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DeStripe: A Self2Self spatio-spectral graph neural network with unfolded hessian for stripe artifact removal in light-sheet microscopy.
No full textLight-sheet fluorescence microscopy (LSFM) is a cutting-edge volumetric imaging technique that allows for three-dimensional imaging of mesoscopic samples with decoupled illumination and detection paths. Although the selective excitation scheme of such a microscope provides intrinsic optical sectioning that minimizes out-of-focus fluorescence background and sample photodamage, it is prone to light absorption and scattering effects, which results in uneven illumination and striping artifacts in the images adversely. To tackle this issue, in this paper, we propose a blind stripe artifact removal algorithm in LSFM, called DeStripe, which combines a self-supervised spatio-spectral graph neural network with unfolded Hessian prior. Specifically, inspired by the desirable properties of Fourier transform in condensing striping information into isolated values in the frequency domain, DeStripe firstly localizes the potentially corrupted Fourier coefficients by exploiting the structural difference between unidirectional stripe artifacts and more isotropic foreground images. Affected Fourier coefficients can then be fed into a graph neural network for recovery, with a Hessian regularization unrolled to further ensure structures in the standard image space are well preserved. Since in realistic, stripe-free LSFM barely exists with a standard image acquisition protocol, DeStripe is equipped with a Self2Self denoising loss term, enabling artifact elimination without access to stripe-free ground truth images. Competitive experimental results demonstrate the efficacy of DeStripe in recovering corrupted biomarkers in LSFM with both synthetic and real stripe artifacts
Study on zinc ions binding to the individual casein fractions: αS1-, β- and κ-casein.
No full textThe presented work is focused on the isotherm study on the Zn2+ ions binding to the individual casein fractions: αS1-, β- and κ-casein (αS1CN, βCN and κCN). The experimental isotherms were evaluated using Freundlich and Langmuir models. Subsequently, the stability of the obtained complexes in the respective Zn2+ ion concentrations (120, 350, 600 mg/L) was determined by carrying out zeta potential measurements. Capillary electrophoresis combined with inductively coupled plasma mass spectrometry (CE-ICP-MS) confirmed the occurring binding process. Additionally, physicochemical characteristics of the obtained metal-protein complexes was performed including scanning electron microscopy (SEM) in two modes (SE and Z-contrast) and the binding sites of caseins to Zn2+ ions were indicated using attenuated total reflectance infrared spectroscopy (FTIR-ATR) and Raman analysis as well as mass spectrometry technique (MALDI-TOF MS). Isothermal studies indicated a heterogeneously complex zinc ion adsorption process, and a stability study showed that the zeta potential is strongly related to the hydrophobicity, size and structure of the casein isoforms studied. Electron microscopy confirmed the modification of casein surfaces due to the addition of Zn2+ ions. Spectroscopic techniques indicated the interaction of zinc ions with polar amino acids of casein, such as glutamic acid (Glu) and aspartic acid (Asp), but also His, Cys. The influence of phosphate groups was also observed. Finally, the study culminated in a molecular docking study of the Zn2+ ion binding process, which confirmed the presence of the listed amino acids responsible for the binding process
How many Fourier coefficients are needed?
No full textWe are looking at families of functions or measures on the torus which are specified by a finite number of parameters N. The task, for a given family, is to look at a small number of Fourier coefficients of the object, at a set of locations that is predetermined and may depend only on N, and determine the object. We look at (a) the indicator functions of at most N intervals of the torus and (b) at sums of at most N complex point masses on the multidimensional torus. In the first case we reprove a theorem of Courtney which says that the Fourier coefficients at the locations 0 , 1 , … , N are sufficient to determine the function (the intervals). In the second case we produce a set of locations of size O(Nlog d-1N) which suffices to determine the measure
The advanced properties of circularized MSP nanodiscs facilitate high-resolution NMR studies of membrane proteins: Advanced NMR properties of circular MSP nanodiscs.
No full textMembrane mimetics are essential for structural and functional studies of membrane proteins. A promising lipid-based system are phospholipid nanodiscs, where two copies of a so-called membrane scaffold protein (MSP) wrap around a patch of lipid bilayer. Consequently, the size of a nanodisc is determined by the length of the MSP. Furthermore, covalent MSP circularization was reported to improve nanodisc stability. However, a more detailed comparative analysis of the biophysical properties of circularized and linear MSP nanodiscs for their use in high-resolution NMR has not been conducted so far. Here, we analyze the membrane fluidity and temperature-dependent size variability of circularized and linear nanodiscs using a large set of analytical methods. We show that MSP circularization does not alter the membrane fluidity in nanodiscs. Further, we show that the phase transition temperature increases for circularized versions, while the cooperativity decreases. We demonstrate that circularized nanodiscs keep a constant size over a large temperature range, in contrast to their linear MSP counterparts. Due to this size stability, circularized nanodiscs are beneficial for high-resolution NMR studies of membrane proteins at elevated temperatures. Despite their slightly larger size as compared to linear nanodiscs, 3D NMR experiments of the voltage-dependent anion channel 1 (VDAC1) in circularized nanodiscs have a markedly improved spectral quality in comparison to VDAC1 incorporated into linear nanodiscs of a similar size. This study provides evidence that circularized MSP nanodiscs are a promising tool to facilitate high-resolution NMR studies of larger and challenging membrane proteins in a native lipid environment
Loss-of-function variants in <em>MYCBP2</em> cause neurobehavioural phenotypes and corpus callosum defects.
No full textThe corpus callosum is a bundle of axon fibers that connects the two hemispheres of the brain. Neurodevelopmental disorders that feature dysgenesis of the corpus callosum as a core phenotype offer a valuable window into pathology derived from abnormal axon development. Here, we describe a cohort of eight patients with a neurodevelopmental disorder characterized by a range of deficits including corpus callosum abnormalities, developmental delay, intellectual disability, epilepsy, and autistic features. Each patient harbored a distinct de novo variant in MYCBP2, a gene encoding an atypical RING ubiquitin ligase and signaling hub with evolutionarily conserved functions in axon development. We used CRISPR/Cas9 gene editing to introduce disease-associated variants into conserved residues in the C. elegans MYCBP2 ortholog, RPM-1, and evaluated functional outcomes in vivo. Consistent with variable phenotypes in patients with MYCBP2 variants, C. elegans carrying the corresponding human mutations in rpm-1 displayed axonal and behavioral abnormalities including altered habituation. Furthermore, abnormal axonal accumulation of the autophagy marker LGG-1/LC3 occurred in variants that affect RPM-1 ubiquitin ligase activity. Functional genetic outcomes from anatomical, cell biological and behavioral readouts indicate that MYCBP2 variants are likely to result in loss of function. Collectively, our results from multiple human patients and CRISPR gene editing with an in vivo animal model support a direct link between MYCBP2 and a human neurodevelopmental spectrum disorder that we term, MYCBP2-related developmental delay with corpus callosum defects (MDCD)
Proton pump inhibitors and the risk of cardiovascular events and cardiovascular mortality: A systematic review and meta-analysis of observational studies.
No full textBACKGROUND AND AIMS: Observational research has indicated that proton pump inhibitors (PPIs) might increase the long-term risk of cardiovascular events. This study evaluated the evidence from observational studies for an effect of PPI monotherapy on the risk of incident cardiovascular events and cardiovascular mortality. METHODS: The databases MEDLINE, EMBASE, and Scopus were systematically searched up to September 2021. The primary outcome was first cardiovascular event, i.e. first myocardial infarction or first ischaemic stroke. The secondary outcome was cardiovascular mortality. Studies were included following a detailed risk of bias assessment with the ROBINS-I tool. Sensitivity and bias analyses adjusted for potential publication bias, immortal time bias, and unmeasured confounding. RESULTS: We included ten studies with 75,371 first cardiovascular events, as well as seven studies on cardiovascular mortality with 50,329 cardiovascular deaths in total. The pooled hazard ratios (HRs) for PPI use and cardiovascular events were 1.05 with a 95% confidence interval of (0.96; 1.15) before and 0.99 (0.93; 1.04) after adjusting for observational study design bias. The pooled HRs for PPI use and cardiovascular mortality were 1.27 (1.11; 1.44) before and 1.06 (0.96; 1.16) after adjusting for publication bias and observational study design bias. CONCLUSION: It is questionable, whether PPI monotherapy constitutes a cardiovascular risk factor
The constitutional gain-of-function variant p.Glu1099Lys in NSD2 is associated with a novel syndrome.
No full textNSD2 dimethylates histone H3 at lysine 36 (H3K36me2) and is located in the Wolf-Hirschhorn syndrome (WHS) critical region. Recent descriptions have delineated loss-of-function (LoF) variants in NSD2 with a distinct disorder. The oncogenic missense variant p.Glu1099Lys occurs somatically in leukemia and has a gain-of-function (GoF) effect. We describe two individuals carrying p.Glu1099Lys as heterozygous de novo germline variant identified by exome sequencing (ES) of blood DNA and subsequently confirmed in two ectodermal tissues. Clinically, these individuals are characterized by intellectual disability, coarse/ square facial gestalt, abnormalities of the hands, and organomegaly. Public cell lines with NSD2 GoF variants had increased K36me2, DNA promoter methylation, and dysregulated RNA expression. NSD2 GoF caused by p.Glu1099Lys is associated with a novel phenotype different from WHS and Rauch-Steindl syndrome (RAUST)
Protonation-dependent sequencing of 5-formylcytidine in RNA.
No full textChemical modification of cytidine in non-coding RNAs plays a key role in regulating translation and disease. However, the distribution and dynamics of many of these modifications remains unknown due to a lack of sensitive site-specific sequencing technologies. Here we report a protonation-dependent sequencing reaction for detection of 5-formylcytidine (5fC) and 5-carboxycytidine (5caC) in RNA. First, we evaluate how protonation combined with electron withdrawing substituents alters the molecular orbital energies and reduction of modified cytidine nucleosides, highlighting 5fC and 5caC as reactive species. Next, we apply this reaction to detect these modifications in synthetic oligonucleotides as well as endogenous human tRNA. Finally, we demonstrate the utility of our method to characterize a patient-derived model of 5fC-deficiency, where it enables facile monitoring of both pathogenic loss and exogenous rescue of NSUN3-dependent 5fC within the wobble base of human mitochondrial tRNAMet . These studies showcase the ability of protonation to enhance the reactivity and sensitive detection of 5fC in RNA, and provide a molecular foundation for applying optimized sequencing reactions to better understand the role of oxidized RNA cytidine nucleobases in disease
The emotional well-being of parents with children at genetic risk for type 1 diabetes before and during participation in the POInT-study.
No full textThis study examined the emotional impact that parents experience when confronted with an increased genetic risk of type 1 diabetes (T1D) in their child. Population-based screening of neonates for genetic risk of chronic disease carries the risk of increased emotional burden for parents. Information was collected using a well-being questionnaire for parents of infants identified as having an increased risk for T1D in a multinational research study. Parents were asked to complete this questionnaire after they were told their child had an increased risk for T1D (Freder1k-study) and at several timepoints during an intervention study (POInT-study), where oral insulin was administered daily. Data were collected from 2595 parents of 1371 children across five countries. Disease-specific anxiety was found in a larger group of parents (47.2%) during the intervention study. Panic-related anxiety symptoms were reported by only 4.9% after hearing about their child having an increased risk. Symptoms of depression were limited to 19.4% of the parents at the result-communication visit and declined over time during the intervention study. Mothers and parents with a first-degree relative (FDR) with T1D reported more symptoms of depression and disease-specific anxiety (p < 0.001) than fathers and parents without a FDR. Overall, symptoms of depression and panic-related anxiety are comparable with the German general population. However, high levels of disease-specific anxiety were found during the intervention study, which should be kept in mind when considering population-based screening. As certain subgroups are more prone, it will be important to continue psychological screening and, when necessary, to provide support by an experienced, multidisciplinary team. This article is protected by copyright. All rights reserved