368 research outputs found
Semisynthetic Nanoreactor for Reversible Single-Molecule Covalent Chemistry
Protein engineering has been used to remodel pores for applications in biotechnology. For example, the heptameric alpha-hemolysin pore (alpha HL) has been engineered to form a nanoreactor to study covalent chemistry at the single -molecule level. Previous work has been confined largely to the chemistry of cysteine side chains or, in one instance, to an irreversible reaction of an unnatural amino acid side chain bearing a terminal alkyne. Here, we present four different alpha HL pores obtained by coupling either two or three fragments by native chemical ligation (NCL). The synthetic alpha HL monomers were folded and incorporated into heptameric pores. The functionality of the pores was validated by hemolysis assays and by single-channel current recording. By using NCL to introduce a ketone amino acid, the nanoreactor approach was extended to an investigation of reversible covalent chemistry on an unnatural side chain at the single -molecule level
The effects of supernovae on the dynamical evolution of binary stars and star clusters
In this chapter I review the effects of supernovae explosions on the
dynamical evolution of (1) binary stars and (2) star clusters.
(1) Supernovae in binaries can drastically alter the orbit of the system,
sometimes disrupting it entirely, and are thought to be partially responsible
for `runaway' massive stars - stars in the Galaxy with large peculiar
velocities. The ejection of the lower-mass secondary component of a binary
occurs often in the event of the more massive primary star exploding as a
supernova. The orbital properties of binaries that contain massive stars mean
that the observed velocities of runaway stars (10s - 100s km s) are
consistent with this scenario.
(2) Star formation is an inherently inefficient process, and much of the
potential in young star clusters remains in the form of gas. Supernovae can in
principle expel this gas, which would drastically alter the dynamics of the
cluster by unbinding the stars from the potential. However, recent numerical
simulations, and observational evidence that gas-free clusters are observed to
be bound, suggest that the effects of supernova explosions on the dynamics of
star clusters are likely to be minimal.Comment: 16 pages, to appear in the 'Handbook of Supernovae', eds. Paul Murdin
and Athem Alsabti. This version replaces an earlier version that contained
several typo
Temporal Evolution of Serum Concentrations of High-Sensitivity Cardiac Troponin During 1 Year After Acute Coronary Syndrome Admission
BACKGROUND: Detailed insights in temporal evolution of high-sensitivity cardiac troponin following acute coronary syndrome
(ACS) are currently missing. We aimed to describe and compare the post-ACS kinetics of high-sensitivity cardiac troponin I
(hs-cTnI) and high-sensitivity cardiac troponin T (hs-cTnT), and to determine their intra- and interindividual variation in clinically
stable patients.
METHODS AND RESULTS: We determined hs-cTnI (Abbott) and hs-cTnT (Roche) in 1507 repeated blood samples, derived from 191
patients with ACS (median, 8/patient) who remained free from adverse cardiac events during 1-year follow-up. Post-ACS kinetics
were studied by linear mixed-effect models. Using the samples collected in the 6- to 12-month post-ACS time frame, patients
were then considered to have chronic coronary syndrome. We determined (differences between) the average hs-cTnI and average
hs-cTnT concentration, and the intra- and interindividual variation for both biomarkers. Compared with hs-cTnT, hs-cTnI peaked
higher (median 3506 ng/L versus 494 ng/L; P<0.001) and was quicker below the biomarker-specific upper reference limit (16 versus 19 days; P<0.001). In the post–6-month samples, hs-cTnI and hs-cTnT showed modest correlation (rspearman=0.60), whereas
the average hs-cTnT concentration was 5 times more likely to be above the upper reference limit than hs-cTnI. The intraindividual
variations of hs-cTnI and hs-cTnT were 14.0% and 18.1%, while the interindividual variations were 94.1% and 75.9%.
CONCLUSIONS: Hs-cTnI peaked higher after ACS and was quicker below the upper reference limit. In the post–6-month samples, hs-cTnI and hs-cTnT were clearly not interchangeable, and average hs-cTnT concentrations were much more often above
the upper reference limit than hs-cTnI. For both markers, the within-patient variation fell largely below beween-patient variation.
REGISTRATION: URL: https://www.trialregister.nl; unique identifiers: NTR1698 and NTR1106
Catalytic enantioselective syn hydration of enones in water using a DNA-based catalyst
The enantioselective addition of water to olefins in an aqueous environment is a common transformation in biological systems, but was beyond the ability of synthetic chemists. Here, we present the first examples of a non-enzymatic catalytic enantioselective hydration of enones, for which we used a catalyst that comprises a copper complex, based on an achiral ligand, non-covalently bound to (deoxy)ribonucleic acid, which is the only source of chirality present under the reaction conditions. The chiral β-hydroxy ketone product was obtained in up to 82% enantiomeric excess. Deuterium-labelling studies demonstrated that the reaction is diastereospecific, with only the syn hydration product formed. So far, this diastereospecific and enantioselective reaction had no equivalent in conventional homogeneous catalysis
Primary Results From the Understanding Outcomes With the S-ICD in Primary Prevention Patients With Low Ejection Fraction (UNTOUCHED) Trial
BACKGROUND: The subcutaneous (S) implantable cardioverter-defibrillator (ICD) is safe and effective for sudden cardiac death prevention. However, patients in previous S-ICD studies had fewer comorbidities, had less left ventricular dysfunction, and received more inappropriate shocks (IAS) than in typical transvenous ICD trials. The UNTOUCHED trial (Understanding Outcomes With the S-ICD in Primary Prevention Patients With Low Ejection Fraction) was designed to evaluate the IAS rate in a more typical, contemporary ICD patient population implanted with the S-ICD using standardized programming and enhanced discrimination algorithms. METHODS: Primary prevention patients with left ventricular ejection fraction ≤35% and no pacing indications were included. Generation 2 or 3 S-ICD devices were implanted and programmed with rate-based therapy delivery for rates ≥250 beats per minute and morphology discrimination for rates ≥200 and <250 beats per minute. Patients were followed for 18 months. The primary end point was the IAS-free rate compared with a 91.6% performance goal, derived from the results for the ICD-only patients in the MADIT-RIT study (Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy). Kaplan-Meier analyses were performed to evaluate event-free rates for IAS, all-cause shock, and complications. Multivariable proportional hazard analysis was performed to determine predictors of end points. RESULTS: S-ICD implant was attempted in 1116 patients, and 1111 patients were included in postimplant follow-up analysis. The cohort had a mean age of 55.8±12.4 years, 25.6% were women, 23.4% were Black, 53.5% had ischemic heart disease, 87.7% had symptomatic heart failure, and the mean left ventricular ejection fraction was 26.4±5.8%. Eighteen-month freedom from IAS was 95.9% (lower confidence limit, 94.8%). Predictors of reduced incidence of IAS were implanting the most recent generation of device, using the 3-incision technique, no history of atrial fibrillation, and ischemic cause. The 18-month all-cause shock-free rate was 90.6% (lower confidence limit, 89.0%), meeting the prespecified performance goal of 85.8%. Conversion success rate for appropriate, discrete episodes was 98.4%. Complication-free rate at 18 months was 92.7%. CONCLUSIONS: This study demonstrates high efficacy and safety with contemporary S-ICD devices and programming despite the relatively high incidence of comorbidities in comparison with earlier S-ICD trials. The inappropriate shock rate (3.1% at 1 year) is the lowest reported for the S-ICD and lower than many transvenous ICD studies using contemporary programming to reduce IAS. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02433379
Timescales of Massive Human Entrainment
The past two decades have seen an upsurge of interest in the collective
behaviors of complex systems composed of many agents entrained to each other
and to external events. In this paper, we extend concepts of entrainment to the
dynamics of human collective attention. We conducted a detailed investigation
of the unfolding of human entrainment - as expressed by the content and
patterns of hundreds of thousands of messages on Twitter - during the 2012 US
presidential debates. By time locking these data sources, we quantify the
impact of the unfolding debate on human attention. We show that collective
social behavior covaries second-by-second to the interactional dynamics of the
debates: A candidate speaking induces rapid increases in mentions of his name
on social media and decreases in mentions of the other candidate. Moreover,
interruptions by an interlocutor increase the attention received. We also
highlight a distinct time scale for the impact of salient moments in the
debate: Mentions in social media start within 5-10 seconds after the moment;
peak at approximately one minute; and slowly decay in a consistent fashion
across well-known events during the debates. Finally, we show that public
attention after an initial burst slowly decays through the course of the
debates. Thus we demonstrate that large-scale human entrainment may hold across
a number of distinct scales, in an exquisitely time-locked fashion. The methods
and results pave the way for careful study of the dynamics and mechanisms of
large-scale human entrainment.Comment: 20 pages, 7 figures, 6 tables, 4 supplementary figures. 2nd version
revised according to peer reviewers' comments: more detailed explanation of
the methods, and grounding of the hypothese
The temporal pattern of immune and inflammatory proteins prior to a recurrent coronary event in post-acute coronary syndrome patients
PURPOSE: We assessed the temporal pattern of 29 immune and inflammatory proteins in post-acute coronary syndrome (ACS) patients, prior to the development of recurrent ACS. METHODS: High-frequency blood sampling was performed in 844 patients admitted for ACS during one-year follow-up. We conducted a case-control study on the 45 patients who experienced reACS (cases) and two matched event-free patients (controls) per case. Olink Proteomics' immunoassay was used to obtain serum levels of the 29 proteins, expressed in an arbitrary unit on the log2-scale (Normalized Protein eXpression, NPX). Linear mixed-effects models were applied to examine the temporal pattern of the proteins, and to illustrate differences between cases and controls. RESULTS: Mean age was 66 ± 12 years and 80% were men. Cases and controls had similar baseline clinical characteristics. During the first 30 days, and after multiple testing correction, cases had significantly higher serum levels of CXCL1 (difference of 1.00 NPX, p = 0.002), CD84 (difference of 0.64 NPX, p = 0.002) and TNFRSF10A (difference of 0.41 NPX, p < 0.001) than controls. After 30 days, serum levels of all 29 proteins were similar in cases and controls. In particular, no increase was observed prior to reACS. CONCLUSIONS: Among 29 immune and inflammatory proteins, CXCL1, CD84 and TNFRSF10A were associated with early reACS after initial ACS-admission
Characterisation of metabolites of the putative cancer chemopreventive agent quercetin and their effect on cyclo-oxygenase activity
Quercetin (3,5,7,3′,4′-pentahydroxyflavone) is a flavone with putative ability to prevent cancer and cardiovascular diseases. Its metabolism was evaluated in rats and human. Rats received quercetin via the intravenous (i.v.) route and metabolites were isolated from the plasma, urine and bile. Analysis was by high-performance liquid chromatography and confirmation of species identity was achieved by mass spectrometry. Quercetin and isorhamnetin, the 3′-O-methyl analogue, were found in both the plasma and urine. In addition, several polar peaks were characterised as sulphated and glucuronidated conjugates of quercetin and isorhamnetin. Extension of the metabolism studies to a cancer patient who had received quercetin as an i.v. bolus showed that (Quercetin removed) isorhamnetin and quercetin 3′-O-sulphate were major plasma metabolites. As a catechol, quercetin can potentially be converted to a quinone and subsequently conjugated with glutathione (GSH). Oxidation of quercetin with mushroom tyrosinase in the presence of GSH furnished GSH conjugates of quercetin, two mono- and one bis-substituted conjugates. However, these species were not found in biomatrices in rats treated with quercetin. As cyclo-oxygenase-2 (COX-2) expression is mechanistically linked to carcinogenesis, we examined whether quercetin and its metabolites can inhibit COX-2 in a human colorectal cancer cell line (HCA-7). Isorhamnetin and its 4′-isomer tamarixetin were potent inhibitors, reflected in a 90% decrease in prostaglandin E-2 (PGE-2) levels, a marker of COX-2 activity. Quercetin was less effective, with a 50% decline. Quercetin 3- and 7-O-sulphate had no effect on PGE-2. The results indicate that quercetin may exert its pharmacological effects, at least in part, via its metabolites
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