Multiple recent studies have found aberrant expression profiles of microRNAome in human cancers. While several target genes have been experimentally identified for some microRNAs in various tumors, ...the global pattern of cellular functions and pathways affected by co-expressed microRNAs in cancer remains elusive. The goal of this study was to develop a computational approach to global analysis of the major biological processes and signaling pathways that are most likely to be affected collectively by co-expressed microRNAs in cancer cells.
We report results of computational analysis of five datasets of aberrantly expressed microRNAs in five human cancers published by the authors (pancreatic cancer) and others (breast cancer, colon cancer, lung cancer and lymphoma). Using the combinatorial target prediction algorithm miRgate and a two-step data reduction procedure we have determined Gene Ontology categories as well as biological functions, disease categories, toxicological categories and signaling pathways that are: targeted by multiple microRNAs; statistically significantly enriched with target genes; and known to be affected in specific cancers.
Our global analysis of predicted miRNA targets suggests that co-expressed miRNAs collectively provide systemic compensatory response to the abnormal phenotypic changes in cancer cells by targeting a broad range of functional categories and signaling pathways known to be affected in a particular cancer. Such systems biology based approach provides new avenues for biological interpretation of miRNA profiling data and generation of experimentally testable hypotheses regarding collective regulatory functions of miRNA in cancer.
ABSTRACT
High-energy neutrinos are a promising tool for identifying astrophysical sources of high and ultra-high energy cosmic rays (UHECRs). Prospects of detecting neutrinos at high energies (≳TeV) ...from blazars have been boosted after the recent association of IceCube-170922A and TXS 0506+056. We investigate the high-energy neutrino, IceCube-190331A, a high-energy starting event (HESE) with a high likelihood of being astrophysical in origin. We initiated a Swift/XRT and UVOT tiling mosaic of the neutrino localization and followed up with ATCA radio observations, compiling a multiwavelength spectral energy distribution (SED) for the most likely source of origin. NuSTAR observations of the neutrino location and a nearby X-ray source were also performed. We find two promising counterpart in the 90 per cent confidence localization region and identify the brightest as the most likely counterpart. However, no Fermi/LAT γ-ray source and no prompt Swift/BAT source is consistent with the neutrino event. At this point, it is unclear whether any of the counterparts produced IceCube-190331A. We note that the Helix Nebula is also consistent with the position of the neutrino event and we calculate that associated particle acceleration processes cannot produce the required energies to generate a high-energy HESE neutrino.
The large amounts of opioids and the emergence of increasingly potent illicitly manufactured synthetic opioids circulating in the unregulated drug supply in North America and Europe are fueling not ...only the ongoing public health crisis of overdose deaths but also raise the risk of another type of disaster: deliberate opioid release with the intention to cause mass harm. Synthetic opioids are highly potent, rapidly acting, can cause fatal ventilatory depression, are widely available, and have the potential to be disseminated for mass exposure, for example, if effectively formulated, via inhalation or ingestion. As in many other chemical incidents, the health consequences of a deliberate release of synthetic opioid would manifest quickly, within minutes. Such an incident is unlikely, but the consequences could be grave. Awareness of the risk of this type of incident and preparedness to respond are required to save lives and reduce illness. Coordinated planning across the entire local community emergency response system is also critical. The ability to rapidly recognize the opioid toxidrome, education on personal protective actions, and training in medical management of individuals experiencing an opioid overdose are key components of preparedness for an opioid mass casualty incident.
A limitation of current antiplatelet therapies is their inability to separate thrombotic events from bleeding occurrences. A better understanding of the molecular mechanisms leading to platelet ...activation is important for the development of improved therapies. Recently, protein tyrosine phosphatases have emerged as critical regulators of platelet function.
This is the first report implicating the dual-specificity phosphatase 3 (DUSP3) in platelet signaling and thrombosis. This phosphatase is highly expressed in human and mouse platelets. Platelets from DUSP3-deficient mice displayed a selective impairment of aggregation and granule secretion mediated by the collagen receptor glycoprotein VI and the C-type lectin-like receptor 2. DUSP3-deficient mice were more resistant to collagen- and epinephrine-induced thromboembolism compared with wild-type mice and showed severely impaired thrombus formation on ferric chloride-induced carotid artery injury. Intriguingly, bleeding times were not altered in DUSP3-deficient mice. At the molecular level, DUSP3 deficiency impaired Syk tyrosine phosphorylation, subsequently reducing phosphorylation of phospholipase Cγ2 and calcium fluxes. To investigate DUSP3 function in human platelets, a novel small-molecule inhibitor of DUSP3 was developed. This compound specifically inhibited collagen- and C-type lectin-like receptor 2-induced human platelet aggregation, thereby phenocopying the effect of DUSP3 deficiency in murine cells.
DUSP3 plays a selective and essential role in collagen- and C-type lectin-like receptor 2-mediated platelet activation and thrombus formation in vivo. Inhibition of DUSP3 may prove therapeutic for arterial thrombosis. This is the first time a protein tyrosine phosphatase, implicated in platelet signaling, has been targeted with a small-molecule drug.
Autophagy is a lysosomal degradation pathway that converts macromolecules into substrates for energy production during nutrient-scarce conditions such as those encountered in tumor microenvironments. ...Constitutive mitochondrial uptake of endoplasmic reticulum (ER) Ca²⁺ mediated by inositol triphosphate receptors (IP₃Rs) maintains cellular bioenergetics, thus suppressing autophagy. We show that the ER membrane protein Bax inhibitor-1 (BI-1) promotes autophagy in an IP₃R-dependent manner. By reducing steady-state levels of ER Ca²⁺ via IP₃Rs, BI-1 influences mitochondrial bioenergetics, reducing oxygen consumption, impacting cellular ATP levels, and stimulating autophagy. Furthermore, BI-1-deficient mice show reduced basal autophagy, and experimentally reducing BI-1 expression impairs tumor xenograft growth in vivo. BI-1's ability to promote autophagy could be dissociated from its known function as a modulator of IRE1 signaling in the context of ER stress. The results reveal BI-1 as a novel autophagy regulator that bridges Ca²⁺ signaling between ER and mitochondria, reducing cellular oxygen consumption and contributing to cellular resilience in the face of metabolic stress.
Teleosts and other aquatic ectotherms have the ability to withstand prolonged periods of low water temperatures (cold-acclimation) and fasting, and can often respond with phases of accelerated ...(compensatory) growth when favorable conditions are restored. We assessed whether complete feed restriction prior to (24 ...C, days 0-23) and/or during (14 ...C, days 24-114) a simulated period of coldacclimation could elicit episodes of compensatory growth (CG) and catch-up growth upon warm-up to 24 ...C and satiation feeding (days 115-148). Control hybrid striped bass (HSB: Morone chrysops x Morone saxatilis ) were fed to satiation throughout the entire experiment under these temperature fluctuations. Compensatory growth and ultimately catch-up growth were achieved in groups of HSB that were deprived of feed during either the initial period at 24 ...C (days 0-23), during the coldacclimation period (14 ...C, days 24-114), or during both of these periods (days 0-114). Further, it appears that HSB are better able to compensate for weight loss when skeletal length is not significantly compromised during the treatment period, which occurred in HSB feed restricted during cold-acclimation only. The most dramatic CG responses were defined by specific growth rates (SGRs) up to 4.2 times that of controls and were accompanied by hyperphagia and improvements in temporal and overall feed conversion. Levels of plasma insulin-like growth factor (IGF)-1 and muscle IGF-1 mRNA were significantly correlated to growth rate for all groups throughout the experiment (R... = 0.40, 0.23, respectively), with an overcompensation of both observed in HSB with the most elevated SGRs during the CG response. Interestingly, opposing trends were observed between muscle mRNA expression of growth hormone receptor (GHR)-1 and -2, with fasting at 24 ...C and 14 ...C resulting in depressed levels of GHR-1 and elevated levels of GHR-2 relative to controls. Levels of muscle myostatin (MSTN)-1 mRNA were significantly depressed in HSB fasted at 24 ...C and/or 14 ...C while MSTN-2 mRNA was lower following initial feed restriction at 24 ...C. Likewise, levels of unprocessed pro-MSTN (precursor) and mature MSTN protein were both depressed in fasted fish at 24 ...C. This study demonstrates that a previous period of feed restriction and cold-acclimation followed by realimentation at more favorable water temperatures produces a strong CG response and catch-up growth in fish. These studies also suggest that an overcompensation of circulating and local IGF-1 along with changes in MSTN mRNA and protein expression may contribute to accelerated growth rates characteristic of CG. Furthermore, our studies indicate that overall feed conversion can improve by as much as 30% with CG induced through temperature and feeding manipulations with no adverse effects on growth of HSB. This raises the possibility that CG protocols can improve production efficiency of HSB and other temperate teleosts in pond or tank culture. (ProQuest: ... denotes formulae/symbols omitted.)
Sickle cell disease (SCD) is a monogenic hemoglobinopathy associated with significant morbidity and mortality. Cardiopulmonary, vascular and sudden death are the reasons for the majority of young ...adult mortality in SCD. To better understand the clinical importance of multi‐level vascular dysfunction, in 2009 we assessed cardiac function including tricuspid regurgitant jet velocity (TRV), tissue velocity in systole(S′) and diastole (E′), inflammatory, rheologic and hemolytic biomarkers as predictors of mortality in patients with SCD. With up to 9 years of follow up, we determined survival in 95 children, adolescents and adults with SCD. Thirty‐eight patients (40%) were less than 21 years old at initial evaluation. Survival and Cox proportional‐hazards analysis were performed. There was 19% mortality in our cohort, with median age at death of 35 years. In the pediatric subset, there was 11% mortality during the follow up period. The causes of death included cardiovascular and pulmonary complications in addition to other end‐organ failure. On Cox proportional‐hazards analysis, our model predicts that a 0.1 m/s increase in TRV increases risk of mortality 3%, 1 cm/s increase in S′ results in a 91% increase, and 1 cm/s decrease in E′ results in a 43% increase in mortality. While excluding cardiac parameters, higher plasma free hemoglobin was significantly associated with risk of mortality (p=.049). In conclusion, elevated TRV and altered markers of cardiac systolic and diastolic function predict mortality in a cohort of adolescents and young adult patients with SCD. These predictors should be considered when counseling cardiovascular risk and therapeutic optimization at transition to adult providers.
Abstract Objective Paravalvular regurgitation is a known complication after transcatheter and sutureless aortic valve replacement. Paravalvular regurgitation also may develop in patients undergoing ...percutaneous mitral valve replacement. There are few studies on contemporary surgical valve replacement for comparison. We sought to determine the contemporary occurrence of paravalvular regurgitation after conventional surgical valve replacement. Methods We performed a single-center retrospective database review involving 1774 patients who underwent valve replacement surgery from April 2004 to December 2012: aortic in 1244, mitral in 386, and combined aortic and mitral in 144. Follow-up echocardiography was performed in 73% of patients. Patients with endocarditis were analyzed separately from noninfectious paravalvular leaks. Statistical comparisons were performed to determine differences in paravalvular regurgitation incidence and survival. Results During follow-up, 1+ or greater (mild or more) paravalvular regurgitation occurred in 2.2% of aortic cases and 2.9% of mitral cases. There was 2+ or greater (moderate or more) paravalvular regurgitation in 0.9% of aortic and 2.2% of mitral cases ( P = .10). After excluding endocarditis, late noninfectious regurgitation 2+ or greater was detected in 0.5% of aortic and 0.4% of mitral cases ( P = .93); there were no reoperations or percutaneous closures for noninfectious paravalvular regurgitation. Conclusions In an academic medical center, the overall rate of paravalvular regurgitation is low, and late clinically significant noninfectious paravalvular regurgitation is rare. The benchmark for paravalvular regurgitation after conventional valve replacement is high and should be considered when evaluating patients for transcatheter or sutureless valve replacement.
Studies examining the effects of feeding lipid oxidation products (LOPs) to pigs on pork quality and storage stability have mostly focused on refrigerated storage and produced mixed results. We ...investigated the effects of adding yellow grease, containing commercially relevant levels of LOPs, to swine diets on quality and storage stability of ground salted pork. Twenty-four domestic pigs were divided into three study groups and fed the following diet regimens for five months: (1) Standard Diet (STD), (2) STD + yellow grease (YG, high LOPs), or (3) STD + corn oil (CO, negligible LOPs). Post-harvest carcass characteristics and the effects of frozen and refrigerated storage on color and lipid oxidation of salted pork patties were studied. While feeding of yellow grease had no impact on color, it increased the susceptibility of pork patties to lipid oxidation during storage (186% and 73% higher accumulation of LOPs in patties from pigs fed STD + YG when compared to those fed STD and STD + CO, respectively).
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