1,130 research outputs found
Classification of Protein-Binding Sites Using a Spherical Convolutional Neural Network
The analysis and comparison of protein-binding sites aid various applications in the drug discovery process, e.g., hit finding, drug repurposing, and polypharmacology. Classification of binding sites has been a hot topic for the past 30 years, and many different methods have been published. The rapid development of machine learning computational algorithms, coupled with the large volume of publicly available protein–ligand 3D structures, makes it possible to apply deep learning techniques in binding site comparison. Our method uses a cutting-edge spherical convolutional neural network based on the DeepSphere architecture to learn global representations of protein-binding sites. The model was trained on TOUGH-C1 and TOUGH-M1 data and validated with the ProSPECCTs datasets. Our results show that our model can (1) perform well in protein-binding site similarity and classification tasks and (2) learn and separate the physicochemical properties of binding sites. Lastly, we tested the model on a set of kinases, where the results show that it is able to cluster the different kinase subfamilies effectively. This example demonstrates the method’s promise for lead hopping within or outside a protein target, directly based on binding site information
Transcatheter Closure of a Secundum Atrial Septal Defect with Deficient Aortic Rim Through the Left Internal Jugular Vein in a Child with Situs Inversus and Interrupted Inferior Vena Cava: Device's Choice Matters
Percutaneous closure of secundum atrial septal defect (sASD) in children with interrupted inferior vena cava is challenging, especially in case of deficient aortic rim. Trans-jugular access is generally preferred in this scenario. Patients with situs inversus and sASD also carry technical difficulties for transcatheter closure because of the orientation of the atrial septum. We report a successful case of percutaneous closure of a sASD with deficient aortic rim using an occlutech figulla flex II ASD device through the left internal jugular vein in a child with situs inversus, dextrocardia, and interrupted IVC. This case was facilitated by the absence of left-sided hub of the Occlutech device to provide stable opening of the device into the left atrium, whereas the ball-connection of the delivery system allowed an angle of almost 180 degrees between the device and the atrial septum
Time-resolved comparative molecular evolution of oxygenic photosynthesis
AbstractOxygenic photosynthesis starts with the oxidation of water to O2, a light-driven reaction catalysed by photosystem II. Cyanobacteria are the only prokaryotes capable of water oxidation and therefore, it is assumed that relative to the origin of life and bioenergetics, the origin of oxygenic photosynthesis is a late innovation. However, when exactly water oxidation originated remains an unanswered question. Here we use relaxed molecular clocks to compare one of the two ancestral core duplications that are unique to water-oxidizing photosystem II, that leading to CP43 and CP47, with some of the oldest well-described events in the history of life. Namely, the duplication leading to the Alpha and Beta subunits of the catalytic head of ATP synthase, and the divergence of archaeal and bacterial RNA polymerases and ribosomes. We also compare it with more recent events such as the duplication of cyanobacteria-specific FtsH metalloprotease subunits, of CP43 variants used in a variety of photoacclimation responses, and the speciation events leading to Margulisbacteria, Sericytochromatia, Vampirovibrionia, and other clades containing anoxygenic phototrophs. We demonstrate that the ancestral core duplication of photosystem II exhibits patterns in the rates of protein evolution through geological time that are nearly identical to those of the ATP synthase, RNA polymerase, or the ribosome. Furthermore, we use ancestral sequence reconstruction in combination with comparative structural biology of photosystem subunits, to provide additional evidence supporting the premise that water oxidation had originated before the ancestral core duplications. Our work suggests that photosynthetic water oxidation originated closer to the origin of life and bioenergetics than can be documented based on species trees alone.</jats:p
PARP3 is a sensor of nicked nucleosomes and monoribosylates histone H2B(Glu2).
PARP3 is a member of the ADP-ribosyl transferase superfamily that we show accelerates the repair of chromosomal DNA single-strand breaks in avian DT40 cells. Two-dimensional nuclear magnetic resonance experiments reveal that PARP3 employs a conserved DNA-binding interface to detect and stably bind DNA breaks and to accumulate at sites of chromosome damage. PARP3 preferentially binds to and is activated by mononucleosomes containing nicked DNA and which target PARP3 trans-ribosylation activity to a single-histone substrate. Although nicks in naked DNA stimulate PARP3 autoribosylation, nicks in mononucleosomes promote the trans-ribosylation of histone H2B specifically at Glu2. These data identify PARP3 as a molecular sensor of nicked nucleosomes and demonstrate, for the first time, the ribosylation of chromatin at a site-specific DNA single-strand break
Low-Temperature Growth of Carbon Nanotube Forests Consisting of Tubes with Narrow Inner Spacing Using Co/Al/Mo Catalyst on Conductive Supports.
We grow dense carbon nanotube forests at 450 °C on Cu support using Co/Al/Mo multilayer catalyst. As a partial barrier layer for the diffusion of Co into Mo, we apply very thin Al layer with the nominal thickness of 0.50 nm between Co and Mo. This Al layer plays an important role in the growth of dense CNT forests, partially preventing the Co-Mo interaction. The forests have an average height of ∼300 nm and a mass density of 1.2 g cm(-3) with tubes exhibiting extremely narrow inner spacing. An ohmic behavior is confirmed between the forest and Cu support with the lowest resistance of ∼8 kΩ. The forest shows a high thermal effusivity of 1840 J s(-0.5) m(-2) K(-1), and a thermal conductivity of 4.0 J s(-1) m(-1) K(-1), suggesting that these forests are useful for heat dissipation devices.This work has been funded by the European projects Technotubes and Grafol. H.S. acknowledges a research fellowship from the Japanese Society for the Promotion of Science (JSPS).This is the accepted manuscript. The final version is available at http://pubs.acs.org/doi/abs/10.1021/acsami.5b04846
Treatment of stage I seminoma: is it time to change your practice?
At the plenary session of the 2008 annual meeting of the American Society of Clinical Oncology, updated results were presented from a large randomized phase III trial comparing adjuvant radiation therapy (RT) and one cycle of Carboplatin for the adjuvant treatment of Stage I seminoma. Results of this Medical Research Council (MRC) trial led its investigators to conclude that one cycle of carboplatin was equivalent in safety and efficacy and less toxic than RT. In this editorial, the trial's design, statistics, toxicity, and length of follow-up are discussed within the context of historical treatments of this disease. With a 1.3% increase in relapse rate (5.3% with carboplatin vs. 4.0% with radiation), a 3% or greater increase in relapse rate could not be excluded, the primary endpoint of the study. A decrease in second testicular germ cell tumors was observed, but was equivalent to the increase in relapse rate. Acute toxicity was generally less with carboplatin. However, the extent of late toxicity, including late second neoplasms, cannot be evaluated because of the short median follow-up. Carboplatin is not yet a standard of care. Surveillance-based strategies, including risk-adapted policies that limit RT to patients with the greatest likelihood of relapse remain prudent at this time
Differential Methylation as a Biomarker of Response to Etanercept in Patients With Rheumatoid Arthritis
Objective: Biologic drug therapies represent a huge advance in the treatment of rheumatoid arthritis (RA). However, very good disease control is achieved in only 30% of patients, making identification of biomarkers of response a research priority. We undertook this study to test our hypothesis that differential DNA methylation patterns may provide biomarkers predictive of response to tumor necrosis factor inhibitor (TNFi) therapy in patients with RA. Methods: An epigenome-wide association study was performed on pretreatment whole blood DNA from patients with RA. Patients who displayed good response (n = 36) or no response (n = 36) to etanercept therapy at 3 months were selected. Differentially methylated positions were identified using linear regression. Variance of methylation at differentially methylated positions was assessed for correlation with cis-acting single-nucleotide polymorphisms (SNPs). A replication experiment for prioritized SNPs was performed in an independent cohort of 1,204 RA patients. Results: Five positions that were differentially methylated between responder groups were identified, with a false discovery rate of <5%. The top 2 differentially methylated positions mapped to exon 7 of the LRPAP1 gene on chromosome 4 (cg04857395, P = 1.39 × 10−8 and cg26401028, P = 1.69 × 10−8). The A allele of the SNP rs3468 was correlated with higher levels of methylation for both of the top 2 differentially methylated positions (P = 2.63 × 10−7 and P = 1.05 × 10−6, respectively). Furthermore, the A allele of rs3468 was correlated with European League Against Rheumatism nonresponse in the discovery cohort (P = 0.03; n = 56) and in the independent replication cohort (P = 0.003; n = 1,204). Conclusion: We identify DNA methylation as a potential biomarker of response to TNFi therapy, and we report the association between response and the LRPAP1 gene, which encodes a chaperone of low-density lipoprotein receptor–related protein 1. Additional replication experiments in independent sample collections are now needed
Structural basis for the inactivation of cytosolic DNA sensing by the vaccinia virus.
Detection of cytosolic DNA is a central element of the innate immunity system against viral infection. The Ku heterodimer, a component of the NHEJ pathway of DNA repair in the nucleus, functions as DNA sensor that detects dsDNA of viruses that replicate in the cytoplasm. Vaccinia virus expresses two proteins, C4 and C16, that inactivate DNA sensing and enhance virulence. The structural basis for this is unknown. Here we determine the structure of the C16 - Ku complex using cryoEM. Ku binds dsDNA by a preformed ring but C16 sterically blocks this access route, abrogating binding to a dsDNA end and its insertion into DNA-PK, thereby averting signalling into the downstream innate immunity system. C4 replicates these activities using a domain with 54% identity to C16. Our results reveal how vaccinia virus subverts the capacity of Ku to recognize viral DNA
In vitro sensitivity testing of human renal cell carcinoma with cytostatic agents and interferon alpha-2a
Determinants of response to a parent questionnaire about development and behaviour in 3 year olds: European multicentre study of congenital toxoplasmosis.
Background:
We aimed to determine how response to a parent-completed postal questionnaire measuring development, behaviour, impairment, and parental concerns and anxiety, varies in different European centres.
Methods:
Prospective cohort study of 3 year old children, with and without congenital toxoplasmosis, who were identified by prenatal or neonatal screening for toxoplasmosis in 11 centres in 7 countries. Parents were mailed a questionnaire that comprised all or part of existing validated tools. We determined the effect of characteristics of the centre and child on response, age at questionnaire completion, and response to child drawing tasks.
Results:
The questionnaire took 21 minutes to complete on average. 67% (714/1058) of parents responded. Few parents (60/1058) refused to participate. The strongest determinants of response were the score for organisational attributes of the study centre (such as direct involvement in follow up and access to an address register), and infection with congenital toxoplasmosis. Age at completion was associated with study centre, presence of neurological abnormalities in early infancy, and duration of prenatal treatment. Completion rates for individual questions exceeded 92% except for child completed drawings of a man (70%), which were completed more by girls, older children, and in certain centres.
Conclusion:
Differences in response across European centres were predominantly related to the organisation of follow up and access to correct addresses. The questionnaire was acceptable in all six countries and offers a low cost tool for assessing development, behaviour, and parental concerns and anxiety, in multinational studies
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