Untreated hypothyroidism is associated with acquired von Willebrand syndrome, and hyperthyroidism is associated with increased thrombosis risk. However, the causal effects of thyroid function on ...hemostasis, coagulation, and fibrinolysis are unknown.
In a two-sample Mendelian randomization (MR) study with genome-wide association variants, we assessed causality of genetically predicted hypothyroidism (
= 134,641), normal-range thyrotropin (TSH;
= 54,288) and free thyroxine (fT4) (
= 49,269), hyperthyroidism (
= 51,823), and thyroid peroxidase antibody positivity (
= 25,821) on coagulation (activated partial thromboplastin time, von Willebrand factor VWF, factor VIII FVIII, prothrombin time, factor VII, fibrinogen) and fibrinolysis (D-dimer, tissue plasminogen activator TPA, plasminogen activator inhibitor-1) from the CHARGE Hemostasis Consortium (
= 2583-120,246). Inverse-variance-weighted random effects were the main MR analysis followed by sensitivity analyses. Two-sided
< 0.05 was nominally significant, and
< 0.0011 = 0.05/(5 exposures × 9 outcomes) was Bonferroni significant for the main MR analysis.
Genetically increased TSH was associated with decreased VWF β(SE) = -0.020(0.006),
= 0.001 and with decreased fibrinogen β(SE) = -0.008(0.002),
= 0.001. Genetically increased fT4 was associated with increased VWF β(SE) = 0.028(0.011),
= 0.012. Genetically predicted hyperthyroidism was associated with increased VWF β(SE) = 0.012(0.004),
= 0.006 and increased FVIII β(SE) = 0.013(0.005),
= 0.007. Genetically predicted hypothyroidism and hyperthyroidism were associated with decreased TPA β(SE) = -0.009(0.024),
= 0.024 and increased TPA β(SE) = 0.022(0.008),
= 0.008, respectively. MR sensitivity analyses showed similar direction but lower precision. Other coagulation and fibrinolytic factors were inconclusive.
In the largest genetic studies currently available, genetically increased TSH and fT4 may be associated with decreased and increased synthesis of VWF, respectively. Since Bonferroni correction may be too conservative given the correlation between the analyzed traits, we cannot reject nominal associations of thyroid traits with coagulation or fibrinolytic factors.
Peroxisomes play key roles in energy metabolism, cell signaling, and plant development. A better understanding of these important functions will be achieved with a more complete definition of the ...peroxisome proteome. The isolation of peroxisomes and their separation from mitochondria and other major membrane systems have been significant challenges in the Arabidopsis (Arabidopsis thaliana) model system. In this study, we present new data on the Arabidopsis peroxisome proteome obtained using two new technical advances that have not previously been applied to studies of plant peroxisomes. First, we followed density gradient centrifugation with free-flow electrophoresis to improve the separation of peroxisomes from mitochondria. Second, we used quantitative proteomics to identify proteins enriched in the peroxisome fractions relative to mitochondrial fractions. We provide evidence for peroxisomal localization of 89 proteins, 36 of which have not previously been identified in other analyses of Arabidopsis peroxisomes. Chimeric green fluorescent protein constructs of 35 proteins have been used to confirm their localization in peroxisomes or to identify endoplasmic reticulum contaminants. The distribution of many of these peroxisomal proteins between soluble, membrane-associated, and integral membrane locations has also been determined. This core peroxisomal proteome from nonphotosynthetic cultured cells contains a proportion of proteins that cannot be predicted to be peroxisomal due to the lack of recognizable peroxisomal targeting sequence 1 (PTS1) or PTS2 signals. Proteins identified are likely to be components in peroxisome biogenesis, β-oxidation for fatty acid degradation and hormone biosynthesis, photorespiration, and metabolite transport. A considerable number of the proteins found in peroxisomes have no known function, and potential roles of these proteins in peroxisomal metabolism are discussed. This is aided by a metabolic network analysis that reveals a tight integration of functions and highlights specific metabolite nodes that most probably represent entry and exit metabolites that could require transport across the peroxisomal membrane.
In an unmodified state, positively charged histone N-terminal tails engage nucleosomal DNA in a manner which restricts access to not only the underlying DNA but also key tail residues subject to ...binding and/or modification. Charge-neutralizing modifications, such as histone acetylation, serve to disrupt this DNA–tail interaction, facilitating access to such residues. We previously showed that a polyacetylation-mediated chromatin “switch” governs the read-write capability of H3K4me3 by the MLL1 methyltransferase complex. Here, we discern the relative contributions of site-specific acetylation states along the H3 tail and extend our interrogation to other chromatin modifiers. We show that the contributions of H3 tail acetylation to H3K4 methylation by MLL1 are highly variable, with H3K18 and H3K23 acetylation exhibiting robust stimulatory effects and that this extends to the related H3K4 methyltransferase complex, MLL4. We show that H3K4me1 and H3K4me3 are found preferentially co-enriched with H3 N-terminal tail proteoforms bearing dual H3K18 and H3K23 acetylation (H3{K18acK23ac}). We further show that this effect is specific to H3K4 methylation, while methyltransferases targeting other H3 tail residues (H3K9, H3K27, & H3K36), a methyltransferase targeting the nucleosome core (H3K79), and a kinase targeting a residue directly adjacent to H3K4 (H3T3) are insensitive to tail acetylation. Together, these findings indicate a unique and robust stimulation of H3K4 methylation by H3K18 and H3K23 acetylation and provide key insight into why H3K4 methylation is often associated with histone acetylation in the context of active gene expression.
Background
Thirty to seventy percent of all venous thromboembolism (VTE) events are associated with hospitalization. The absolute and relative risks during and after hospitalization are poorly ...characterized.
Objectives
Quantify the absolute rate and relative risk of VTE during and up to 3 months after medical and surgical hospitalizations.
Patients/Methods
We conducted an observational cohort study between 2010 and 2016 of patients cared for by the University of Vermont (UVM) Health Network's primary care population. Cox proportional hazard models with hospitalization modeled as a time‐varying covariate were used to estimate VTE risk.
Results
Over 4.3 years of follow‐up, 55 220 hospitalizations (156 per 1000 person‐years) and 713 first venous thromboembolism events (2.0 per 1000 person‐years) occurred. Among individuals not recently hospitalized, the rate of venous thromboembolism was 1.4 per 1000 person‐years and 71.8 per 1000 person‐years during hospitalization. During the first, second, and third months after discharge, the rates of venous thromboembolism were 35.1, 11.3, and 5.2 per 1000 person‐years, respectively. Relative to those not recently hospitalized, the age‐ and sex‐adjusted HRs of venous thromboembolism were 38.0 (95% CI 28.0, 51.5) during hospitalization, and 18.4 (95% CI 15.0, 22.6), 6.3 (95% CI 4.3, 9.0), and 3.0 (95% CI 1.7, 5.4) during the first, second, and third months after discharge, respectively. Stratified by medical versus surgical services the rates were similar.
Conclusion
Hospitalization and up to 3 months after discharge were strongly associated with increased venous thromboembolism risk. These data quantify this risk for use in future studies.
Animal microbiomes are assembled predominantly from environmental microbes, yet the mechanisms by which individual symbionts regulate their transmission into hosts remain underexplored. By tracking ...the experimental evolution of Aeromonas veronii in gnotobiotic zebrafish, we identify bacterial traits promoting host colonization. Multiple independently evolved isolates with increased immigration harbored mutations in a gene we named sensor of proline diguanylate cyclase enzyme (SpdE) based on structural, biochemical, and phenotypic evidence that SpdE encodes an amino-acid-sensing diguanylate cyclase. SpdE detects free proline and to a lesser extent valine and isoleucine, resulting in reduced production of intracellular c-di-GMP, a second messenger controlling bacterial motility. Indeed, SpdE binding to amino acids increased bacterial motility and host colonization. Hosts serve as sources of SpdE-detected amino acids, with levels varying based on microbial colonization status. Our work demonstrates that bacteria use chemically regulated motility, or chemokinesis, to sense host-emitted cues that trigger active immigration into hosts.
Display omitted
•Bacteria can regulate motility, via chemokinesis, to trigger immigration into hosts•In Aeromonas, SpdE controls chemokinesis in response to host-emitted amino acid cues•SpdE’s tPAS/dCache crystal structure reveals proline binding specificity•The host microbiome mediates spdE-dependent Aeromonas host colonization
The strategies bacteria use to detect and colonize animal hosts are underexplored. Robinson et al. evolved a zebrafish symbiont, Aeromonas, to become a better colonizer. Their study revealed that Aeromonas senses host-emitted amino acid cues to modulate motility, via a process called chemokinesis, and rapidly immigrate into the zebrafish intestine.
Transferrin (Tf)-functionalized p(HEMA-
ran
-GMA) nanoparticles were designed to incorporate and release a water-soluble combination of three ion channel antagonists, namely zonampanel monohydrate ...(YM872), oxidized adenosine triphosphate (oxATP) and lomerizine hydrochloride (LOM) identified as a promising therapy for secondary degeneration that follows neurotrauma. Coupled with a mean hydrodynamic size of 285 nm and near-neutral surface charge of −5.98 mV, the hydrophilic nature of the functionalized polymeric nanoparticles was pivotal in effectively encapsulating the highly water soluble YM872 and oxATP, as well as lipophilic LOM dissolved in water-based medium, by a back-filling method. Maximum loading efficiencies of 11.8 ± 1.05% (w/w), 13.9 ± 1.50% (w/w) and 22.7 ± 4.00% (w/w) LOM, YM872 and oxATP respectively were reported. To obtain an estimate of drug exposure
in vivo
, drug release kinetics assessment by HPLC was conducted in representative physiological milieu containing 55% (v/v) human serum at 37 °C. In comparison to serum-free conditions, it was demonstrated that the inevitable adsorption of serum proteins on the Tf-functionalized nanoparticle surface as a protein corona impeded the rate of release of LOM and YM872 at both pH 5 and 7.4 over a period of 1 hour. While the release of oxATP from the nanoparticles was detectable for up to 30 minutes under serum-free conditions at pH 7.4, the presence of serum proteins and a slightly acidic environment impaired the detection of the drug, possibly due to its molecular instability. Nevertheless, under representative physiological conditions, all three drugs were released in combination from Tf-functionalized p(HEMA-
ran
-GMA) nanoparticles and detected for up to 20 minutes. Taken together, the study provided enhanced insight into potential physiological outcomes in the presence of serum proteins, and suggests that p(HEMA-
ran
-GMA)-based therapeutic nanoparticles may be promising drug delivery vehicles for CNS therapy.
Transferrin (Tf)-functionalized p(HEMA-
ran
-GMA) nanoparticles were designed to incorporate and release a water-soluble combination of three ion channel antagonists, identified as a promising therapy for secondary degeneration following neurotrauma.
The composition of the protein corona formed on poly(ethylene glycol)-functionalized (PEGylated) poly(glycidyl methacrylate) (PGMA) nanoparticles (NPs) was qualitatively and quantitatively compared ...to the protein corona on non-PEGylated PGMA NPs. Despite the reputation of PEGylated NPs for stealth functionality, we demonstrate the preferential enrichment of specific serum proteins of varied biological function in the protein corona on PEGylated NPs when compared to non-PEGylated NPs. Additionally, we suggest that the base material of polymeric NPs plays a role in the preferential enrichment of select serum proteins to the hard corona.
There are acknowledged difficulties in epidemiological studies to accurately assign exposure to air pollution for large populations, and large, long-term cohort studies have typically relied upon ...data from central monitoring stations. This approach has generally been adequate when populations span large areas or diverse cities. However, when the effects of intra-urban differences in exposure are being studied, the use of these existing central sites are likely to be inadequate for representing spatial variability that exists within an urban area.
As part of the Border Air Quality Strategy (BAQS), an international agreement between the governments of Canada and the United States, a number of air health effects studies are being undertaken by Health Canada and the US EPA. Health Canada's research largely focuses on the chronic exposure of elementary school children to air pollution. The exposure characterization for this population to a variety of air pollutants has been assessed using land-use regression (LUR) models. This approach has been applied in several cities to nitrogen dioxide (NO
2), as an assumed traffic exposure marker. However, the models have largely been developed from limited periods of saturation monitoring data and often only represent one or two seasons. Two key questions from these previous efforts, which are examined in this paper, are: If NO
2 is a traffic marker, what other pollutants, potentially traffic related, might it actually represent? How well is the within city spatial variability of NO
2, and other traffic-related pollutants, characterized by a single saturation monitoring campaign. Input data for the models developed in this paper were obtained across a network of 54 monitoring sites situated across Windsor, Ontario. The pollutants studied were NO
2, sulfur dioxide (SO
2) and volatile organic compounds, which were measured in all four seasons by deploying passive samplers for 2-week periods. Correlations among these pollutants were calculated to assess what other pollutants NO
2 might represent, and correlations across seasons for a given pollutant were determined to assess how much the within-city spatial pattern varies with time. LUR models were then developed for NO
2, SO
2, benzene, and toluene. A multiple regression model including proximity to the Ambassador Bridge (the main Canada—US border crossing point), and proximity to highways and major roads, predicted NO
2 concentrations with an
R
2=0.77. The SO
2 model predictors included distance to the Ambassador Bridge, dwelling density within 1500
m, and Detroit-based SO
2 emitters within 3000
m resulting in a model with an
R
2=0.69. Benzene and toluene LUR models included traffic predictors as well as point source emitters resulting in
R
2=0.73 and 0.46, respectively.
Between season pollutant correlations were all significant although actual concentrations for each site varied by season. This suggests that if one season were to be selected to represent the annual concentrations for a specific site this may lead to a potential under or overestimation in exposure, which could be significant for health research. All pollutants had strong inter-pollutant correlations suggesting that NO
2 could represent SO
2, benzene, and toluene.
The adsorption of serum proteins on the surface of nanoparticles (NPs) delivered into a biological environment has been known to alter NP surface properties and consequently their targeting ...efficiency. In this paper, we use random copolymer (p(HEMA-ran-GMA))-based NPs synthesized using 2-hydroxyethyl methacrylate (HEMA) and glycidyl methacrylate (GMA). We show that serum proteins bind to the NP and that functionalization with antibodies and peptides designed to facilitate NP passage across the blood–brain barrier (BBB) to bind specific cell types is ineffective. In particular, we use systematic in vitro and in vivo analyses to demonstrate that p(HEMA-ran-GMA) NPs functionalized with HIV-1 trans-activating transcriptor peptide (known to cross the BBB) and α neural/glial antigen 2 (NG2) (known for targeting oligodendrocyte precursor cells (OPCs)), individually and in combination, do not specifically target OPCs and are unable to cross the BBB, likely due to the serum protein binding to the NPs.
Concerns over fishing impacts on marine populations and ecosystems have intensified the need to improve ocean management. One increasingly popular market-based instrument for ecological stewardship ...is the use of certification and eco-labeling programs to highlight sustainable fisheries with low environmental impacts. The Marine Stewardship Council (MSC) is the most prominent of these programs. Despite widespread discussions about the rigor of the MSC standards, no comprehensive analysis of the performance of MSC-certified fish stocks has yet been conducted. We compared status and abundance trends of 45 certified stocks with those of 179 uncertified stocks, finding that 74% of certified fisheries were above biomass levels that would produce maximum sustainable yield, compared with only 44% of uncertified fisheries. On average, the biomass of certified stocks increased by 46% over the past 10 years, whereas uncertified fisheries increased by just 9%. As part of the MSC process, fisheries initially go through a confidential pre-assessment process. When certified fisheries are compared with those that decline to pursue full certification after pre-assessment, certified stocks had much lower mean exploitation rates (67% of the rate producing maximum sustainable yield vs. 92% for those declining to pursue certification), allowing for more sustainable harvesting and in many cases biomass rebuilding. From a consumer's point of view this means that MSC-certified seafood is 3-5 times less likely to be subject to harmful fishing than uncertified seafood. Thus, MSC-certification accurately identifies healthy fish stocks and conveys reliable information on stock status to seafood consumers.
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