Chromatin is traditionally viewed as a nuclear entity that regulates gene expression and silencing. However, we recently discovered the presence of cytoplasmic chromatin fragments that pinch off from ...intact nuclei of primary cells during senescence, a form of terminal cell-cycle arrest associated with pro-inflammatory responses. The functional significance of chromatin in the cytoplasm is unclear. Here we show that cytoplasmic chromatin activates the innate immunity cytosolic DNA-sensing cGAS-STING (cyclic GMP-AMP synthase linked to stimulator of interferon genes) pathway, leading both to short-term inflammation to restrain activated oncogenes and to chronic inflammation that associates with tissue destruction and cancer. The cytoplasmic chromatin-cGAS-STING pathway promotes the senescence-associated secretory phenotype in primary human cells and in mice. Mice deficient in STING show impaired immuno-surveillance of oncogenic RAS and reduced tissue inflammation upon ionizing radiation. Furthermore, this pathway is activated in cancer cells, and correlates with pro-inflammatory gene expression in human cancers. Overall, our findings indicate that genomic DNA serves as a reservoir to initiate a pro-inflammatory pathway in the cytoplasm in senescence and cancer. Targeting the cytoplasmic chromatin-mediated pathway may hold promise in treating inflammation-related disorders.
A suite of climate data sets and multiple representations of atmospheric moisture demand are used to calculate many estimates of the self‐calibrated Palmer Drought Severity Index, a proxy for ...near‐surface soil moisture, across California from 1901 to 2014 at high spatial resolution. Based on the ensemble of calculations, California drought conditions were record breaking in 2014, but probably not record breaking in 2012–2014, contrary to prior findings. Regionally, the 2012–2014 drought was record breaking in the agriculturally important southern Central Valley and highly populated coastal areas. Contributions of individual climate variables to recent drought are also examined, including the temperature component associated with anthropogenic warming. Precipitation is the primary driver of drought variability but anthropogenic warming is estimated to have accounted for 8–27% of the observed drought anomaly in 2012–2014 and 5–18% in 2014. Although natural variability dominates, anthropogenic warming has substantially increased the overall likelihood of extreme California droughts.
Key Points
Warming since 1901 caused a significant trend toward drought in California
Recent drought was naturally driven and modestly intensified by warming
Warming has rapidly amplified the probability of severe drought
Enzymes that catalyse CpG methylation in DNA, including the DNA methyltransferases 1 (DNMT1), 3A (DNMT3A) and 3B (DNMT3B), are indispensable for mammalian tissue development and homeostasis
. They ...are also implicated in human developmental disorders and cancers
, supporting the critical role of DNA methylation in the specification and maintenance of cell fate. Previous studies have suggested that post-translational modifications of histones are involved in specifying patterns of DNA methyltransferase localization and DNA methylation at promoters and actively transcribed gene bodies
. However, the mechanisms that control the establishment and maintenance of intergenic DNA methylation remain poorly understood. Tatton-Brown-Rahman syndrome (TBRS) is a childhood overgrowth disorder that is defined by germline mutations in DNMT3A. TBRS shares clinical features with Sotos syndrome (which is caused by haploinsufficiency of NSD1, a histone methyltransferase that catalyses the dimethylation of histone H3 at K36 (H3K36me2)
), which suggests that there is a mechanistic link between these two diseases. Here we report that NSD1-mediated H3K36me2 is required for the recruitment of DNMT3A and maintenance of DNA methylation at intergenic regions. Genome-wide analysis shows that the binding and activity of DNMT3A colocalize with H3K36me2 at non-coding regions of euchromatin. Genetic ablation of Nsd1 and its paralogue Nsd2 in mouse cells results in a redistribution of DNMT3A to H3K36me3-modified gene bodies and a reduction in the methylation of intergenic DNA. Blood samples from patients with Sotos syndrome and NSD1-mutant tumours also exhibit hypomethylation of intergenic DNA. The PWWP domain of DNMT3A shows dual recognition of H3K36me2 and H3K36me3 in vitro, with a higher binding affinity towards H3K36me2 that is abrogated by TBRS-derived missense mutations. Together, our study reveals a trans-chromatin regulatory pathway that connects aberrant intergenic CpG methylation to human neoplastic and developmental overgrowth.
Dementia with Lewy bodies (DLB) is the underlying aetiology of 10-15% of all cases of dementia and as such is a clinically important diagnosis. In the past few years, substantial advances have been ...made in understanding the genetics and pathology of this condition. For example, research has expanded our knowledge of the proteinaceous inclusions that characterize the disease, has provided an appreciation of the role of disease-associated processes such as inflammation and has revealed an association between DLB and genes such as GBA. These insights might have broader relevance to other neurodegenerative conditions and are beginning to be translated into clinical trials. In this Review, we provide clinical insights for the basic scientist and a basic science foundation for the clinician. We discuss the history of the condition; the definition of DLB; the relationship between DLB and other neurodegenerative conditions; current understanding of the pathology, genetics, clinical presentation and diagnosis of DLB; options for treatment; and potential future directions for research.
Severe and persistent 21st-century drought in southwestern North America (SWNA) motivates comparisons to medieval megadroughts and questions about the role of anthropogenic climate change. We use ...hydrological modeling and new 1200-year tree-ring reconstructions of summer soil moisture to demonstrate that the 2000–2018 SWNA drought was the second driest 19-year period since 800 CE, exceeded only by a late-1500s megadrought. The megadrought-like trajectory of 2000–2018 soil moisture was driven by natural variability superimposed on drying due to anthropogenic warming. Anthropogenic trends in temperature, relative humidity, and precipitation estimated from 31 climate models account for 47% (model interquartiles of 35 to 105%) of the 2000–2018 drought severity, pushing an otherwise moderate drought onto a trajectory comparable to the worst SWNA megadroughts since 800 CE.
Small-cell lung cancer (SCLC) is an aggressive malignancy associated with a poor prognosis. First-line treatment has remained unchanged for decades, and a paucity of effective treatment options ...exists for recurrent disease. Nonetheless, advances in our understanding of SCLC biology have led to the development of novel experimental therapies. Poly ADP-ribose polymerase (PARP) inhibitors have shown promise in preclinical models, and are under clinical investigation in combination with cytotoxic therapies and inhibitors of cell-cycle checkpoints.Preclinical data indicate that targeting of histone-lysine N-methyltransferase EZH2, a regulator of chromatin remodelling implicated in acquired therapeutic resistance, might augment and prolong chemotherapy responses. High expression of the inhibitory Notch ligand Delta-like protein 3 (DLL3) in most SCLCs has been linked to expression of Achaete-scute homologue 1 (ASCL1; also known as ASH-1), a key transcription factor driving SCLC oncogenesis; encouraging preclinical and clinical activity has been demonstrated for an anti-DLL3-antibody-drug conjugate. The immune microenvironment of SCLC seems to be distinct from that of other solid tumours, with few tumour-infiltrating lymphocytes and low levels of the immune-checkpoint protein programmed cell death 1 ligand 1 (PD-L1). Nonetheless, immunotherapy with immune-checkpoint inhibitors holds promise for patients with this disease, independent of PD-L1 status. Herein, we review the progress made in uncovering aspects of the biology of SCLC and its microenvironment that are defining new therapeutic strategies and offering renewed hope for patients.
Origin of interannual variability in global mean sea level Hamlington, Benjamin D.; Piecuch, Christopher G.; Reager, John T. ...
Proceedings of the National Academy of Sciences - PNAS,
06/2020, Letnik:
117, Številka:
25
Journal Article
Recenzirano
Odprti dostop
The two dominant drivers of the global mean sea level (GMSL) variability at interannual timescales are steric changes due to changes in ocean heat content and barystatic changes due to the exchange ...of water mass between land and ocean. With Gravity Recovery and Climate Experiment (GRACE) satellites and Argo profiling floats, it has been possible to measure the relative steric and barystatic contributions to GMSL since 2004. While efforts to “close the GMSL budget” with satellite altimetry and other observing systems have been largely successful with regards to trends, the short time period covered by these records prohibits a full understanding of the drivers of interannual to decadal variability in GMSL. One particular area of focus is the link between variations in the El Niño−Southern Oscillation (ENSO) and GMSL. Recent literature disagrees on the relative importance of steric and barystatic contributions to interannual to decadal variability in GMSL. Here, we use a multivariate data analysis technique to estimate variability in barystatic and steric contributions to GMSL back to 1982. These independent estimates explain most of the observed interannual variability in satellite altimeter-measured GMSL. Both processes, which are highly correlated with ENSO variations, contribute about equally to observed interannual GMSL variability. A theoretical scaling analysis corroborates the observational results. The improved understanding of the origins of interannual variability in GMSL has important implications for our understanding of long-term trends in sea level, the hydrological cycle, and the planet’s radiation imbalance.
Summary Background Current systemic treatments for children younger than 6 years with moderate-to-severe atopic dermatitis that is uncontrolled with topical therapies might have suboptimal efficacy ...and safety. Dupilumab is approved for older children and adults with atopic dermatitis and for other type 2 inflammatory conditions. We aimed to evaluate efficacy and safety of dupilumab with concomitant low-potency topical corticosteroids in children aged 6 months to younger than 6 years with moderate-to-severe atopic dermatitis. Methods This randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial was conducted in 31 hospitals, clinics, and academic institutions in Europe and North America. Eligible patients were aged 6 months to younger than 6 years, with moderate-to-severe atopic dermatitis (Investigator's Global Assessment IGA score 3–4) diagnosed according to consensus criteria of the American Academy of Dermatology, and an inadequate response to topical corticosteroids. Patients were randomly assigned (1:1) to subcutaneous placebo or dupilumab (bodyweight ≥5 kg to <15 kg: 200 mg; bodyweight ≥15 kg to <30 kg: 300 mg) every 4 weeks plus low-potency topical corticosteroids (hydrocortisone acetate 1% cream) for 16 weeks. Randomisation was stratified by age, baseline bodyweight, and region. Patient allocation was done via a central interactive web response system, and treatment allocation was masked. The primary endpoint at week 16 was the proportion of patients with IGA score 0–1 (clear or almost clear skin). The key secondary endpoint (coprimary endpoint for the EU and EU reference market) at week 16 was the proportion of patients with at least a 75% improvement from baseline in Eczema Area and Severity Index (EASI-75). Primary analyses were done in the full analysis set (ie, all randomly assigned patients, as randomly assigned) and safety analyses were done in all patients who received any study drug. This study was registered with ClinicalTrials.gov, NCT03346434. Findings Between June 30, 2020, and Feb 12, 2021, 197 patients were screened for eligibility, 162 of whom were randomly assigned to receive dupilumab (n=83) or placebo (n=79) plus topical corticosteroids. At week 16, significantly more patients in the dupilumab group than in the placebo group had IGA 0–1 (23 28% vs three 4%, difference 24% 95% CI 13–34; p<0·0001) and EASI-75 (44 53% vs eight 11%, difference 42% 95% CI 29–55; p<0·0001). Overall prevalence of adverse events was similar in the dupilumab group (53 64% of 83 patients) and placebo group (58 74% of 78 patients). Conjunctivitis incidence was higher in the dupilumab group (four 5%) than the placebo group (none). No dupilumab-related adverse events were serious or led to treatment discontinuation. Interpretation Dupilumab significantly improved atopic dermatitis signs and symptoms versus placebo in children younger than 6 years. Dupilumab was well tolerated and showed an acceptable safety profile, similar to results in older children and adults. Funding Sanofi and Regeneron Pharmaceuticals
Urinary incontinence after prostate treatment (IPT) is one of the few urologic diseases that is iatrogenic, and, therefore, predictable and perhaps preventable. Evaluation of the incontinent patient, ...risk factors for IPT, the assessment of the patient prior to intervention, and a stepwise approach to management are covered in this guideline. Algorithms for patient evaluation, surgical management, and device failure are also provided.
This guideline was developed using a systematic review from the Mayo Clinic Evidence Based Practice Center with additional supplementation by the authors. A research librarian conducted searches from 2000 to December 21
, 2017 using Ovid, MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Databases of Systematic Reviews. Additional references through 12/31/2018 were identified.
This guideline was developed by a multi-disciplinary panel to inform clinicians on the proper assessment of patients with IPT and the safe and effective management of the condition in both surgical and non-surgical contexts. Statements guiding the clinician on proper management of device failure are also included.
Most patients who undergo radical prostatectomy (RP), and some patients who undergo radiation therapy (RT) or surgery for benign prostatic hyperplasia (BPH), will experience IPT. Although non-surgical options, such as pelvic floor muscle exercises (PFME), can hasten continence recovery, patients who remain incontinent at one-year post-procedure, or have severe incontinence at six months, may elect to undergo surgical treatment (e.g. artificial urinary sphincter). Prior to IPT surgery, the risks, benefits, alternatives, and additional likely procedures should be discussed with the patient.
The end of the RNA polymerase II (Pol II) transcription cycle is strictly regulated to prevent interference between neighbouring genes and to safeguard transcriptome integrity
. The accumulation of ...Pol II downstream of the cleavage and polyadenylation signal can facilitate the recruitment of factors involved in mRNA 3'-end formation and termination
, but how this sequence is initiated remains unclear. In a chemical-genetic screen, human protein phosphatase 1 (PP1) isoforms were identified as substrates of positive transcription elongation factor b (P-TEFb), also known as the cyclin-dependent kinase 9 (Cdk9)-cyclin T1 (CycT1) complex
. Here we show that Cdk9 and PP1 govern phosphorylation of the conserved elongation factor Spt5 in the fission yeast Schizosaccharomyces pombe. Cdk9 phosphorylates both Spt5 and a negative regulatory site on the PP1 isoform Dis2
. Sites targeted by Cdk9 in the Spt5 carboxy-terminal domain can be dephosphorylated by Dis2 in vitro, and dis2 mutations retard Spt5 dephosphorylation after inhibition of Cdk9 in vivo. Chromatin immunoprecipitation and sequencing analysis indicates that Spt5 is dephosphorylated as transcription complexes traverse the cleavage and polyadenylation signal, concomitant with the accumulation of Pol II phosphorylated at residue Ser2 of the carboxy-terminal domain consensus heptad repeat
. A conditionally lethal Dis2-inactivating mutation attenuates the drop in Spt5 phosphorylation on chromatin, promotes transcription beyond the normal termination zone (as detected by precision run-on transcription and sequencing
) and is genetically suppressed by the ablation of Cdk9 target sites in Spt5. These results suggest that the transition of Pol II from elongation to termination coincides with a Dis2-dependent reversal of Cdk9 signalling-a switch that is analogous to a Cdk1-PP1 circuit that controls mitotic progression
.
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