Optical and Infrared Spectroscopy

Contains research objectives and reports on one research project

Outpatient prescription practices in patients with atrial fibrillation (from the NCDR PINNACLE registry)

This study sought to evaluate inappropriate prescribing practices in an atrial fibrillation (AF) population, as outlined by the 2016 ACC/AHA Clinical Performance and Quality Measures for Adults with Atrial Fibrillation or Atrial Flutter document. The 2016 AF quality measures document specified medications to avoid in certain AF populations, including aspirin and anticoagulant combination therapy in patients without cardiovascular disease, and non-dihydropyridine calcium channel blockers in patients with reduced ejection fraction. Using data from the NCDR PINNACLE registry, a national outpatient cardiology practice registry, we assessed rates of inappropriate prescription of two types of medications among AF outpatients from 5/1/2008-5/1/2016. Overall rates of inappropriate prescription and variation by practice were calculated. Patient and practice factors associated with inappropriate prescription were assessed in adjusted analyses. A total of 107,759 of 658,250 (16.4%) patients without cardiovascular disease were inappropriately prescribed an antiplatelet and anticoagulant together, and 5,731 of 150,079 (3.8%) patients with reduced ejection fraction were inappropriately prescribed a non-dihydropyridine calcium channel blocker. Overall, 14.8% of AF patients were prescribed medications that were not recommended. Both patient and practice factors were associated with inappropriate prescribing, and the adjusted practice-level median odds ratio for inappropriate prescription was 1.70 (95% CI: 1.61-1.82), indicating a 70% likelihood that 2 random practices would treat identical AF patients differently. In a large registry of AF patients treated in cardiology practices, overall rates of inappropriate prescription practices, as defined by the 2016 AF quality measures, were relatively low, but significant practice variation was present

Coal fly ash: Linking immersion freezing behavior and physicochemical particle properties

To date, only a few studies have investigated the potential of coal fly ash particles to trigger heterogeneous ice nucleation in cloud droplets. The presented measurements aim at expanding the sparse dataset and improving process understanding of how physicochemical particle properties can influence the freezing behavior of coal fly ash particles immersed in water. Firstly, immersion freezing measurements were performed with two single particle techniques, i.e., the Leipzig Aerosol Cloud Interaction Simulator (LACIS) and the SPectrometer for Ice Nuclei (SPIN). The effect of suspension time on the efficiency of the coal fly ash particles when immersed in a cloud droplet is analyzed based on the different residence times of the two instruments and employing both dry and wet particle generation. Secondly, two cold-stage setups, one using microliter sized droplets (Leipzig Ice Nucleation Array) and one using nanoliter sized droplets (WeIzmann Supercooled Droplets Observation on Microarray setup) were applied. We found that coal fly ash particles are comparable to mineral dust in their immersion freezing behavior when being dry generated. However, a significant decrease in immersion freezing efficiency was observed during experiments with wet-generated particles in LACIS and SPIN. The efficiency of wet-generated particles is in agreement with the cold-stage measurements. In order to understand the reason behind the deactivation, a series of chemical composition, morphology, and crystallography analyses (single particle mass spectrometry, scanning electron microscopy coupled with energy dispersive X-ray microanalysis, X-ray diffraction analysis) were performed with dry- and wet-generated particles. From these investigations, we conclude that anhydrous CaSO4 and CaO - which, if investigated in pure form, show the same qualitative immersion freezing behavior as observed for dry-generated coal fly ash particles - contribute to triggering heterogeneous ice nucleation at the particle-water interface. The observed deactivation in contact with water is related to changes in the particle surface properties which are potentially caused by hydration of CaSO4 and CaO. The contribution of coal fly ash to the ambient population of ice-nucleating particles therefore depends on whether and for how long particles are immersed in cloud droplets

Identification of SERPINA1 as single marker for papillary thyroid carcinoma through microarray meta analysis and quantification of its discriminatory power in independent validation

<p>Abstract</p> <p>Background</p> <p>Several DNA microarray based expression signatures for the different clinically relevant thyroid tumor entities have been described over the past few years. However, reproducibility of these signatures is generally low, mainly due to study biases, small sample sizes and the highly multivariate nature of microarrays. While there are new technologies available for a more accurate high throughput expression analysis, we show that there is still a lot of information to be gained from data deposited in public microarray databases. In this study we were aiming (1) to identify potential markers for papillary thyroid carcinomas through meta analysis of public microarray data and (2) to confirm these markers in an independent dataset using an independent technology.</p> <p>Methods</p> <p>We adopted a meta analysis approach for four publicly available microarray datasets on papillary thyroid carcinoma (PTC) nodules versus nodular goitre (NG) from N2-frozen tissue. The methodology included merging of datasets, bias removal using distance weighted discrimination (DWD), feature selection/inference statistics, classification/crossvalidation and gene set enrichment analysis (GSEA). External Validation was performed on an independent dataset using an independent technology, quantitative RT-PCR (RT-qPCR) in our laboratory.</p> <p>Results</p> <p>From meta analysis we identified one gene (SERPINA1) which identifies papillary thyroid carcinoma against benign nodules with 99% accuracy (n = 99, sensitivity = 0.98, specificity = 1, PPV = 1, NPV = 0.98). In the independent validation data, which included not only PTC and NG, but all major histological thyroid entities plus a few variants, SERPINA1 was again markedly up regulated (36-fold, p = 1:3*10^-10) in PTC and identification of papillary carcinoma was possible with 93% accuracy (n = 82, sensitivity = 1, specificity = 0.90, PPV = 0.76, NPV = 1). We also show that the extracellular matrix pathway is strongly activated in the meta analysis data, suggesting an important role of tumor-stroma interaction in the carcinogenesis of papillary thyroid carcinoma.</p> <p>Conclusions</p> <p>We show that valuable new information can be gained from meta analysis of existing microarray data deposited in public repositories. While single microarray studies rarely exhibit a sample number which allows robust feature selection, this can be achieved by combining published data using DWD. This approach is not only efficient, but also very cost-effective. Independent validation shows the validity of the results from this meta analysis and confirms SERPINA1 as a potent mRNA marker for PTC in a total (meta analysis plus validation) of 181 samples.</p

Spectroscopic investigations of a semi-synthetic [FeFe] hydrogenase with propane di-selenol as bridging ligand in the binuclear subsite: comparison to the wild type and propane di-thiol variants

[FeFe] Hydrogenases catalyze the reversible conversion of H2 into electrons and protons. Their catalytic site, the H-cluster, contains a generic [4Fe–4S]H cluster coupled to a [2Fe]H subsite [Fe2(ADT)(CO)3(CN)2]2−, ADT = µ(SCH2)2NH. Heterologously expressed [FeFe] hydrogenases (apo-hydrogenase) lack the [2Fe]H unit, but this can be incorporated through artificial maturation with a synthetic precursor [Fe2(ADT)(CO)4(CN)2]2−. Maturation with a [2Fe] complex in which the essential ADT amine moiety has been replaced by CH2 (PDT = propane-dithiolate) results in a low activity enzyme with structural and spectroscopic properties similar to those of the native enzyme, but with simplified redox behavior. Here, we study the effect of sulfur-to-selenium (S-to-Se) substitution in the bridging PDT ligand incorporated in the [FeFe] hydrogenase HydA1 from Chlamydomonas reinhardtii using magnetic resonance (EPR, NMR), FTIR and spectroelectrochemistry. The resulting HydA1-PDSe enzyme shows the same redox behavior as the parent HydA1-PDT. In addition, a state is observed in which extraneous CO is bound to the open coordination site of the [2Fe]H unit. This state was previously observed only in the native enzyme HydA1-ADT and not in HydA1-PDT. The spectroscopic features and redox behavior of HydA1-PDSe, resulting from maturation with [Fe2(PDSe)(CO)4(CN)2]2−, are discussed in terms of spin and charge density shifts and provide interesting insight into the electronic structure of the H-cluster. We also studied the effect of S-to-Se substitution in the [4Fe–4S] subcluster. The reduced form of HydA1 containing only the [4Fe–4Se]H cluster shows a characteristic S = 7/2 spin state which converts back into the S = 1/2 spin state upon maturation with a [2Fe]–PDT/ADT complex

Atrial Fibrillation Genetic Risk and Ischemic Stroke Mechanisms

$\textit{Background and Purpose:}$ Atrial fibrillation (AF) is a leading cause of cardioembolic stroke, but the relationship between AF and noncardioembolic stroke subtypes are unclear. Because AF may be unrecognized, and because AF has a substantial genetic basis, we assessed for predisposition to AF across ischemic stroke subtypes. $\textit{Methods:}$ We examined associations between AF genetic risk and Trial of Org 10172 in Acute Stroke Treatment stroke subtypes in 2374 ambulatory individuals with ischemic stroke and 5175 without from the Wellcome Trust Case-Control Consortium 2 using logistic regression. We calculated AF genetic risk scores using single-nucleotide polymorphisms associated with AF in a previous independent analysis across a range of preselected significance thresholds. $\textit{Results:}$ There were 460 (19.4%) individuals with cardioembolic stroke, 498 (21.0%) with large vessel, 474 (20.0%) with small vessel, and 814 (32.3%) individuals with strokes of undetermined cause. Most AF genetic risk scores were associated with stroke, with the strongest association ($P$=6×10$^{-4}$) attributed to scores of 944 single-nucleotide polymorphisms (each associated with AF at $P$<1×10$^{-3}$) in a previous analysis). Associations between AF genetic risk and stroke were enriched in the cardioembolic stroke subset (strongest $P$=1.2×10$^{-9}$), 944 single-nucleotide polymorphism score). In contrast, AF genetic risk was not significantly associated with noncardioembolic stroke subtypes. $\textit{Conclusions:}$ Comprehensive AF genetic risk scores were specific for cardioembolic stroke. Incomplete workups and subtype misclassification may have limited the power to detect associations with strokes of undetermined pathogenesis. Future studies are warranted to determine whether AF genetic risk is a useful biomarker to enhance clinical discrimination of stroke pathogeneses.Dr. Lubitz is supported by NIH grants K23HL114724 and a Doris Duke Charitable Foundation Clinical Scientist Development Award 2014105. Dr. Traylor is supported by a British Heart Foundation programme grant (RG/16/4/32218). Dr. Ellinor and Benjamin are supported by 1RO1HL092577, R01HL128914. Dr. Ellinor is supported by grants from the National Institutes of Health K24HL105780 and an Established Investigator Award from the American Heart Association (13EIA14220013) and by the Fondation Leducq (14CVD01). Dr. Dichgans and Dr. Malik were supported by grants from the Deutsche Forschungsgemeinschaft (CRC 1123 [B3] and Munich Cluster for Systems Neurology [SyNergy]), the German Federal Ministry of Education and Research (BMBF, e:Med programme e:AtheroSysMed), the FP7/2007-2103 European Union project CVgenes@target (grant agreement No Health-F2-2013-601456), the European Union Horizon2020 projects SVDs@target (grant agreement No 66688) and CoSTREAM (grant agreement No 667375), the Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of Small Vessel Disease of the Brain), the Vascular Dementia Research Foundation, and the Jackstaedt Foundation

Isolation of a Ru(IV) side-on peroxo intermediate in the water oxidation reaction

The electrons that nature uses to reduce CO2 during photosynthesis come from water oxidation at the oxygen-evolving complex of photosystem II. Molecular catalysts have served as models to understand its mechanism, in particular the O-O bond-forming reaction, which is still not fully understood. Here we report a Ru(IV) side-on peroxo complex that serves as a 'missing link' for the species that form after the rate-determining O-O bond-forming step. The Ru(IV) side-on peroxo complex (eta(2)-1(IV)-OO) is generated from the isolated Ru(IV) oxo complex (1(IV)=O) in the presence of an excess of oxidant. The oxidation (IV) and spin state (singlet) of eta(2)-1(IV)-OO were determined by a combination of experimental and theoretical studies. O-18- and H-2-labelling studies evidence the direct evolution of O-2 through the nucleophilic attack of a H2O molecule on the highly electrophilic metal-oxo species via the formation of eta(2)-1(IV)-OO. These studies demonstrate water nucleophilic attack as a viable mechanism for O-O bond formation, as previously proposed based on indirect evidence

The role of ATP and adenosine in the brain under normoxic and ischemic conditions

By taking advantage of some recently synthesized compounds that are able to block ecto-ATPase activity, we demonstrated that adenosine triphosphate (ATP) in the hippocampus exerts an inhibitory action independent of its degradation to adenosine. In addition, tonic activation of P2 receptors contributes to the normally recorded excitatory neurotransmission. The role of P2 receptors becomes critical during ischemia when extracellular ATP concentrations increase. Under such conditions, P2 antagonism is protective. Although ATP exerts a detrimental role under ischemia, it also exerts a trophic role in terms of cell division and differentiation. We recently reported that ATP is spontaneously released from human mesenchymal stem cells (hMSCs) in culture. Moreover, it decreases hMSC proliferation rate at early stages of culture. Increased hMSC differentiation could account for an ATP-induced decrease in cell proliferation. ATP as a homeostatic regulator might exert a different effect on cell trophism according to the rate of its efflux and receptor expression during the cell life cycle. During ischemia, adenosine formed by intracellular ATP escapes from cells through the equilibrative transporter. The protective role of adenosine A1 receptors during ischemia is well accepted. However, the use of selective A1 agonists is hampered by unwanted peripheral effects, thus attention has been focused on A2A and A3 receptors. The protective effects of A2A antagonists in brain ischemia may be largely due to reduced glutamate outflow from neurones and glial cells. Reduced activation of p38 mitogen-activated protein kinases that are involved in neuronal death through transcriptional mechanisms may also contribute to protection by A2A antagonism. Evidence that A3 receptor antagonism may be protective after ischemia is also reported