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In principle, evolutionary outcomes could be largely predicted if all of the relevant physicochemical variants of a particular protein function under selection were known and integrated into an appropriate physiological model. We have tested this principle by generating a family of variants of the tetracycline resistance protein TetX2 and identified the physicochemical properties most correlated with organismal fitness. Surprisingly, small changes in the K ₘ₍MCN₎, less than twofold, were sufficient to produce highly successful adaptive mutants over clinically relevant drug concentrations. We then built a quantitative model directly relating the in vitro physicochemical properties of the mutant enzymes to the growth rates of bacteria carrying a single chromosomal copy of the tet(X2) variants over a wide range of minocycline (MCN) concentrations. Importantly, this model allows the prediction of enzymatic properties directly from cellular growth rates as well as the physicochemical-fitness landscape of TetX2. Using experimental evolution and deep sequencing to monitor the allelic frequencies of the seven most biochemically efficient TetX2 mutants in 10 independently evolving populations, we showed that the model correctly predicted the success of the two most beneficial variants tet(X2) T₂₈₀A and tet(X2) N₃₇₁I. The structure of the most efficient variant, TetX2 T₂₈₀A, in complex with MCN at 2.7 Å resolution suggests an indirect effect on enzyme kinetics. Taken together, these findings support an important role for readily accessible small steps in protein evolution that can, in turn, greatly increase the fitness of an organism during natural selection.

DNA methylation (DNAm) provides a window to characterize the impacts of environmental exposures and the biological aging process. Epigenetic clocks are often trained on DNAm using penalized regression of CpG sites, but recent evidence suggests potential benefits of training epigenetic predictors on principal components. We developed a pipeline to simultaneously train three epigenetic predictors; a traditional CpG Clock, a PCA Clock, and a SuperLearner PCA Clock (SL PCA). We gathered publicly available DNAm datasets to generate i) a novel childhood epigenetic clock, ii) a reconstructed Hannum adult blood clock, and iii) as a proof of concept, a predictor of polybrominated biphenyl exposure using the three developmental methodologies. We used correlation coefficients and median absolute error to assess fit between predicted and observed measures, as well as agreement between duplicates. The SL PCA clocks improved fit with observed phenotypes relative to the PCA clocks or CpG clocks across several datasets. We found evidence for higher agreement between duplicate samples run on alternate DNAm arrays when using SL PCA clocks relative to traditional methods. Analyses examining associations between relevant exposures and epigenetic age acceleration (EAA) produced more precise effect estimates when using predictions derived from SL PCA clocks. We introduce a novel method for the development of DNAm-based predictors that combines the improved reliability conferred by training on principal components with advanced ensemble-based machine learning. Coupling SuperLearner with PCA in the predictor development process may be especially relevant for studies with longitudinal designs utilizing multiple array types, as well as for the development of predictors of more complex phenotypic traits.

Exposure to ambient air pollution has significant adverse health effects; however, whether air pollution is associated with urological cancer is largely unknown. We conduct a systematic review and meta-analysis with epidemiological studies, showing that a 5 μg/m 3 increase in PM 2.5 exposure is associated with a 6%, 7%, and 9%, increased risk of overall urological, bladder, and kidney cancer, respectively; and a 10 μg/m 3 increase in NO 2 is linked to a 3%, 4%, and 4% higher risk of overall urological, bladder, and prostate cancer, respectively. Were these associations to reflect causal relationships, lowering PM 2.5 levels to 5.8 μg/m 3 could reduce the age-standardized rate of urological cancer by 1.5 ~ 27/100,000 across the 15 countries with the highest PM 2.5 level from the top 30 countries with the highest urological cancer burden. Implementing global health policies that can improve air quality could potentially reduce the risk of urologic cancer and alleviate its burden. Whether air pollufion is associated with urological cancer is largely unknown. In this study, the authors reveal correlafions between air pollufion and urological cancer risk: an increase of 5 μg/m 3 in PM 2.5 and 10 μg/m 3 in NO 2 would raise risks by 6-9% and 3-4%, respecfively; while lowering PM 2.5 to 5.8 μg/m 3 may reduce urological cancer burden.

The nasal cellular epigenome may serve as biomarker of airway disease and environmental response. Here we collect nasal swabs from the anterior nares of 547 children (mean-age 12.9 y), and measure DNA methylation (DNAm) with the Infinium MethylationEPIC BeadChip. We perform nasal Epigenome-Wide Association analyses (EWAS) of current asthma, allergen sensitization, allergic rhinitis, fractional exhaled nitric oxide (FeNO) and lung function. We find multiple differentially methylated CpGs (FDR < 0.05) and Regions (DMRs; ≥ 5-CpGs and FDR < 0.05) for asthma (285-CpGs), FeNO (8,372-CpGs; 191-DMRs), total IgE (3-CpGs; 3-DMRs), environment IgE (17-CpGs; 4-DMRs), allergic asthma (1,235-CpGs; 7-DMRs) and bronchodilator response (130-CpGs). Discovered DMRs annotated to genes implicated in allergic asthma, Th2 activation and eosinophilia ( EPX , IL4, IL13 ) and genes previously associated with asthma and IgE in EWAS of blood ( ACOT7, SLC25A25 ). Asthma, IgE and FeNO were associated with nasal epigenetic age acceleration. The nasal epigenome is a sensitive biomarker of asthma, allergy and airway inflammation. Epigenetic differences in nasal epithelium have been proposed as a biomarker for lower airway disease and asthma. Here, in epigenome-wide association studies for asthma and other airway traits using nasal swabs, the authors identify differentially methylated CpGs that highlight genes involved in T H 2 response.

The diversification of the three major marine faunas during the Phanerozoic was intimately coupled to the evolution of the biogeochemical cycles of carbon and nutrients via nutrient runoff from land and the diversification of phosphorus-rich phytoplankton. Nutrient input to the oceans has previously been demonstrated to have occurred in response to orogeny and fueling marine diversification. Although volcanism has typically been associated with extinction, the eruption of continental Large Igneous Provinces (LIPs) is also a very significant, but previously overlooked, source of phosphorus involved in the diversification of the marine biosphere. We demonstrate that phosphorus input to the oceans peaked repeatedly following the eruption and weathering of LIPs, stimulating the diversification of nutrient-rich calcareous and siliceous phytoplankton at the base of marine food webs that in turn helped fuel diversification at higher levels. These developments were likely furthered by the evolution of terrestrial floras. Results for the Meso-Cenozoic hold implications for the Paleozoic Era. Early-to-middle Paleozoic diversity was, in contrast to the Meso-Cenozoic, limited by nutrient-poor phytoplankton resulting from less frequent tectonism and poorly-developed terrestrial floras. Nutrient runoff and primary productivity during the Permo-Carboniferous likely increased, based on widespread orogeny, the spread of deeper-rooting forests, the fossil record of phytoplankton, and biogeochemical indices. Our results suggest that marine biodiversity on geologic time scales is unbounded (unlimited), provided sufficient habitat, nutrients, and nutrient-rich phytoplankton are also available in optimal amounts and on optimal timescales.

ObjectiveThis study aims to evaluate the effects of exposure time and irradiance on the dentin bonding properties (microtensile bond strength (μTBS) and nanoleakage (NL)) of the Clearfil Universal Bond Quick (CUQ) adhesive and Scotchbond Universal Adhesive (SBU) immediately and after 2 years of water storage.Material and methodsHence, 128 human molars were randomly assigned to 16 groups based on adhesive strategy, irradiance/exposure times, and storage time for each universal adhesive tested. The adhesives were applied using the etch-and-rinse and self-etch strategies and were light-cured using four different irradiance/exposure times: 1400 mW/cm2 for 5 s (1400 × 5), 1400 mW/cm2 for 10 s (1400 × 10), 3200 mW/cm2 for 5 s (3200 × 5), and 3200 mW/cm2 for 10 s (3200 × 10). Then, each sample was restored and sectioned into a resin-dentin bonded stick to be tested for μTBS and NL (immediately and after 2 years of water storage). The mean μTBS and NL of all resin-dentin bonded sticks from the same hemi-tooth (factor time) were statistically analyzed using a three-way ANOVA and Tukey’s test (a = 0.05).ResultsDespite a significant decrease in the μTBS values for all groups after 2 years of water storage, the 3200 × 5 group showed higher μTBS values, whereas the 3200 × 10 group showed lower μTBS values for both universal adhesives tested. Although a significant increase in the NL values was observed for all groups after 2 years of water storage, the 3200 × 10 group showed higher NL values than the other groups (p < 0.001).ConclusionResults indicate that light-curing the adhesive layer with 14–16 J/cm2 led to an improvement in the stability of the resin-dentin adhesive interface. A longer exposure time (10 s) coupled with a higher irradiance (3200 mW/cm2) resulted in a greater degree of degradation of the adhesive interface.Clinical significanceTo guarantee better stability of the adhesive interface, clinicians could be preferred a light-cured universal adhesive layer with 14–16 J/cm2. Higher irradiances should be avoided.

This in vitro study aimed to evaluate the effect of different bonding strategies on the micro-shear bond strength (μSBS) of luting agents to CAD–CAM composites. Surface scanning electron microscopy (SEM) and spectroscopy by energy-dispersive X-ray spectroscopy (EDS) were performed to analyze the surfaces of the composite before and after bonding treatment. Three CAD–CAM composites were evaluated: Lava Ultimate restorative (LU), Brava Blocks (BR), and Vita Enamic (VE). The LU and BR surfaces were sandblasted using aluminum oxide, while the VE surfaces were etched using a 5% hydrofluoric acid gel according to the manufacturers’ recommendations. All surfaces were subjected to the following bonding strategies (n = 15): adhesive with silane and MDP (ScotchBond Universal, 3M Oral Care, St Paul, MI, USA); adhesive with MDP (Ambar Universal, FGM, Joinville, Brazil); adhesive without silane or MDP (Prime&Bond Elect, Dentsply Sirona, Charlotte, NC, USA), pure silane without MDP (Angelus, Londrina, Brazil), and pure silane with MDP (Monobond N, Ivoclar Vivadent, Schaan, Liechtenstei). Afterwards, tygons were filled with RelyX Ultimate (3M Oral Care), AllCem (FGM), or Enforce (Dentsply Sirona), which were light-cured and subjected to the μSBS test. Data were analyzed using two-way ANOVA and Bonferroni’s post hoc test (α = 0.05). Additional blocks (n = 15) were subjected to scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDS) before and after the surface treatment. The μSBS values on VE surfaces were higher than those observed on LU and BR surfaces (p < 0.001). Silane without MDP (Allcem) promoted the highest μSBS values, while silane with MDP (RelyX Ultimate) provided the highest values among all bonding strategies (p < 0.001). Enforce promoted no significant difference in μSBS values. SEM and EDS analyses detected noticeable changes to the surface morphology and composition after the surface treatment. The effectiveness of the bonding strategy may vary according not only to the CAD–CAM composite but also to resin cement/bonding agent/silane used.

Prenatal exposure to mercury, a known neurotoxic metal, is associated with lower cognitive performance during childhood. Disruption of fetal epigenetic programming could explain mercury’s neurodevelopmental effects. We screened for epigenome-wide methylation differences associated with maternal prenatal blood mercury levels in 321 cord blood DNA samples and examined the persistence of these alterations during early (n = 75; 2.9–4.9 years) and mid-childhood (n = 291; 6.7–10.5 years). Among males, prenatal mercury levels were associated with lower regional cord blood DNA methylation at the Paraoxonase 1 gene ( PON1 ) that persisted in early childhood and was attenuated in mid-childhood blood. Cord blood methylation at the PON1 locus predicted lower cognitive test scores measured during early childhood. Methylation at the PON1 locus was associated with PON1 expression in an independent set of cord blood samples. The observed persistent epigenetic disruption of the PON1 gene may modulate mercury toxicity in humans and might serve as a biomarker of exposure and disease susceptibility.

Smoking-associated DNA methylation (DNAm) signatures are reproducible among studies of mostly European descent, with mixed evidence if smoking accelerates epigenetic aging and its relationship to longevity. We evaluated smoking-associated DNAm signatures in the Costa Rican Study on Longevity and Healthy Aging (CRELES), including participants from the high longevity region of Nicoya. We measured genome-wide DNAm in leukocytes, tested Epigenetic Age Acceleration (EAA) from five clocks and estimates of telomere length (DNAmTL), and examined effect modification by the high longevity region. 489 participants had a mean (SD) age of 79.4 (10.8) years, and 18% were from Nicoya. Overall, 7.6% reported currently smoking, 35% were former smokers, and 57.4% never smoked. 46 CpGs and five regions (e.g. AHRR , SCARNA6 / SNORD39 , SNORA20 , and F2RL3 ) were differentially methylated for current smokers. Former smokers had increased Horvath’s EAA (1.69-years; 95% CI 0.72, 2.67), Hannum’s EAA (0.77-years; 95% CI 0.01, 1.52), GrimAge (2.34-years; 95% CI1.66, 3.02), extrinsic EAA (1.27-years; 95% CI 0.34, 2.21), intrinsic EAA (1.03-years; 95% CI 0.12, 1.94) and shorter DNAmTL (− 0.04-kb; 95% CI − 0.08, − 0.01) relative to non-smokers. There was no evidence of effect modification among residents of Nicoya. Our findings recapitulate previously reported and novel smoking-associated DNAm changes in a Latino cohort.

The diversity of marine life has varied throughout the past 500 million years. Statistical analyses suggest that fluctuations in the availability of marine nutrients has been one important regulator of rates of origination during this time. Throughout the Phanerozoic eon (∼542 Myr ago to the present), the diversity of marine organisms has varied. These changes are fairly well resolved 1 , but the controls on origination and diversification are less well understood. Changes in origination rates are thought to arise from a complex interplay between biological forces such as competition and predation 2 , phytoplankton stoichiometry 3 and bioturbation 3 and abiotic controls such as environmental setting 4 , temperature 5 , 6 , sea level 7 and nutrient availability 8 . Here we statistically assess relationships between records of environmental conditions 9 , 10 , 11 , 12 , 13 , 14 and global marine origination rates 2 during the Phanerozoic. We find significant positive correlations between changes in origination rates and variations in indicators of continental weathering ( 87 Sr/ 86 Sr) and phosphorus recycling ( δ 34 S), as well as a significant negative correlation between variability in origination rates and eustatic sea level. We suggest that continental weathering, phosphorus recycling and sea level—through the exposure of the continental shelf area to erosion—are all controls on the availability of marine nutrients. We therefore propose that over secular timescales, nutrient availability, as controlled by continental weathering and phosphorus recycling, is an important regulator of genus-level origination in the marine realm, with periods of increased nutrient availability associated with higher origination rates.