We present a theoretical study of the positive charge transfer in stilbene-linked DNA hairpins containing only AT base pairs using a tight-binding model that includes a description of structural ...fluctuations. The parameters are the charge transfer integral between neighboring units and the site energies. Fluctuations in these parameters were studied by a combination of molecular dynamics simulations of the structural dynamics and density functional theory calculations of charge transfer integrals and orbital energies. The fluctuations in both parameters were found to be substantial and to occur on subpicosecond time scales. Tight-binding calculations of the dynamics of charge transfer show that for short DNA hairpins (<4 base pairs) the charge moves by a single-step superexchange mechanism with a relatively strong distance dependence. For longer hairpins, a crossover to a fluctuation-assisted incoherent mechanism was found. Analysis of the charge distribution during the charge transfer process indicates that for longer bridges substantial charge density builds up on the bridge, but this charge density is mostly confined to the adenine next to the hole donor. This is caused by the electrostatic interaction between the hole on the AT bridge and the negative charge on the hole donor. We conclude both that the relatively strong distance dependence for short bridges is mostly due to this electrostatic interaction and that structural fluctuations play a critical role in the charge transfer, especially for longer bridge lengths.
Minimally invasive detection of cell death could prove an invaluable resource in many physiologic and pathologic situations. Cell-free circulating DNA (cfDNA) released from dying cells is emerging as ...a diagnostic tool for monitoring cancer dynamics and graft failure. However, existing methods rely on differences in DNA sequences in source tissues, so that cell death cannot be identified in tissues with a normal genome. We developed amethod of detecting tissue-specific cell death in humans based on tissue-specific methylation patterns in cfDNA. We interrogated tissue-specific methylome databases to identify cell type-specific DNA methylation signatures and developed a method to detect these signatures in mixed DNA samples. We isolated cfDNA from plasma or serum of donors, treated the cfDNA with bisulfite, PCR-amplified the cfDNA, and sequenced it to quantify cfDNA carrying the methylation markers of the cell type of interest. Pancreatic β-cell DNA was identified in the circulation of patients with recently diagnosed type-1 diabetes and islet-graft recipients; oligodendrocyte DNA was identified in patients with relapsing multiple sclerosis; neuronal/glial DNA was identified in patients after traumatic brain injury or cardiac arrest; and exocrine pancreas DNA was identified in patients with pancreatic cancer or pancreatitis. This proof-of-concept study demonstrates that the tissue origins of cfDNA and thus the rate of death of specific cell types can be determined in humans. The approach can be adapted to identify cfDNA derived from any cell type in the body, offering a minimally invasive window for diagnosing and monitoring a broad spectrum of human pathologies as well as providing a better understanding of normal tissue dynamics.
Summary
The Network for Pancreatic Organ donors with Diabetes (nPOD) programme was developed in response to an unmet research need for human pancreatic tissue obtained from individuals with type 1 ...diabetes mellitus and people at increased risk i.e. autoantibody (AAb)‐positive for the disease. This necessitated the establishment of a type 1 diabetes‐specific AAb screening platform for organ procurement organizations (OPOs). Assay protocols for commercially available enzyme‐linked immunosorbent assays (elisas) determining AAb against glutamic acid decarboxylase (GADA), insulinoma‐associated protein‐2 (IA‐2A) and zinc transporter‐8 (ZnT8A) were modified to identify AAb‐positive donors within strict time requirements associated with organ donation programmes. These rapid elisas were evaluated by the international islet AAb standardization programme (IASP) and used by OPO laboratories as an adjunct to routine serological tests evaluating donors for organ transplantation. The rapid elisas performed well in three IASPs (2011, 2013, 2015) with 98‐100% specificity for all three assays, including sensitivities of 64–82% (GADA), 60–64% (IA‐2A) and 62–68% (ZnT8A). Since 2009, nPOD has screened 4442 organ donors by rapid elisa; 250 (5·6%) were identified as positive for one AAb and 14 (0.3%) for multiple AAb with 20 of these cases received by nPOD for follow‐up studies (14 GADA+, two IA‐2A+, four multiple AAb‐positive). Rapid screening for type 1 diabetes‐associated AAb in organ donors is feasible, allowing for identification of non‐diabetic, high‐risk individuals and procurement of valuable tissues for natural history studies of this disease.
Type 1 diabetes mellitus Katsarou, Anastasia; Gudbjörnsdottir, Soffia; Rawshani, Araz ...
Nature reviews. Disease primers,
03/2017, Letnik:
3
Journal Article
Recenzirano
Type 1 diabetes mellitus (T1DM), also known as autoimmune diabetes, is a chronic disease characterized by insulin deficiency due to pancreatic β-cell loss and leads to hyperglycaemia. Although the ...age of symptomatic onset is usually during childhood or adolescence, symptoms can sometimes develop much later. Although the aetiology of T1DM is not completely understood, the pathogenesis of the disease is thought to involve T cell-mediated destruction of β-cells. Islet-targeting autoantibodies that target insulin, 65 kDa glutamic acid decarboxylase, insulinoma-associated protein 2 and zinc transporter 8 - all of which are proteins associated with secretory granules in β-cells - are biomarkers of T1DM-associated autoimmunity that are found months to years before symptom onset, and can be used to identify and study individuals who are at risk of developing T1DM. The type of autoantibody that appears first depends on the environmental trigger and on genetic factors. The pathogenesis of T1DM can be divided into three stages depending on the absence or presence of hyperglycaemia and hyperglycaemia-associated symptoms (such as polyuria and thirst). A cure is not available, and patients depend on lifelong insulin injections; novel approaches to insulin treatment, such as insulin pumps, continuous glucose monitoring and hybrid closed-loop systems, are in development. Although intensive glycaemic control has reduced the incidence of microvascular and macrovascular complications, the majority of patients with T1DM are still developing these complications. Major research efforts are needed to achieve early diagnosis, prevent β-cell loss and develop better treatment options to improve the quality of life and prognosis of those affected.
Context.
Direct imaging of Earth-like planets is one of the main science cases for the next generation of extremely large telescopes. This is very challenging due to the star-planet contrast that has ...to be overcome. Most current high-contrast imaging instruments are limited in sensitivity at small angular separations due to non-common path aberrations (NCPA). The NCPA leak through the corona-graph and create bright speckles that limit the on-sky contrast and therefore also the post-processed contrast.
Aims.
We aim to remove the NCPA by active focal plane wavefront control using a data-driven approach.
Methods.
We developed a new approach to dark hole creation and maintenance that does not require an instrument model. This new approach is called implicit Electric Field Conjugation (iEFC) and it can be empirically calibrated. This makes it robust for complex instruments where optical models might be difficult to realize. Numerical simulations have been used to explore the performance of iEFC for different coronagraphs. The method was validated on the internal source of the Magellan Adaptive Optics extreme (MagAO-X) instrument to demonstrate iEFC’s performance on a real instrument.
Results.
Numerical experiments demonstrate that iEFC can achieve deep contrast below 10
−9
with several coronagraphs. The method is easily extended to broadband measurements and the simulations show that a bandwidth up to 40% can be handled without problems. Lab experiments with MagAO-X showed a contrast gain of a factor 10 in a broadband light and a factor 20–200 in narrowband light. A contrast of 5 × 10
−8
was achieved with the Phase Apodized Pupil Lyot Coronagraph at 7.5
λ
/
D.
Conclusions.
The new iEFC method has been demonstrated to work in numerical and lab experiments. It is a method that can be empirically calibrated and it can achieve deep contrast. This makes it a valuable approach for complex ground-based high-contrast imaging systems.
The first complete measurement of the β-decay strength distribution of _{17}^{45}Cl_{28} was performed at the Facility for Rare Isotope Beams (FRIB) with the FRIB Decay Station Initiator during the ...second FRIB experiment. The measurement involved the detection of neutrons and γ rays in two focal planes of the FRIB Decay Station Initiator in a single experiment for the first time. This enabled an analytical consistency in extracting the β-decay strength distribution over the large range of excitation energies, including neutron unbound states. We observe a rapid increase in the β-decay strength distribution above the neutron separation energy in _{18}^{45}Ar_{27}. This was interpreted to be caused by the transitioning of neutrons into protons excited across the Z=20 shell gap. The SDPF-MU interaction with reduced shell gap best reproduced the data. The measurement demonstrates a new approach that is sensitive to the proton shell gap in neutron rich nuclei according to SDPF-MU calculations.
In this article, a theoretical study of the electronic and spectroscopic properties of well-defined DNA hairpins is presented. The excited states in the hairpins are described in terms of an exciton ...Hamiltonan model, and the structural dynamics of the DNA model systems is explicitly taken into account by molecular dynamics simulations. The results show that the model reproduces the experimentally observed absorption and circular dichroism spectra accurately in most cases. It is shown that structural disorder leads to excited states that are largely localized on a single base pair, even for regular DNA sequences consisting only of AT base pairs. Variations in the base pair sequence have a significant effect on the appearance of the spectra but also on the degree of delocalization of the excited state.
Ductal structures of the adult pancreas contain stem cells that differentiate into islets of Langerhans. Here, we grew pancreatic ductal epithelial cells isolated from prediabetic adult non-obese ...diabetic mice in long-term cultures, where they were induced to produce functioning islets containing alpha, beta and delta cells. These in vitro-generated islets showed temporal changes in mRNA transcripts for islet cell-associated differentiation markers, responded in vitro to glucose challenge, and reversed insulin-dependent diabetes after being implanted into diabetic non-obese diabetic mice. The ability to control growth and differentiation of islet stem cells provides an abundant islet source for beta-cell reconstitution in type I diabetes.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Although several early trials indicate treatment of restenosis with radiation therapy is safe and effective, the long-term impact of this new technology has been questioned. The objective of this ...report is to document angiographic and clinical outcome 3 years after treatment of restenotic stented coronary arteries with catheter-based (192)Ir.
A double-blind, randomized trial compared (192)Ir with placebo sources in patients with previous restenosis after coronary angioplasty. Over a 9-month period, 55 patients were enrolled; 26 were randomized to (192)Ir and 29 to placebo. At 3-year follow-up, target-lesion revascularization was significantly lower in the (192)Ir group (15. 4% versus 48.3%; P<0.01). The dichotomous restenosis rate at 3-year follow-up was also significantly lower in (192)Ir patients (33% versus 64%; P<0.05). In a subgroup of patients with 3-year angiographic follow-up not subjected to target-lesion revascularization by the 6-month angiogram, the mean minimal luminal diameter between 6 months and 3 years decreased from 2.49+/-0.81 to 2.12+/-0.73 mm in (192)Ir patients but was unchanged in placebo patients.
The early clinical benefits observed after treatment of coronary restenosis with (192)Ir appear durable at late follow-up. Angiographic restenosis continues to be significantly reduced in (192)Ir-treated patients, but a small amount of late loss was observed between the 6-month and 3-year follow-up time points. No events occurred in the (192)Ir group to suggest major untoward effects of vascular radiotherapy. At 3-year follow-up, vascular radiotherapy continues to be a promising new treatment for restenosis.
Aims
Misclassification of diabetes is common due to an overlap in the clinical features of type 1 and type 2 diabetes. Combined diagnostic models incorporating clinical and biomarker information have ...recently been developed that can aid classification, but they have not been validated using pancreatic pathology. We evaluated a clinical diagnostic model against histologically defined type 1 diabetes.
Methods
We classified cases from the Network for Pancreatic Organ donors with Diabetes (nPOD) biobank as type 1 (n = 111) or non‐type 1 (n = 42) diabetes using histopathology. Type 1 diabetes was defined by lobular loss of insulin‐containing islets along with multiple insulin‐deficient islets. We assessed the discriminative performance of previously described type 1 diabetes diagnostic models, based on clinical features (age at diagnosis, BMI) and biomarker data autoantibodies, type 1 diabetes genetic risk score (T1D‐GRS), and singular features for identifying type 1 diabetes by the area under the curve of the receiver operator characteristic (AUC‐ROC).
Results
Diagnostic models validated well against histologically defined type 1 diabetes. The model combining clinical features, islet autoantibodies and T1D‐GRS was strongly discriminative of type 1 diabetes, and performed better than clinical features alone (AUC‐ROC 0.97 vs. 0.95; P = 0.03). Histological classification of type 1 diabetes was concordant with serum C‐peptide median < 17 pmol/l (limit of detection) vs. 1037 pmol/l in non‐type 1 diabetes; P < 0.0001.
Conclusions
Our study provides robust histological evidence that a clinical diagnostic model, combining clinical features and biomarkers, could improve diabetes classification. Our study also provides reassurance that a C‐peptide‐based definition of type 1 diabetes is an appropriate surrogate outcome that can be used in large clinical studies where histological definition is impossible.
Parts of this study were presented in form at the Network for Pancreatic Organ Donors Conference, Florida, USA, 19–22 February 2019 and Diabetes UK Professional Conference, Liverpool, UK, 6–8 March 2019.
What’s new?
Misclassification of diabetes at diagnosis is common due to an overlap in the clinical features of type 1 and type 2 diabetes.
Combining clinical features and biomarkers in a diagnostic model improved discrimination of diabetes type, defined by insulin deficiency (measured by C‐peptide assays), over use of any single characteristic.
No diabetes classification studies have used pancreatic histology to define type 1 diabetes.
A diagnostic model, developed using diabetes type defined by C‐peptide level as an outcome, validates against histologically defined insulin deficiency.
C‐peptide provides a robust surrogate definition of type 1 diabetes that can be used in diagnostic model development.
Our study provides the first histological evidence for a clinical diagnostic model having utility to identify type 1 diabetes in clinical practice.
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