448 research outputs found
Protein disulfide-isomerase interacts with a substrate protein at all stages along its folding pathway
In contrast to molecular chaperones that couple protein folding to ATP hydrolysis, protein disulfide-isomerase (PDI) catalyzes protein folding coupled to formation of disulfide bonds (oxidative folding). However, we do not know how PDI distinguishes folded, partly-folded and unfolded protein substrates. As a model intermediate in an oxidative folding pathway, we prepared a two-disulfide mutant of basic pancreatic trypsin inhibitor (BPTI) and showed by NMR that it is partly-folded and highly dynamic. NMR studies show that it binds to PDI at the same site that binds peptide ligands, with rapid binding and dissociation kinetics; surface plasmon resonance shows its interaction with PDI has a Kd of ca. 10−5 M. For comparison, we characterized the interactions of PDI with native BPTI and fully-unfolded BPTI. Interestingly, PDI does bind native BPTI, but binding is quantitatively weaker than with partly-folded and unfolded BPTI. Hence PDI recognizes and binds substrates via permanently or transiently unfolded regions. This is the first study of PDI's interaction with a partly-folded protein, and the first to analyze this folding catalyst's changing interactions with substrates along an oxidative folding pathway. We have identified key features that make PDI an effective catalyst of oxidative protein folding – differential affinity, rapid ligand exchange and conformational flexibility
Founder mutations in the Netherlands: familial idiopathic ventricular fibrillation and DPP6
Quantifying measures to limit wind driven resuspension of sediments for improvement of the ecological quality in some shallow Dutch lakes
Although phosphorus loadings are considered the main pressure for most shallow lakes, wind-driven resuspension can cause additional problems for these aquatic ecosystems. We quantified the potential effectiveness of measures to reduce the contribution of resuspended sediments, resulting from wind action, to the overall light attenuation for three comparable shallow peat lakes with poor ecological status in the Netherlands: Loosdrecht, Nieuwkoop, and Reeuwijk (1.8–2.7 m depth, 1.6–2.5 km fetch). These measures are: 1. wave reducing barriers, 2. water level fluctuations, 3. capping of the sediment with sand, and 4. combinations of above. Critical shear stress of the sediments for resuspension (Vcrit), size distribution, and optical properties of the suspended material were quantified in the field (June 2009) and laboratory. Water quality monitoring data (2002–2009) showed that light attenuation by organic suspended matter in all lakes is high. Spatial modeling of the impact of these measures showed that in Lake Loosdrecht limiting wave action can have significant effects (reductions from 6% exceedance to 2% exceedance of Vcrit), whereas in Lake Nieuwkoop and Lake Reeuwijk this is less effective. The depth distribution and shape of Lake Nieuwkoop and Lake Reeuwijk limit the role of wind-driven resuspension in the total suspended matter concentration. Although the lakes are similar in general appearance (origin, size, and depth range) measures suitable to improve their ecological status differ. This calls for care when defining the programme of measures to improve the ecological status of a specific lake based on experience from other lakes.
Genome-wide analyses for personality traits identify six genomic loci and show correlations with psychiatric disorders
Personality is influenced by genetic and environmental factors1
and associated with mental health. However, the underlying
genetic determinants are largely unknown. We identified six
genetic loci, including five novel loci2,3, significantly associated
with personality traits in a meta-analysis of genome-wide
association studies (N = 123,132–260,861). Of these genomewide
significant loci, extraversion was associated with variants
in WSCD2 and near PCDH15, and neuroticism with variants
on chromosome 8p23.1 and in L3MBTL2. We performed a
principal component analysis to extract major dimensions
underlying genetic variations among five personality traits
and six psychiatric disorders (N = 5,422–18,759). The first
genetic dimension separated personality traits and psychiatric
disorders, except that neuroticism and openness to experience
were clustered with the disorders. High genetic correlations
were found between extraversion and attention-deficit–
hyperactivity disorder (ADHD) and between openness and
schizophrenia and bipolar disorder. The second genetic
dimension was closely aligned with extraversion–introversion
and grouped neuroticism with internalizing psychopathology
(e.g., depression or anxiety)
The role of negative CO2 emissions for reaching 2 °C—insights from integrated assessment modelling
Wall roughness induces asymptotic ultimate turbulence
Turbulence is omnipresent in Nature and technology, governing the transport
of heat, mass, and momentum on multiple scales. For real-world applications of
wall-bounded turbulence, the underlying surfaces are virtually always rough;
yet characterizing and understanding the effects of wall roughness for
turbulence remains a challenge, especially for rotating and thermally driven
turbulence. By combining extensive experiments and numerical simulations, here,
taking as example the paradigmatic Taylor-Couette system (the closed flow
between two independently rotating coaxial cylinders), we show how wall
roughness greatly enhances the overall transport properties and the
corresponding scaling exponents. If only one of the walls is rough, we reveal
that the bulk velocity is slaved to the rough side, due to the much stronger
coupling to that wall by the detaching flow structures. If both walls are
rough, the viscosity dependence is thoroughly eliminated in the boundary layers
and we thus achieve asymptotic ultimate turbulence, i.e. the upper limit of
transport, whose existence had been predicted by Robert Kraichnan in 1962
(Phys. Fluids {\bf 5}, 1374 (1962)) and in which the scalings laws can be
extrapolated to arbitrarily large Reynolds numbers
Renal artery stenosis-when to screen, what to stent?
Renal artery stensosis (RAS) continues to be a problem for clinicians, with no clear consensus on how to investigate and assess the clinical significance of stenotic lesions and manage the findings. RAS caused by fibromuscular dysplasia is probably commoner than previously appreciated, should be actively looked for in younger hypertensive patients and can be managed successfully with angioplasty. Atheromatous RAS is associated with increased incidence of cardiovascular events and increased cardiovascular mortality, and is likely to be seen with increasing frequency. Evidence from large clinical trials has led clinicians away from recommending interventional revascularisation towards aggressive medical management. There is now interest in looking more closely at patient selection for intervention, with focus on intervening only in patients with the highest-risk presentations such as flash pulmonary oedema, rapidly declining renal function and severe resistant hypertension. The potential benefits in terms of improving hard cardiovascular outcomes may outweigh the risks of intervention in this group, and further research is needed
Sudden Cardiac Death Prediction in Arrhythmogenic Right Ventricular Cardiomyopathy: A Multinational Collaboration.
BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with ventricular arrhythmias (VA) and sudden cardiac death (SCD). A model was recently developed to predict incident sustained VA in patients with ARVC. However, since this outcome may overestimate the risk for SCD, we aimed to specifically predict life-threatening VA (LTVA) as a closer surrogate for SCD. METHODS: We assembled a retrospective cohort of definite ARVC cases from 15 centers in North America and Europe. Association of 8 prespecified clinical predictors with LTVA (SCD, aborted SCD, sustained, or implantable cardioverter-defibrillator treated ventricular tachycardia >250 beats per minute) in follow-up was assessed by Cox regression with backward selection. Candidate variables included age, sex, prior sustained VA (≥30s, hemodynamically unstable, or implantable cardioverter-defibrillator treated ventricular tachycardia; or aborted SCD), syncope, 24-hour premature ventricular complexes count, the number of anterior and inferior leads with T-wave inversion, left and right ventricular ejection fraction. The resulting model was internally validated using bootstrapping. RESULTS: A total of 864 patients with definite ARVC (40±16 years; 53% male) were included. Over 5.75 years (interquartile range, 2.77-10.58) of follow-up, 93 (10.8%) patients experienced LTVA including 15 with SCD/aborted SCD (1.7%). Of the 8 prespecified clinical predictors, only 4 (younger age, male sex, premature ventricular complex count, and number of leads with T-wave inversion) were associated with LTVA. Notably, prior sustained VA did not predict subsequent LTVA (P=0.850). A model including only these 4 predictors had an optimism-corrected C-index of 0.74 (95% CI, 0.69-0.80) and calibration slope of 0.95 (95% CI, 0.94-0.98) indicating minimal over-optimism. CONCLUSIONS: LTVA events in patients with ARVC can be predicted by a novel simple prediction model using only 4 clinical predictors. Prior sustained VA and the extent of functional heart disease are not associated with subsequent LTVA events
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