases of human monkeypox were recorded in 17 states, including seven deaths (case fatality rate 6%). People infected with monkeypox virus were aged between 2 days and 50 years (median 29 years IQR 14), and 84 (69%) were male. All 122 patients had vesiculopustular rash, and fever, pruritus, headache, and lymphadenopathy were also common. The rash affected all parts of the body, with the face being most affected. The distribution of cases and contacts suggested both primary zoonotic and secondary human-to-human transmission. Two cases of health-care-associated infection were recorded. Genomic analysis suggested multiple introductions of the virus and a single introduction along with human-to-human transmission in a prison facility.
This study describes the largest documented human outbreak of the west African clade of the monkeypox virus. Our results suggest endemicity of monkeypox virus in Nigeria, with some evidence of human-to-human transmission. Further studies are necessary to explore animal reservoirs and risk factors for transmission of the virus in Nigeria.
None.
Epstein-Barr virus (EBV) is a complex oncogenic symbiont. The molecular mechanisms governing EBV carcinogenesis remain elusive and the functional interactions between virus and host cells are ...incompletely defined. Here we present a comprehensive map of the host cell-pathogen interactome in EBV-associated cancers. We systematically analyzed RNA sequencing from >1,000 patients with 15 different cancer types, comparing virus and host factors of EBV
to EBV
tissues. EBV preferentially integrated at highly accessible regions of the cancer genome, with significant enrichment in super-enhancer architecture. Twelve EBV transcripts, including LMP1 and LMP2, correlated inversely with EBV reactivation signature. Overexpression of these genes significantly suppressed viral reactivation, consistent with a "virostatic" function. In cancer samples, hundreds of novel frequent missense and nonsense variations in virostatic genes were identified, and variant genes failed to regulate their viral and cellular targets in cancer. For example, one-third of patients with EBV
NK/T-cell lymphoma carried two novel nonsense variants (Q322X, G342X) of
and both variant proteins failed to restrict viral reactivation, confirming loss of virostatic function. Host cell transcriptional changes in response to EBV infection classified tumors into two molecular subtypes based on patterns of IFN signature genes and immune checkpoint markers, such as PD-L1 and IDO1. Overall, these findings uncover novel points of interaction between a common oncovirus and the human genome and identify novel regulatory nodes and druggable targets for individualized EBV and cancer-specific therapies. SIGNIFICANCE: This study provides a comprehensive map of the host cell-pathogen interactome in EBV
malignancies.
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