Neuroblastoma is a neural crest-derived embryonal tumour of the postganglionic sympathetic nervous system and a disease with several different chromosomal gains and losses, which include ...MYCN-amplified neuroblastoma on chromosome 2, deletions of parts of the chromosomes 1p and 11q, gain of parts of 17q and triploidy. Recently, activating mutations of the ALK (Anaplastic Lymphoma Kinase) RTK (Receptor Tyrosine Kinase) gene have been described in neuroblastoma. A meta-analysis of neuroblastoma cases revealed that ALK mutations (49 of 709 cases) in relation to genomic subtype were most frequently observed in MYCN amplified tumours (8.9%), correlating with a poor clinical outcome. MYCN proteins target proliferation and apoptotic pathways, and have an important role in the progression of neuroblastoma. Here, we show that both wild-type and gain-of-function mutants in ALK are able to stimulate transcription at the MYCN promoter and initiate mRNA transcription of the MYCN gene in both neuronal and neuroblastoma cell lines. Further, this stimulation of MYCN gene transcription and de novo MYCN protein expression is abrogated by specific ALK inhibitors, such as crizotinib (PF-2341066), NVP-TAE684, and by small interfering RNA to ALK resulting in a decrease in proliferation rate. Finally, co-transfection of ALK gain-of-function mutations together with MYCN leads to an increase in transformation potential. Taken together, our results indicate that ALK signalling regulates initiation of transcription of the MYCN gene providing a possible explanation for the poor clinical outcome observed when MYCN is amplified together with activated ALK.
Four-section multisection CT angiography (MSCTA) accurately detects aneurysms at or more than 4 mm but is less accurate for those less than 4 mm. Our purpose was to determine the accuracy of ...64-section MSCTA (64MSCTA) in aneurysm detection versus combined digital subtraction angiography (DSA) and 3D rotational angiography (3DRA).
In a retrospective review of patients studied because of acute symptoms suspicious for arising from an intracranial aneurysm, 63 subjects were included who had undergone CT angiography (CTA). Of these, 36 underwent catheter DSA; all but 4 were also studied with 3DRA. The most common indication was subarachnoid hemorrhage (SAH; n = 43). Two neuroradiologists independently reviewed each CTA, DSA, and 3DRA.
A total of 41 aneurysms were found in 28 patients. The mean size was 6.09 mm on DSA/3DRA and 5.98 mm on 64MSCTA. kappa was excellent (0.97) between the aneurysm size on 64MSCTA and DSA/3DRA. Ultimately, 37 aneurysms were detected by DSA/3DRA in 25 of the 36 patients who underwent conventional angiography. The reviewers noted four 1- to 1.5-mm sessile outpouchings only on 3DRA; none were considered a source of SAH. One 64MSCTA was false positive, whereas one 2-mm aneurysm was missed by CTA. The sensitivity of CTA for aneurysms less than 4 mm was 92.3%, whereas it was 100% for those 4-10 mm and more than 10 mm, excluding the indeterminate, sessile lesions.
In comparison with the available literature, 64MSCTA may have improved the detection of less than 4-mm aneurysms compared with 4- or 16-section CTA. However, the combination of DSA with 3DRA is currently the most sensitive technique to detect untreated aneurysms and should be considered in suspicious cases of SAH where the aneurysm is not depicted by 64MSCTA, because 64MSCTA may occasionally miss aneurysms less than 3-4 mm size.
Summary
Neutrophil extracellular traps (NETs) comprise extracellular chromatin and granule protein complexes that immobilize and kill bacteria. NET release represents a recently discovered, novel ...anti‐microbial strategy regulated non‐exclusively by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase generation of reactive oxygen intermediates (ROIs), particularly hydrogen peroxide. This study aimed to characterize the role of ROIs in the process of NET release and to identify the dominant ROI trigger. We employed various enzymes, inhibitors and ROIs to record their effect fluorometrically on in vitro NET release by human peripheral blood neutrophils. Treatment with exogenous superoxide dismutase (SOD) supported the established link between hydrogen peroxide and NET production. However, treatment with myeloperoxidase inhibitors and direct addition of hypochlorous acid (HOCl; generated in situ from sodium hypochlorite) established that HOCl was a necessary and sufficient ROI for NET release. This was confirmed by the ability of HOCl to stimulate NET release in chronic granulomatous disease (CGD) patient neutrophils which, due to the lack of a functional NADPH oxidase, also lack the capacity for NET release in response to classical stimuli. Moreover, the exogenous addition of taurine, abundantly present within the neutrophil cytosol, abrogated NET production stimulated by phorbol myristate acetate (PMA) and HOCl, providing a novel mode of cytoprotection by taurine against oxidative stress by taurine.
Self-regulation (SR) is critical to healthy development in children, and intervention approaches (i.e., professional training, classroom-based curricula, parent-focused intervention) have shown to ...support or enhance SR. However, to our knowledge, none have tested whether changes in children's SR across an intervention relate to changes in children's health behavior and outcomes. This study, the Promoting Activity and Trajectories of Health (PATH) for Children-SR Study uses a cluster-randomized control trial to examine the immediate effects of a mastery-climate motor skills intervention on SR. Secondly, this study examines the associations between changes in SR and changes in children's health behaviors (i.e., motor competence, physical activity, and perceived competence) and outcomes (i.e., body mass index and waist circumference) (ClinicalTrials.gov Identifier, NCT03189862).
The PATH-SR study will be a cluster-randomized clinical trial. A total of 120 children between the ages of 3.5 to 5 years of age will be randomized to a mastery-climate motor skills intervention (n = 70) or control (n = 50) condition. SR will be assessed using measures that evaluate cognitive SR (cognitive flexibility and working memory), behavioral SR (behavioral inhibition), and emotional SR (emotional regulation). Health behaviors will be assessed with motor skills, physical activity, and perceived competence (motor and physical) and health outcomes will be waist circumference and body mass index. SR, health behaviors, and health outcomes will be assessed before and after the intervention (pre-test and post-test). Given the randomization design, 70 children in the intervention group and 50 in the control group, we have 80% power to detect an effect size of 0.52, at a Type I error level of 0.05. With the data collected, we will test the intervention effect on SR with a two-sample t-test comparing the intervention group and the control group. We will further evaluate the associations between changes in SR and changes in children's health behaviors and health outcomes, using mixed effect regression models, with a random effect to account for within-subject correlations. The PATH-SR study addresses gaps in pediatric exercise science and child development research. Findings hold the potential to help shape public health and educational policies and interventions that support healthy development during the early years.
Ethical approval for this study was obtained through the Health Sciences and Behavioral Sciences Institutional Review Board, University of Michigan (HUM00133319). The PATH-SR study is funded by the National Institutes of Health Common Fund. Findings will be disseminated via print, online media, dissemination events and practitioner and/or research journals.
ClinicalTrials.gov Identifier, NCT03189862.
The Morphometry of Impact Craters on Bennu Daly, R. T.; Bierhaus, E. B.; Barnouin, O. S. ...
Geophysical research letters,
28 December 2020, Letnik:
47, Številka:
24
Journal Article
Recenzirano
Odprti dostop
Bennu is an ~500‐m‐diameter rubble‐pile asteroid that is the target of detailed study by the Origins, Spectral Interpretation, Resource Identification, and Security–Regolith Explorer (OSIRIS‐REx) ...mission. Here we use data from the OSIRIS‐REx Laser Altimeter to assess depth‐to‐diameter ratios (d/D) of 108 impact craters larger than 10 m in diameter. The d/D of craters on Bennu ranges from 0.02 to 0.19. The mean is 0.10 ± 0.03. The smallest craters show the broadest range in d/D, consistent with d/D measurements on other asteroids. A few craters have central mounds, which is interpreted as evidence that a more competent substrate lies a few meters beneath them. The range of d/D narrows as crater size increases, with craters larger than 80 m tending toward smaller d/D. At large scales, increases in target strength with depth, combined with target curvature, may affect crater morphometry.
Plain Language Summary
Between 2018 and 2020, National Aeronautics and Space Administration (NASA)'s Origins, Spectral Interpretation, Resource Identification, and Security–Regolith Explorer (OSIRIS‐REx) spacecraft orbited a small asteroid called Bennu in preparation to collect a sample for return to Earth. Bennu is a “rubble‐pile” asteroid, meaning an aggregate of rock fragments that have coalesced together in space. OSIRIS‐REx observations showed that Bennu has many craters on its surface, which formed when other, smaller objects collided with it in the past. Crater depths and widths (diameters), in addition to relating to the size and speed of the impacting object, also reflect the physical characteristics of the impacted surface. Accordingly, we measured the depths and diameters of many of Bennu's craters to better understand the surface and interior properties of this rubble‐pile asteroid and how it compares to other asteroids. The smaller craters on Bennu have a variety of depths, even among similarly sized craters. The largest are so wide that they appear to be affected by the curvature of Bennu's surface and by the presence of stronger material at depth. We observe mounds inside some of the smaller craters, supporting the idea that a more competent substrate underlies the surface material.
Key Points
The depth‐to‐diameter ratio (d/D) of asteroid Bennu's craters >10 m in diameter ranges from 0.02 to 0.19 with a mean of 0.10 ± 0.03
Small craters show the greatest diversity in d/D, whereas larger craters (>80 m) span a narrower range in d/D and tend to be shallower
For craters >80 m, increases in target strength with depth, combined with target curvature, likely contribute to smaller d/D
The discovery of neutrophil extracellular traps in 2004 opened a fascinating new chapter in immune‐mediated microbial killing. Brinkman et al. demonstrated that neutrophils, when catastrophically ...stimulated, undergo a novel form of programmed cell death (neutrophil extracellular trap formation) whereby they decondense their entire nuclear chromatin/DNA and release the resulting structure into the cytoplasm to mix with granule‐derived antimicrobial peptides before extruding these web‐like structures into the extracellular environment. The process requires the activation of the granule enzyme peptidyl arginine deiminase‐4, the formation of reactive oxygen species (in particular hypochlorous acid), the neutrophil microtubular system and the actin cytoskeleton. Recent work by Yousefi et al. demonstrated that exposure to different agents for shorter stimulation periods resulted in neutrophil extracellular trap release from viable granulocytes, and that such neutrophil extracellular traps comprised mitochondrial DNA rather than nuclear DNA and were also capable of microbial entrapment and destruction. Deficiency in NADPH‐oxidase production (as found in patients with chronic granulomatous disease) results in an inability to produce neutrophil extracellular traps and, along with their failure to produce antimicrobial reactive oxygen species, these patients suffer from severe, and sometimes life‐threatening, infections. However, conversely the release of nuclear chromatin into tissues is also potentially autoimmunogenic and is now associated with the generation of anti‐citrullinated protein antibodies in seropositive rheumatoid arthritis. Other neutrophil‐derived nuclear and cytoplasmic contents are also pathogenic, either through direct effects on tissues or via autoimmune processes (e.g. autoimmune vasculitis). In this review, we discuss the plant origins of a highly conserved innate immune method of microbial killing, the history and biology of neutrophil extracellular traps and their role in defence and in human diseases. We attempt to resolve areas of controversy and propose roles for excess neutrophil extracellular trap release from hyperactive/reactive neutrophils and for the unique peptidyl arginine deiminase enzyme of Porphyromonas gingivalis in the pathogenesis of periodontitis, and subsequently a role for periodontitis/the peptidyl arginine deiminase enzyme of P. gingivalis in the causal pathway of autoimmune diseases such as rheumatoid arthritis. We propose that neutrophil extracellular trap and peptidyl arginine deiminase release may propagate tissue‐destructive mechanisms rather than provide protection in susceptible individuals and that release of host‐derived DNase may play an important role in the digestion and removal of neutrophil extracellular traps within tissues.
The Origins, Spectral Interpretation, Resource Identification, Security–Regolith Explorer mission will return a sample to Earth from asteroid (101955) Bennu. Digital terrain models (DTMs) of the ...asteroid, and products enabled by them, are key to understanding the origin and evolution of the asteroid, providing geological and geophysical context for the sample, maximizing the amount of sample returned, navigating the spacecraft, and ensuring the safety of the spacecraft during sampling.
The mission has two approaches for producing these DTMs: a camera-based approach and a lidar-based approach. We provide an overview of the methods used for these two approaches and how they fit into the originally planned mission. We also discuss a summary of tests using these plans to evaluate the expected performance of the DTMs and describe the data products derived from them.
•OSIRIS-REx uses two approaches to make digital terrain maps of asteroid Bennu.•Digital terrain maps are produced at global and local scales.•Global shape models from images and laser altimetry achieve 1 to 0.1 m accuracy.•A simulated truth shape model shows that stereophotoclinometry is effective.•Products such as geopotential elevation, slope, and tilt can be derived from the DTMs.
'Latent autoimmune diabetes in adults' (LADA) is the term coined to describe adults who have a slowly progressive form of autoimmune or type 1 diabetes that can be treated initially without insulin ...injections. The diagnosis of LADA is currently based on three clinical criteria: (1) adult age at onset of diabetes; (2) the presence of circulating islet autoantibodies, which distinguishes LADA from type 2 diabetes; and (3) insulin independence at diagnosis, which distinguishes LADA from classic type 1 diabetes. The prevalence of LADA in adults presenting with non-insulin-requiring diabetes is approximately 10%. Recognition of LADA expands the concept and prevalence of autoimmune diabetes, but LADA remains poorly understood at both a clinical and research level. In this perspective, we review the nomenclature, diagnostic criteria, genetics, pathology and therapy of LADA, to arrive at recommendations that might advance knowledge and management of this form of diabetes.
Holstein cows (
n
=
221) from eight commercial dairy herds were examined for endometritis between 28 and 41 days postpartum using 5 diagnostic techniques: (1) vaginoscopy; (2) ultrasonographic ...assessment of uterine fluid volume; (3) ultrasonographic assessment of endometrial thickness; (4) endometrial cytology collected by cytobrush; and (5) endometrial cytology collected by uterine lavage. Concordance correlation was used to evaluate the reliability of cytobrush and lavage cytology. Cytobrush cytology was found to have the greatest intraobserver repeatability (cytobrush,
ρ
c
=
0.85 versus lavage,
ρ
c
=
0.76) and was chosen as the reference diagnostic test. Pregnancy data at 150 days postpartum was available for 189 cows. Survival analysis was used to determine the lowest percentage of polymorphonuclear cells associated with time to pregnancy. The sensitivity and specificity of the diagnostic techniques was determined using pregnancy status at 150 days and cytobrush cytology as the diagnostic standards.
The risk of non-pregnancy at 150 days was 1.9 times higher in cows with more than 8% PMNs identified using cytobrush cytology than in cows with less than 8% PMNs (
P
=
0.04). Twenty-one cows of 189 cows (11.1%) had >8% PMNs and were considered to be positive for endometritis. Cows with endometritis had a 17.9% lower first service conception rate (
P
=
0.03) and a 24-day increase in median days open (
P
=
0.04). The sensitivities of all five diagnostic tests relative to 150-day pregnancy status ranged from 7.1 to 14.3% and the specificities from 84.0 to 93.3%. Relative to cytobrush cytology, the respective sensitivity and specificity values are as follows: vaginoscopy (53.9%, 95.4%); lavage cytology (92.3%, 93.9%); ultrasonographic assessment of uterine fluid (30.8%, 92.8%); and ultrasonographic assessment of endometrial thickness (3.9%, 89.2%). Endometritis impaired reproductive performance. Cytobrush cytology was the most reliable method of diagnosing endometritis in cattle.
Risky decision-making is a common, heritable endophenotype seen across many psychiatric disorders. Its underlying genetic architecture is incompletely explored. We examined behavior in the Balloon ...Analogue Risk Task (BART), which tests risky decision-making, in two independent samples of European ancestry. One sample (n = 1138) comprised healthy participants and some psychiatric patients (53 schizophrenia, 42 bipolar disorder, 47 ADHD); the other (n = 911) excluded for recent treatment of various psychiatric disorders but not ADHD. Participants provided DNA and performed the BART, indexed by mean adjusted pumps. We constructed a polygenic risk score (PRS) for discovery in each dataset and tested it in the other as replication. Subsequently, a genome-wide MEGA-analysis, combining both samples, tested genetic correlation with risk-taking self-report in the UK Biobank sample and psychiatric phenotypes characterized by risk-taking (ADHD, Bipolar Disorder, Alcohol Use Disorder, prior cannabis use) in the Psychiatric Genomics Consortium. The PRS for BART performance in one dataset predicted task performance in the replication sample (r = 0.13, p = 0.000012, pFDR = 0.000052), as did the reciprocal analysis (r = 0.09, p = 0.0083, pFDR=0.04). Excluding participants with psychiatric diagnoses produced similar results. The MEGA-GWAS identified a single SNP (rs12023073; p = 3.24 × 10
) near IGSF21, a protein involved in inhibitory brain synapses; replication samples are needed to validate this result. A PRS for self-reported cannabis use (p = 0.00047, pFDR = 0.0053), but not self-reported risk-taking or psychiatric disorder status, predicted behavior on the BART in our MEGA-GWAS sample. The findings reveal polygenic architecture of risky decision-making as measured by the BART and highlight its overlap with cannabis use.
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