Although numerous studies have investigated the association of ambient air pollution with hypertension and blood pressure (BP), the results were inconsistent. We performed a comprehensive systematic ...review and meta-analysis of these studies. Seven international and Chinese databases were searched for studies examining the associations of particulate (diameter<2.5 μm (PM2.5), 2.5–10 μm (PM2.5-10) or >10 μm (PM10)) and gaseous (sulfur dioxide (SO2), nitrogen dioxide (NO2), nitrogen oxides (NOx), ozone (O3), carbon monoxide (CO)) air pollutants with hypertension or BP. Odds ratios (OR), regression coefficients (β) and their 95% confidence intervals were calculated to evaluate the strength of the associations. Subgroup analysis, sensitivity analysis, and meta-regression analysis were also conducted. The overall meta-analysis showed significant associations of long-term exposures to PM2.5 with hypertension (OR = 1.05), and of PM10, PM2.5, and NO2 with DBP (β values: 0.47–0.86 mmHg). In addition, short-term exposures to four (PM10, PM2.5, SO2, NO2), two (PM2.5 and SO2), and four air pollutants (PM10, PM2.5, SO2, and NO2), were significantly associated with hypertension (ORs: 1.05–1.10), SBP (β values: 0.53–0.75 mmHg) and DBP (β values: 0.15–0.64 mmHg), respectively. Stratified analyses showed a generally stronger relationship among studies of men, Asians, North Americans, and areas with higher air pollutant levels. In conclusion, our study indicates a positive association between ambient air pollution and increased BP and hypertension. Geographical and socio-demographic factors may modify the pro-hypertensive effects of air pollutants.
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•Evidence on ambient air pollution and blood pressure (BP) remains inconsistent.•A systematic review identified 100 studies involving ≈0.7 million participants.•Meta-analysis showed a positive association between air pollution and elevated BP.•Study-level geographical and socio-demographic factors modify the association.
Meta-analysis shows significant associations between ambient air pollution and hypertension.
Although recent studies have indicated roles of long non-coding RNAs (lncRNAs) in physiological aspects of cell-type determination and tissue homeostasis, their potential involvement in regulated ...gene transcription programs remains rather poorly understood. The androgen receptor regulates a large repertoire of genes central to the identity and behaviour of prostate cancer cells, and functions in a ligand-independent fashion in many prostate cancers when they become hormone refractory after initial androgen deprivation therapy. Here we report that two lncRNAs highly overexpressed in aggressive prostate cancer, PRNCR1 (also known as PCAT8) and PCGEM1, bind successively to the androgen receptor and strongly enhance both ligand-dependent and ligand-independent androgen-receptor-mediated gene activation programs and proliferation in prostate cancer cells. Binding of PRNCR1 to the carboxy-terminally acetylated androgen receptor on enhancers and its association with DOT1L appear to be required for recruitment of the second lncRNA, PCGEM1, to the androgen receptor amino terminus that is methylated by DOT1L. Unexpectedly, recognition of specific protein marks by PCGEM1-recruited pygopus 2 PHD domain enhances selective looping of androgen-receptor-bound enhancers to target gene promoters in these cells. In 'resistant' prostate cancer cells, these overexpressed lncRNAs can interact with, and are required for, the robust activation of both truncated and full-length androgen receptor, causing ligand-independent activation of the androgen receptor transcriptional program and cell proliferation. Conditionally expressed short hairpin RNA targeting these lncRNAs in castration-resistant prostate cancer cell lines strongly suppressed tumour xenograft growth in vivo. Together, these results indicate that these overexpressed lncRNAs can potentially serve as a required component of castration-resistance in prostatic tumours.
A crucial feature of differentiated cells is the rapid activation of enhancer-driven transcriptional programs in response to signals. The potential contributions of physicochemical properties of ...enhancer assembly in signaling events remain poorly understood. Here we report that in human breast cancer cells, the acute 17β-estradiol-dependent activation of functional enhancers requires assembly of an enhancer RNA-dependent ribonucleoprotein (eRNP) complex exhibiting properties of phase-separated condensates. Unexpectedly, while acute ligand-dependent assembly of eRNPs resulted in enhancer activation sensitive to chemical disruption of phase separation, chronically activated enhancers proved resistant to such disruption, with progressive maturation of eRNPs to a more gel-like state. Acute, but not chronic, stimulation resulted in ligand-induced, condensin-dependent changes in spatial chromatin conformation based on homotypic enhancer association, resulting in cooperative enhancer-activation events. Thus, distinct physicochemical properties of eRNP condensates on enhancers serve as determinants of rapid ligand-dependent alterations in chromosomal architecture and cooperative enhancer activation.
Although eukaryotic nuclei contain distinct architectural structures associated with noncoding RNAs (ncRNAs), their potential relationship to regulated transcriptional programs remains poorly ...understood. Here, we report that methylation/demethylation of Polycomb 2 protein (Pc2) controls relocation of growth-control genes between Polycomb bodies (PcGs) and interchromatin granules (ICGs) in response to growth signals. This movement is the consequence of binding of methylated and unmethylated Pc2 to the ncRNAs
TUG1 and
MALAT1/NEAT2, located in PcGs and ICGs, respectively. These ncRNAs mediate assembly of multiple corepressors/coactivators and can serve to switch mark recognition by “readers” of the histone code. Additionally, binding of
NEAT2 to unmethylated Pc2 promotes E2F1 SUMOylation, leading to activation of the growth-control gene program. These observations delineate a molecular pathway linking the actions of subnuclear structure-specific ncRNAs and nonhistone protein methylation to relocation of transcription units in the three-dimensional space of the nucleus, thus achieving coordinated gene expression programs.
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► Suv39h1 methylates Pc2 that is bound to growth-control genes ► Pc2 interacts with NEAT2 RNA in interchromatin granules ► Methylated Pc2 associates with TUG1 RNA in Polycomb bodies ► Regulated ncRNA-Pc2 interactions are required for activation of growth-control genes
Methylation of Polycomb 2 protein (Pc2) determines its association with noncoding RNAs in distinct subnuclear structures. Growth signals change the methylation status of Pc2, leading to relocalization of Pc2-bound genes within the nucleus and activation of the growth control program.
Global deep‐time plate motion models have traditionally followed a classical rigid plate approach, even though plate deformation is known to be significant. Here we present a global Mesozoic–Cenozoic ...deforming plate motion model that captures the progressive extension of all continental margins since the initiation of rifting within Pangea at ~240 Ma. The model also includes major failed continental rifts and compressional deformation along collision zones. The outlines and timing of regional deformation episodes are reconstructed from a wealth of published regional tectonic models and associated geological and geophysical data. We reconstruct absolute plate motions in a mantle reference frame with a joint global inversion using hot spot tracks for the last 80 million years and minimizing global trench migration velocities and net lithospheric rotation. In our optimized model, net rotation is consistently below 0.2°/Myr, and trench migration scatter is substantially reduced. Distributed plate deformation reaches a Mesozoic peak of 30 × 106 km2 in the Late Jurassic (~160–155 Ma), driven by a vast network of rift systems. After a mid‐Cretaceous drop in deformation, it reaches a high of 48 x 106 km2 in the Late Eocene (~35 Ma), driven by the progressive growth of plate collisions and the formation of new rift systems. About a third of the continental crustal area has been deformed since 240 Ma, partitioned roughly into 65% extension and 35% compression. This community plate model provides a framework for building detailed regional deforming plate networks and form a constraint for models of basin evolution and the plate‐mantle system.
Key Points
We present a plate motion model including distributed deformation from the Triassic to the present
The model includes most major rifts and orogens formed since the breakup of the supercontinent Pangea
Our optimized mantle reference frame minimizes trench migration and net rotation
Loss of functional mitochondrial complex I (MCI) in the dopaminergic neurons of the substantia nigra is a hallmark of Parkinson's disease
. Yet, whether this change contributes to Parkinson's disease ...pathogenesis is unclear
. Here we used intersectional genetics to disrupt the function of MCI in mouse dopaminergic neurons. Disruption of MCI induced a Warburg-like shift in metabolism that enabled neuronal survival, but triggered a progressive loss of the dopaminergic phenotype that was first evident in nigrostriatal axons. This axonal deficit was accompanied by motor learning and fine motor deficits, but not by clear levodopa-responsive parkinsonism-which emerged only after the later loss of dopamine release in the substantia nigra. Thus, MCI dysfunction alone is sufficient to cause progressive, human-like parkinsonism in which the loss of nigral dopamine release makes a critical contribution to motor dysfunction, contrary to the current Parkinson's disease paradigm
.
Most fungi and bacteria degrade plant cell walls by secreting free, complementary enzymes that hydrolyze cellulose; however, some bacteria use large enzymatic assemblies called cellulosomes, which ...recruit complementary enzymes to protein scaffolds. The thermophilic bacterium Caldkellulosiruptor besdi uses an intermediate strategy, secreting many free cellulases that contain multiple catalytic domains. One of these, CelA, comprises a glycoside hydrolase family 9 and a family 48 catalytic domain, as well as three type III cellulose-binding modules. In the saccharification of a common cellulose standard, Avicel, CelA outperforms mixtures of commercially relevant exo-and endoglucanases. From transmission electron microscopy studies of cellulose after incubation with CelA, we report morphological features that suggest that CelA not only exploits the common surface ablation mechanism driven by general cellulase processivity, but also excavates extensive cavities into the surface of the substrate. These results suggest that nature's repertoire of cellulose digestion paradigms remain only partially discovered and understood.
Current equations for estimated glomerular filtration rate (eGFR) that use serum creatinine or cystatin C incorporate age, sex, and race to estimate measured GFR. However, race in eGFR equations is a ...social and not a biologic construct.
We developed new eGFR equations without race using data from two development data sets: 10 studies (8254 participants, 31.5% Black) for serum creatinine and 13 studies (5352 participants, 39.7% Black) for both serum creatinine and cystatin C. In a validation data set of 12 studies (4050 participants, 14.3% Black), we compared the accuracy of new eGFR equations to measured GFR. We projected the prevalence of chronic kidney disease (CKD) and GFR stages in a sample of U.S. adults, using current and new equations.
In the validation data set, the current creatinine equation that uses age, sex, and race overestimated measured GFR in Blacks (median, 3.7 ml per minute per 1.73 m
of body-surface area; 95% confidence interval CI, 1.8 to 5.4) and to a lesser degree in non-Blacks (median, 0.5 ml per minute per 1.73 m
; 95% CI, 0.0 to 0.9). When the adjustment for Black race was omitted from the current eGFR equation, measured GFR in Blacks was underestimated (median, 7.1 ml per minute per 1.73 m
; 95% CI, 5.9 to 8.8). A new equation using age and sex and omitting race underestimated measured GFR in Blacks (median, 3.6 ml per minute per 1.73 m
; 95% CI, 1.8 to 5.5) and overestimated measured GFR in non-Blacks (median, 3.9 ml per minute per 1.73 m
; 95% CI, 3.4 to 4.4). For all equations, 85% or more of the eGFRs for Blacks and non-Blacks were within 30% of measured GFR. New creatinine-cystatin C equations without race were more accurate than new creatinine equations, with smaller differences between race groups. As compared with the current creatinine equation, the new creatinine equations, but not the new creatinine-cystatin C equations, increased population estimates of CKD prevalence among Blacks and yielded similar or lower prevalence among non-Blacks.
New eGFR equations that incorporate creatinine and cystatin C but omit race are more accurate and led to smaller differences between Black participants and non-Black participants than new equations without race with either creatinine or cystatin C alone. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.).
Myocarditis is a potentially fatal complication of immune checkpoint inhibitors (ICI). Sparse data exist on the use of cardiovascular magnetic resonance (CMR) in ICI-associated myocarditis. In this ...study, the CMR characteristics and the association between CMR features and cardiovascular events among patients with ICI-associated myocarditis are presented.
From an international registry of patients with ICI-associated myocarditis, clinical, CMR, and histopathological findings were collected. Major adverse cardiovascular events (MACE) were a composite of cardiovascular death, cardiogenic shock, cardiac arrest, and complete heart block. In 103 patients diagnosed with ICI-associated myocarditis who had a CMR, the mean left ventricular ejection fraction (LVEF) was 50%, and 61% of patients had an LVEF ≥50%. Late gadolinium enhancement (LGE) was present in 48% overall, 55% of the reduced EF, and 43% of the preserved EF cohort. Elevated T2-weighted short tau inversion recovery (STIR) was present in 28% overall, 30% of the reduced EF, and 26% of the preserved EF cohort. The presence of LGE increased from 21.6%, when CMR was performed within 4 days of admission to 72.0% when CMR was performed on Day 4 of admission or later. Fifty-six patients had cardiac pathology. Late gadolinium enhancement was present in 35% of patients with pathological fibrosis and elevated T2-weighted STIR signal was present in 26% with a lymphocytic infiltration. Forty-one patients (40%) had MACE over a follow-up time of 5 months. The presence of LGE, LGE pattern, or elevated T2-weighted STIR were not associated with MACE.
These data suggest caution in reliance on LGE or a qualitative T2-STIR-only approach for the exclusion of ICI-associated myocarditis.
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