Background
Impaired ex vivo platelet aggregation is common in trauma patients. The mechanisms driving these impairments remain incompletely understood, but functional platelet exhaustion due to ...excessive in vivo activation is implicated. Given platelet adrenoreceptors and known catecholamine surges after injury, impaired ex vivo platelet aggregation in trauma patients may be linked to catecholamine‐induced functional platelet exhaustion.
Objective
To determine the relationship of catecholamines with platelet‐dependent hemostasis after injury and to model catecholamine‐induced functional platelet exhaustion in healthy donor platelets.
Patients/Methods
Whole blood was collected from 67 trauma patients as part of a prospective cohort study. Platelet aggregometry and rotational thromboelastometry were performed, and plasma epinephrine (EPI) and norepinephrine (NE) concentrations were measured. The effect of catecholamines on healthy donor platelets was examined in a microfluidic model, with platelet aggregometry, and by flow cytometry examining surface markers of platelet activation.
Results
In trauma patients, EPI and NE were associated with impaired platelet aggregation (both p < 0.05), and EPI was additionally associated with decreased viscoelastic clot strength, increased fibrinolysis, and mortality (all p < 0.05). In healthy donors, short duration incubation with EPI enhanced platelet aggregation, platelet adhesion under flow, and increased glycoprotein IIb/IIIa activation, while weaker effects were observed with NE. Compared with short incubation, longer incubation with EPI resulted in decreased platelet adhesion, platelet aggregation, and surface expression of glycoprotein IIb/IIIa.
Conclusions
These findings suggest sympathoadrenal activation in trauma patients contributes to impaired ex vivo platelet aggregation, which mechanistically may be explained by a functionally exhausted platelet phenotype under prolonged exposure to high plasma catecholamine levels.
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FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
IMPORTANCE: Induction chemotherapy followed by high-dose therapy with autologous stem cell transplant and subsequent antidisialoganglioside antibody immunotherapy is standard of care for patients ...with high-risk neuroblastoma, but survival rate among these patients remains low. OBJECTIVE: To determine if tandem autologous transplant improves event-free survival (EFS) compared with single transplant. DESIGN, SETTING, AND PARTICIPANTS: Patients were enrolled in this randomized clinical trial from November 2007 to February 2012 at 142 Children’s Oncology Group centers in the United States, Canada, Switzerland, Australia, and New Zealand. A total of 652 eligible patients aged 30 years or younger with protocol-defined high-risk neuroblastoma were enrolled and 355 were randomized. The final date of follow-up was June 29, 2017, and the data analyses cut-off date was June 30, 2017. INTERVENTIONS: Patients were randomized to receive tandem transplant with thiotepa/cyclophosphamide followed by dose-reduced carboplatin/etoposide/melphalan (n = 176) or single transplant with carboplatin/etoposide/melphalan (n = 179). MAIN OUTCOMES AND MEASURES: The primary outcome was EFS from randomization to the occurrence of the first event (relapse, progression, secondary malignancy, or death from any cause). The study was designed to test the 1-sided hypothesis of superiority of tandem transplant compared with single transplant. RESULTS: Among the 652 eligible patients enrolled, 297 did not undergo randomization because they were nonrandomly assigned (n = 27), ineligible for randomization (n = 62), had no therapy (n = 1), or because of physician/parent preference (n = 207). Among 355 patients randomized (median diagnosis age, 36.1 months; 152 42.8% female), 297 patients (83.7%) completed the study and 21 (5.9%) were lost to follow-up after completing protocol therapy. Three-year EFS from the time of randomization was 61.6% (95% CI, 54.3%-68.9%) in the tandem transplant group and 48.4% (95% CI, 41.0%-55.7%) in the single transplant group (1-sided log-rank P=.006). The median (range) duration of follow-up after randomization for 181 patients without an event was 5.6 (0.6-8.9) years. The most common significant toxicities following tandem vs single transplant were mucosal (11.7% vs 15.4%) and infectious (17.9% vs 18.3%). CONCLUSIONS AND RELEVANCE: Among patients aged 30 years or younger with high-risk neuroblastoma, tandem transplant resulted in a significantly better EFS than single transplant. However, because of the low randomization rate, the findings may not be representative of all patients with high-risk neuroblastoma. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00567567
In Western political philosophy, democracy is generally the dominant view regarding what the best form of government is, and this holds even in respect to promoting minority rights. However, I argue ...that there is a better theory for satisfying minority interests and rights. I amass numerous studies from the social sciences demonstrating how democracy does poorly in accounting for minority interests. I then contend that a particular hybrid view that fuses a meritocracy with democracy can do a better job than democracy in accounting for minority interests and in having more equal rights and fair policies coming from the legislative and executive branches. Finally, I defend this thesis from numerous counters.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The neuron specific RNA-binding proteins NOVA1 and NOVA2 are highly homologous alternative splicing regulators. NOVA proteins regulate at least 700 alternative splicing events in vivo, yet relatively ...little is known about the biologic consequences of NOVA action and in particular about functional differences between NOVA1 and NOVA2. Transcriptome-wide searches for isoform-specific functions, using NOVA1 and NOVA2 specific HITS-CLIP and RNA-seq data from mouse cortex lacking either NOVA isoform, reveals that NOVA2 uniquely regulates alternative splicing events of a series of axon guidance related genes during cortical development. Corresponding axonal pathfinding defects were specific to NOVA2 deficiency: Nova2-/- but not Nova1-/- mice had agenesis of the corpus callosum, and axonal outgrowth defects specific to ventral motoneuron axons and efferent innervation of the cochlea. Thus we have discovered that NOVA2 uniquely regulates alternative splicing of a coordinate set of transcripts encoding key components in cortical, brainstem and spinal axon guidance/outgrowth pathways during neural differentiation, with severe functional consequences in vivo.
Accurate and precise annotation of 3′ UTRs is critical for understanding how mRNAs are regulated by microRNAs (miRNAs) and RNA-binding proteins (RBPs). Here, we describe a method, poly(A) binding ...protein-mediated mRNA 3′ end retrieval by crosslinking immunoprecipitation (PAPERCLIP), that shows high specificity for mRNA 3′ ends and compares favorably with existing 3′ end mapping methods. PAPERCLIP uncovers a previously unrecognized role of CstF64/64tau in promoting the usage of a selected group of non-canonical poly(A) sites, the majority of which contain a downstream GUKKU motif. Furthermore, in the mouse brain, PAPERCLIP discovers extended 3′ UTR sequences harboring functional miRNA binding sites and reveals developmentally regulated APA shifts, including one in Atp2b2 that is evolutionarily conserved in humans and results in the gain of a functional binding site of miR-137. PAPERCLIP provides a powerful tool to decipher post-transcriptional regulation of mRNAs through APA in vivo.
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•PAPERCLIP is a high-performance mRNA 3′ end mapping method based on the CLIP technique•PAPERCLIP provides insights into the regulation of alternative polyadenylation•PAPERCLIP expands knowledge of 3′-UTR-mediated mRNA regulation
Hwang et al. develop PAPERCLIP, a high-performance mRNA 3′ end mapping method based on the CLIP technique. They use PAPERCLIP to show that CstF64/64tau promotes non-canonical poly(A) site usage through a GUKKU motif. Furthermore, they also discover shifts in alternative polyadenylation and identify novel microRNA binding sites during mouse brain development.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Eleven patients (5 men, 6 women) with post-operative thoracic duct injuries and high output chylothorax were treated with thoracic duct embolization (TDE). Six patients underwent intraprocedural ...thoracic duct ligation at the time of original procedure. In all cases, the pleural fluid demonstrated high triglyceride levels (414 mg/dL; interquartile range IQR, 345 mg/dL). Median daily (IQR) chest tube outputs before and after TDE were 900 mL (1,200 mL) and 325 mL (630 mL), respectively. Coil- or plug-assisted ethylene vinyl alcohol (EVOH) copolymer was used as embolic agent in all patients. Technical and clinical success rates were 100% and 82%, respectively. Nontarget venous embolization of EVOH copolymer was not identified on subsequent imaging.
LEAFY COTYLEDON1 (LEC1), an atypical subunit of the nuclear transcription factor Y (NF-Y) CCAAT-binding transcription factor, is a central regulator that controls many aspects of seed development ...including the maturation phase during which seeds accumulate storage macromolecules and embryos acquire the ability to withstand desiccation. To define the gene networks and developmental processes controlled by LEC1, genes regulated directly by and downstream of LEC1 were identified. We compared the mRNA profiles of wild-type and lec1-null mutant seeds at several stages of development to define genes that are down-regulated or up-regulated by the lec1 mutation. We used ChIP and differential gene-expression analyses in Arabidopsis seedlings overexpressing LEC1 and in developing Arabidopsis and soybean seeds to identify globally the target genes that are transcriptionally regulated by LEC1 in planta. Collectively, our results show that LEC1 controls distinct gene sets at different developmental stages, including those that mediate the temporal transition between photosynthesis and chloroplast biogenesis early in seed development and seed maturation late in development. Analyses of enriched DNA sequence motifs that may act as cis-regulatory elements in the promoters of LEC1 target genes suggest that LEC1 may interact with other transcription factors to regulate distinct gene sets at different stages of seed development. Moreover, our results demonstrate strong conservation in the developmental processes and gene networks regulated by LEC1 in two dicotyledonous plants that diverged ∼92 Mya.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
We address the challenge of detecting the contribution of noncoding mutations to disease with a deep-learning-based framework that predicts the specific regulatory effects and the deleterious impact ...of genetic variants. Applying this framework to 1,790 autism spectrum disorder (ASD) simplex families reveals a role in disease for noncoding mutations-ASD probands harbor both transcriptional- and post-transcriptional-regulation-disrupting de novo mutations of significantly higher functional impact than those in unaffected siblings. Further analysis suggests involvement of noncoding mutations in synaptic transmission and neuronal development and, taken together with previous studies, reveals a convergent genetic landscape of coding and noncoding mutations in ASD. We demonstrate that sequences carrying prioritized mutations identified in probands possess allele-specific regulatory activity, and we highlight a link between noncoding mutations and heterogeneity in the IQ of ASD probands. Our predictive genomics framework illuminates the role of noncoding mutations in ASD and prioritizes mutations with high impact for further study, and is broadly applicable to complex human diseases.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
A diverse collection of 14 metal−organic frameworks (MOFs) was screened for CO2 capture from flue gas using a combined experimental and modeling approach. Adsorption measurements are reported for the ...screened MOFs at room temperature up to 1 bar. These data are used to validate a generalized strategy for molecular modeling of CO2 and other small molecules in MOFs. MOFs possessing a high density of open metal sites are found to adsorb significant amounts of CO2 even at low pressure. An excellent correlation is found between the heat of adsorption and the amount of CO2 adsorbed below 1 bar. Molecular modeling can aid in selection of adsorbents for CO2 capture from flue gas by screening a large number of MOFs.
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IJS, KILJ, NUK, PNG, UL, UM
This case series describes a technique to protect nondiseased liver parenchyma during transarterial radioembolization (TARE) using microvascular plugs to occlude nontarget vessels temporarily and ...protect normal liver. This technique, defined as temporary vascular occlusion, was performed in 6 patients, with complete vessel occlusion obtained in 5 of the 6 patients and partial occlusion with flow reduction in 1 of the 6 patients. A statistically significant (P = .001) dose decrease of 5.7 ± 3.1 times was measured using postadministration yttrium-90 positron emission tomography/computed tomography in the protected zone compared with that in the treated zone.
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