4,787 research outputs found
Transcription restores DNA repair to heterochromatin, determining regional mutation rates in cancer genomes
Somatic mutations in cancer are more frequent in heterochromatic and late-replicating regions of the genome. We report that regional disparities in mutation density are virtually abolished within transcriptionally silent genomic regions of cutaneous squamous cell carcinomas (cSCCs) arising in an XPC(-/-) background. XPC(-/-) cells lack global genome nucleotide excision repair (GG-NER), thus establishing differential access of DNA repair machinery within chromatin-rich regions of the genome as the primary cause for the regional disparity. Strikingly, we find that increasing levels of transcription reduce mutation prevalence on both strands of gene bodies embedded within H3K9me3-dense regions, and only to those levels observed in H3K9me3-sparse regions, also in an XPC-dependent manner. Therefore, transcription appears to reduce mutation prevalence specifically by relieving the constraints imposed by chromatin structure on DNA repair. We model this relationship among transcription, chromatin state, and DNA repair, revealing a new, personalized determinant of cancer risk
Regulation of tissue-dependent differences in CD8+ T cell apoptosis during viral infection
Virus-specific CD8+ T cells in the lymphoid organs contract at the resolution of virus infections by apoptosis or by dissemination into peripheral tissues, and those residing in nonlymphoid organs, including the peritoneal cavity and fat pads, are more resistant to apoptosis than those in the spleen and lymph nodes. This stability of memory T cells in the nonlymphoid tissues may enhance protection to secondary challenges. Here, we show that lymphocytic choriomeningitis virus (LCMV)-specific CD8+ T cells in nonlymphoid tissues were enriched for memory precursors (expressing high levels of interleukin-7 receptor and low levels of killer cell lectin-like receptor G1 [IL-7Rhi KLRG1lo]) and had higher expression of CD27, CXCR3, and T cell factor-1 (TCF-1), each a marker that is individually correlated with decreased apoptosis. CD8+ T cells in the peritoneal cavity of TCF-1-deficient mice had decreased survival, suggesting a role for TCF-1 in promoting survival in the nonlymphoid tissues. CXCR3+ CD8+ T cells resisted apoptosis and accumulated in the lymph nodes of mice treated with FTY720, which blocks the export of lymph node cells into peripheral tissue. The peritoneal exudate cells (PEC) expressed increased amounts of CXCR3 ligands, CXCL9 and CXCL10, which may normally recruit these nonapoptotic cells from the lymph nodes. In addition, adoptive transfer of splenic CD8+ T cells into PEC or spleen environments showed that the peritoneal environment promoted survival of CD8+ T cells. Thus, intrinsic stability of T cells which are present in the nonlymphoid tissues along with preferential migration of apoptosis-resistant CD8+ T cells into peripheral sites and the availability of tissue-specific factors that enhance memory cell survival may collectively account for the tissue-dependent apoptotic differences.
IMPORTANCE: Most infections are initiated at nonlymphoid tissue sites, and the presence of memory T cells in nonlymphoid tissues is critical for protective immunity in various viral infection models. Virus-specific CD8+ T cells in the nonlymphoid tissues are more resistant to apoptosis than those in lymphoid organs during the resolution and memory phase of the immune response to acute LCMV infection. Here, we investigated the mechanisms promoting stability of T cells in the nonlymphoid tissues. This increased resistance to apoptosis of virus-specific CD8+ T cells in nonlymphoid tissues was due to several factors. Nonlymphoid tissues were enriched in memory phenotype CD8+ T cells, which were intrinsically resistant to apoptosis irrespective of the tissue environment. Furthermore, apoptosis-resistant CD8+ T cells preferentially migrated into the nonlymphoid tissues, where the availability of tissue-specific factors may enhance memory cell survival. Our findings are relevant for the generation of long-lasting vaccines providing protection at peripheral infection sites
De novo loss of function mutations in KIAA2022 are associated with epilepsy and neurodevelopmental delay in females
Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136530/1/cge12854_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136530/2/cge12854.pd
Serial quantification of myocardial infarction tissue heterogeneity during infarct healing by cardiac MRI provides strong characterization of left ventricular remodeling (the NHLBI PROSPECT-CMR Study)
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Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study.
Ulcerative colitis is a chronic inflammatory disease of the colon that presents as diarrhea and gastrointestinal bleeding. We performed a genome-wide association study using DNA samples from 1,052 individuals with ulcerative colitis and preexisting data from 2,571 controls, all of European ancestry. In an analysis that controlled for gender and population structure, ulcerative colitis loci attaining genome-wide significance and subsequent replication in two independent populations were identified on chromosomes 1p36 (rs6426833, combined P = 5.1 x 10(-13), combined odds ratio OR = 0.73) and 12q15 (rs1558744, combined P = 2.5 x 10(-12), combined OR = 1.35). In addition, combined genome-wide significant evidence for association was found in a region spanning BTNL2 to HLA-DQB1 on chromosome 6p21 (rs2395185, combined P = 1.0 x 10(-16), combined OR = 0.66) and at the IL23R locus on chromosome 1p31 (rs11209026, combined P = 1.3 x 10(-8), combined OR = 0.56; rs10889677, combined P = 1.3 x 10(-8), combined OR = 1.29)
Elevated APOBEC mutational signatures implicate chronic injury in etiology of an aggressive head-and-neck squamous cell carcinoma: a case report.
BACKGROUND: Aggressive squamous cell carcinomas (SCCs) present frequently in the context of chronic skin injury occurring in patients with the congenital blistering disease recessive dystrophic epidermolysis bullosa. Recently, these cancers were shown to harbor mutation signatures associated with endogenous deaminases of the active polynucleotide cytosine deaminase family, collectively termed APOBEC, and clock-like COSMIC [Catalogue of Somatic Mutations in Cancer] signatures, which are associated with normal aging and might result from cumulative DNA replication errors. We present a case of a nasal septal SCC arising in the context of recurrent injury, but also modest past tobacco use. Our genetic analysis of this tumor reveals unusually high APOBEC and clock-like but low tobacco-related COSMIC signatures, suggesting that chronic injury may have played a primary role in somatic mutation. This case report demonstrates how signature-based analyses may implicate key roles for certain mutagenic forces in individual malignancies such as head-and-neck SCC, with multiple etiological origins.
CASE PRESENTATION: We report the case of a 43-year-old male former smoker who presented with congestion and swelling following a traumatic nasal fracture. During surgery, the mucosa surrounding the right nasal valve appeared abnormal, and biopsies revealed invasive keratinizing SCC. Frozen section biopsies revealed multiple areas to be positive for SCC. Gene sequencing showed loss of PTEN (exons 2-8), CDKN2A/B and TP53 (exons 8-9), MYC amplification, and BLM S338*. Exome sequencing data also revealed that 36% of mutations matched an APOBEC mutational signature (COSMIC signatures 2 and 13) and 53% of mutations matched the clock-like mutation signature (COSMIC signature 5). These proportions place this tumor in the 90th percentile bearing each signature, independently, in a reference data set combining cutaneous and The Cancer Genome Atlas (TCGA) head and neck SCC data. In contrast, few mutations harbored a tobacco-related COSMIC signature 4, representing about the 10th percentile in our reference SCC data set. The patient was treated with partial rhinectomy with local flap reconstruction, bilateral neck dissection, and adjuvant radiation therapy; the patient remains disease-free to date.
CONCLUSION: Based on comparative mutational signature analysis, we propose that the history of tobacco use and traumatic injury may have collaborated in activating APOBEC enzymes and the clock-like mutational process, ultimately leading to cancer formation. Clinical awareness of the relationship between epithelial injury and tumorigenesis should enhance earlier detection of this particularly aggressive type of cancer
The turbulent destruction of clouds - I. A k-epsilon treatment of turbulence in 2D models of adiabatic shock-cloud interactions
The interaction of a shock with a cloud has been extensively studied in the
literature, where the effects of magnetic fields, radiative cooling and thermal
conduction have been considered. However, the formation of fully developed
turbulence has often been prevented by the artificial viscosity inherent in
hydrodynamical simulations, and a uniform post-shock flow has been assumed in
all previous single-cloud studies. In reality, the flow behind the shock is
also likely to be turbulent, with non-uniform density, pressure and velocity
structure created as the shock sweeps over inhomogenities upstream of the
cloud. To address these twin issues we use a sub-grid compressible k-epsilon
turbulence model to estimate the properties of the turbulence generated in
shock-cloud interactions and the resulting increase in the transport
coefficients that the turbulence brings. A detailed comparison with the output
from an inviscid hydrodynamical code puts these new results into context.
We find that cloud destruction in inviscid and k-epsilon models occurs at
roughly the same speed when the post-shock flow is smooth and when the density
contrast between the cloud and inter-cloud medium is less than 100. However,
there are increasing and significant differences as this contrast increases.
Clouds subjected to strong ``buffeting'' by a highly turbulent post-shock
environment are destroyed significantly quicker. Additional calculations with
an inviscid code where the post-shock flow is given random, grid-scale, motions
confirms the more rapid destruction of the cloud.
Our results clearly show that turbulence plays an important role in
shock-cloud interactions, and that environmental turbulence adds a new
dimension to the parameter space which has hitherto been studied (abridged).Comment: 31 pages, 22 figures, accepted for publication in MNRA
Relative entropies, suitable weak solutions, and weak strong uniqueness for the compressible Navier-Stokes system
We introduce the notion of relative entropy for the weak solutions of the
compressible Navier-Stokes system. We show that any finite energy weak solution
satisfies a relative entropy inequality for any pair of sufficiently smooth
test functions. As a corollary we establish weak-strong uniqueness principle
for the compressible Navier-Stokes system
Hα Reverberation Mapping of the Intermediate-mass Active Galactic Nucleus in NGC 4395
We present the results of a high-cadence spectroscopic and imaging monitoring campaign of the active galactic nucleus (AGN) of NGC 4395. High signal-to-noise-ratio spectra were obtained at the Gemini-N 8 m telescope using the GMOS integral field spectrograph (IFS) on 2019 March 7 and at the Keck I 10 m telescope using the Low-Resolution Imaging Spectrometer with slit masks on 2019 March 3 and April 2. Photometric data were obtained with a number of 1 m-class telescopes during the same nights. The narrow-line region (NLR) is spatially resolved; therefore, its variable contributions to the slit spectra make the standard procedure of relative flux calibration impractical. We demonstrate that spatially resolved data from the IFS can be effectively used to correct the slit-mask spectral light curves. While we obtained no reliable lag owing to the lack of a strong variability pattern in the light curves, we constrain the broad-line time lag to be less than 3 hr, consistent with the photometric lag of ∼80 minutes reported by Woo et al. By exploiting the high-quality spectra, we measure the second moment of the broad component of the Hα emission line to be 586 ± 19 km s−1, superseding the lower value reported by Woo et al. Combining the revised line dispersion and the photometric time lag, we update the black hole mass to (1.7 ± 0.3) × 104 M⊙
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