During chick gastrulation, inhibition of BMP signaling is required for primitive streak formation and induction of Hensen’s node. We have identified a unique secreted protein, Tsukushi (TSK), which belongs to the Small Leucine-Rich Proteoglycan (SLRP) family and is expressed in the primitive streak and Hensen’s node. Grafts of cells expressing TSK in combination with the middle primitive streak induce an ectopic Hensen’s node, while electroporation of TSK siRNA inhibits induction of the node. In Xenopus embryos, TSK can block BMP function and induce a secondary dorsal axis, while it can dorsalize ventral mesoderm and induce neural tissue in embryonic explants. Biochemical analysis shows that TSK binds directly to both BMP and chordin and forms a ternary complex with them. These observations indicate that TSK is an essential dorsalizing factor involved in the induction of Hensen’s node.
Engrailed-2 (En-2), a homeodomain transcription factor, is expressed in a caudal-to-rostral gradient in the developing mid-brain, where it has an instructive role in patterning the optic tectum—the target of topographic retinal input1,2. In addition to its well-known role in regulating gene expression through its DNA-binding domain, En-2 may also have a role in cell–cell communication, as suggested by the presence of other domains involved in nuclear export, secretion and internalization3. Consistent with this possibility, here we report that an external gradient of En-2 protein strongly repels growth cones of Xenopus axons originating from the temporal retina and, conversely, attracts nasal axons. Fluorescently tagged En-2 accumulates inside growth cones within minutes of exposure, and a mutant form of the protein that cannot enter cells fails to elicit axon turning. Once internalized, En-2 stimulates the rapid phosphorylation of proteins involved in translation initiation and triggers the local synthesis of new proteins. Furthermore, the turning responses of both nasal and temporal growth cones in the presence of En-2 are blocked by inhibitors of protein synthesis. The differential guidance of nasal and temporal axons reported here suggests that En-2 may participate directly in topographic map formation in the vertebrate visual system.
TGF-β, a mediator of pulmonary fibrosis, is a genetic modifier of CF respiratory deterioration. The mechanistic relationship between TGF-β signaling and CF lung disease has not been determined.
To investigate myofibroblast differentiation in CF lung tissue as a novel pathway by which TGF-β signaling may contribute to pulmonary decline, airway remodeling and tissue fibrosis.
Lung samples from CF and non-CF subjects were analyzed morphometrically for total TGF-β1, TGF-β signaling (Smad2 phosphorylation), myofibroblast differentiation (α-smooth muscle actin), and collagen deposition (Masson trichrome stain).
TGF-β signaling and fibrosis are markedly increased in CF (p<0.01), and the presence of myofibroblasts is four-fold higher in CF vs. normal lung tissue (p<0.005). In lung tissue with prominent TGF-β signaling, both myofibroblast differentiation and tissue fibrosis are significantly augmented (p<0.005).
These studies establish for the first time that a pathogenic mechanism described previously in pulmonary fibrosis is also prominent in cystic fibrosis lung disease. The presence of TGF-β dependent signaling in areas of prominent myofibroblast proliferation and fibrosis in CF suggests that strategies under development for other pro-fibrotic lung conditions may also be evaluated for use in CF.
Cell adhesion molecules and diffusible cues both regulate axon pathfinding, yet how these two modes of signalling interact is poorly understood. The homophilic cell adhesion molecule, NF-protocadherin (NFPC) is expressed in the mid-dorsal optic tract neuroepithelium and in the axons of developing retinal ganglion cells (RGC). Here we report that targeted disruption of NFPC function in RGC axons or the optic tract neuroepithelium results in unexpectedly localized pathfinding defects in the mid-optic tract. Sema3A, which lies adjacent to this turn, stimulates rapid protein synthesis-dependent increases in growth cone NFPC and its cofactor, TAF1, in vitro. In vivo, growth cones exhibit marked increases in NFPC translation reporter activity in this mid-optic tract region that are attenuated by blocking Neuropilin-1 function. Our results suggest that translation-linked coupling between regionally localised diffusible cues and cell adhesion can help axons navigate discrete segments of the pathway.
The eye is a peripheral outpost of the central nervous system (CNS) where the retinal ganglion cells (RGCs) reside. RGC axons navigate to their targets in a remarkably stereotyped and error-free manner and it is this process of directed growth that underlies the complex organization of the adult brain. The RGCs are the only retinal neurons to project into the brain and their peripheral location makes them an unusually accessible population of projection neurons for experiments involving in vivo gene transfer, anatomical tracing, transplantation and in vitro culture. In this paper, we review recent findings that have contributed to our understanding of some of the guidance decisions that axons make in the developing visual system. We look at two choice points in the pathway, the optic nerve head (onh) and the midline chiasm, and discuss evidence that supports the idea that key molecules in guiding axon growth at these junctures are netrin-1 (onh) and ephrin-B (chiasm). In the optic tectum where RGC axon terminals are arrayed in topographic order, we present experimental evidence to suggest that in the dorso-ventral dimension, the B-type ephrins and Eph receptors are of prime importance, possibly through attractive interactions. This complements the anterior-posterior topographic mapping known to be mediated through A-type ephrin/Eph repulsive interactions. An emerging theme is that guidance molecules such as ephrin-B and netrin-1 have complex patterns of restricted expression in the pathway and play multiple and changing roles in axon guidance.
retina; axon guidance; netrin; Eph receptor; ephrin
It has been proposed that growth cones navigating through gradients adapt to baseline concentrations of guidance cues. This adaptation process is poorly understood. Using the collapse assay, we show that adaptation in Xenopus laevis retinal growth cones to the guidance cues Sema3A or netrin-1 involves two processes: a fast, ligand-specific desensitization that occurs within 2 min of exposure and is dependent on endocytosis, and a slower, ligand-specific resensitization, which occurs within 5 min and is dependent upon protein synthesis. These two phases of adaptation allow retinal axons to adjust their range of sensitivity to specific guidance cues.
In Xenopus tadpoles, all retinal ganglion cells (RGCs) send axons contralaterally across the optic chiasm. At metamorphosis, a subpopulation of EphB-expressing RGCs in the ventrotemporal retina begin to project ipsilaterally. However, when these metamorphic RGCs are grafted into embryos, they project contralaterally, suggesting that the embryonic chiasm lacks signals that guide axons ipsilaterally. Ephrin-B is expressed discretely at the chiasm of metamorphic but not premetamorphic Xenopus. When expressed prematurely in the embryonic chiasm, ephrin-B causes precocious ipsilateral projections from the EphB-expressing RGCs. Ephrin-B is also found in the chiasm of mammals, which have ipsilateral projections, but not in the chiasm of fish and birds, which do not. These results suggest that ephrin-B/EphB interactions play a key role in the sorting of axons at the vertebrate chiasm.
Recent clinical studies that evaluated the effects of supplemental omega-3 polyunsaturated fatty acids (n-3 PUFAs) on sudden cardiac death have yielded conflicting results. Our aim was to clarify this issue using an established and clinical relevant canine model of sudden cardiac death.
Methods and Results
Susceptibility to ventricular fibrillation (VF) was evaluated using a 2 minute left circumflex artery occlusion during the last minute of an exercise test in 76 dogs (from two independent studies) with healed myocardial infarctions (MI); 44 developed VF (susceptible, VF+) while 32 did not (resistant, VF−). These dogs were then randomly assigned to either placebo (1 g/day, corn oil; 15 VF+, 11 VF−) or n-3 PUFA (1–4 g/day, docosahexaenoic acid + eicosapentaenoic acid ethyl esters, 29 VF+, 21 VF−) groups. Seven sham (no-MI) dogs were also treated with n-3 PUFA (4 g/day). After treatment (3 months), the exercise + ischemia test was repeated. Dietary n-3 PUFAs produced significant (P<0.01) increases in red blood cell and left ventricular n-3 PUFA levels. Nine post MI (5 placebo vs. 4 n-3 PUFA) and 2 sham dogs died suddenly during the 3-month treatment period. The n-3 PUFA treatment failed to prevent arrhythmias in VF+ dogs (decreased in 27% placebo vs. 24% n-3 PUFA, P=0.5646) but induced VT/VF in VF− animals (n-3 PUFA 33% vs. placebo 0%, P=0.0442).
Despite large increases in cardiac tissue n-3 PUFA content, dietary n-3 PUFAs did not prevent ischemia-induced VF and actually increased arrhythmia susceptibility in both non-infarcted and low risk post-MI dogs.
omega-3 polyunsaturated fatty acids; fish oil; ventricular fibrillation; myocardial ischemia; myocardial infarction
Omega-3 fatty acids reduced heart rate (HR) and blood pressure (BP) in some studies, but dose–response studies are rare, and little is known about underlying mechanisms.
We examined effects of 0.85 g/day eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) (low dose) and 3.4 g/day EPA + DHA (high dose) on HR and systemic hemodynamics during rest, speech, and foot cold pressor tasks.
This was a dose–response, placebo-controlled, double-blind, randomized, crossover trial (8-week treatment, 6-week washout) in 26 adults.
Throughout the testing sessions, HR was reduced in a dose-dependent manner. The high dose reduced BP and stroke volume and increased pre-ejection period. Reductions in BP were associated with increases in erythrocyte omega-3 fatty acids.
High-dose long-chain omega-3 fatty acids can reduce BP and HR, at rest and during stress. These findings suggest that at-risk populations may achieve benefits with increased omega-3 intake.
Omega-3; Fish; Hemodynamics; Acute stress
Long chain omega-3 fatty acids (FAs) are effective for reducing plasma triglyceride (TG) levels. At the pharmaceutical dose, 3.4 g/day, they reduce plasma TG by about 25-50% after one month of treatment, resulting primarily from the decline in hepatic very low density lipoprotein (VLDL-TG) production, and secondarily from the increase in VLDL clearance. Numerous mechanisms have been shown to contribute to the TG overproduction, but a key component is an increase in the availability of FAs in the liver. The liver derives FAs from three sources: diet (delivered via chylomicron remnants), de novo lipogenesis, and circulating non-esterified FAs (NEFAs). Of these, NEFAs contribute the largest fraction to VLDL-TG production in both normotriglyceridemic subjects and hypertriglyceridemic, insulin resistant patients. Thus reducing NEFA delivery to the liver would be a likely locus of action for fish oils (FO). The key regulator of plasma NEFA is intracellular adipocyte lipolysis via hormone sensitive lipase (HSL), which increases as insulin sensitivity worsens. FO counteracts intracellular lipolysis in adipocytes by suppressing adipose tissue inflammation. In addition, FO increases extracellular lipolysis by lipoprotein lipase (LpL) in adipose, heart and skeletal muscle and enhances hepatic and skeletal muscle β-oxidation which contributes to reduced FA delivery to the liver. FO could activate transcription factors which control metabolic pathways in a tissue specific manner regulating nutrient traffic and reducing plasma TG.
fish oil; omega-3; plasma triglycerides; lipolysis; NEFA; eicosapentaenoic acid; docosahexaenoic acid
Within the developing vertebrate retina, particular subtypes of amacrine cells (ACs) tend to arise from progenitors expressing the bHLH transcription factor, Atoh7, which is necessary for the early generation of retinal ganglion cells (RGCs). All ACs require the post-mitotic expression of the bHLH transcription factor Ptf1a, however Ptf1a alone is not sufficient to give subtype identities. Here we use functional and in vivo time-lapse studies in the zebrafish retina to investigate on the developmental programs leading to ACs specification within the subsequent divisions of Atoh7-positive progenitors. We find evidences that the homeobox transcription factor Barhl2 is an AC subtype identity-biasing factor that turns on within Atoh7-positive descendants. In vivo lineage tracing reveals that particular modes of cell division tend to generate Barhl2-positive precursors from sisters of RGCs. Additionally, Atoh7 indirectly impacts these division modes to regulate the right number of barhl2-expressing cells. We finally find that Atoh7 itself influences the subtypes of Barhl2-dependent ACs. Taken together, our study uncovers lineage-related and molecular logic of subtype specification in the vertebrate retina, by showing that specific AC subtypes arise via a particular mode of cell division and a transcriptional network cascade involving the sequential expression of first atoh7 followed by ptf1a and then barhl2.
fate determination; cell lineage; Barhl2; subtype specification; retina; zebrafish
Several studies have successfully produced a variety of neural cell types from human embryonic stem cells (hESCs), but there has been limited systematic analysis of how different regional identities are established using well-defined differentiation conditions. We have used adherent, chemically defined cultures to analyse the roles of Activin/Nodal, bone morphogenetic protein (BMP), fibroblast growth factor (FGF) and Wnt/β-catenin signalling in neural induction, anteroposterior patterning and eye field specification in hESCs. We show that either BMP inhibition or activation of FGF signalling is required for effective neural induction, but these two pathways have distinct outcomes on rostrocaudal patterning. While BMP inhibition leads to specification of forebrain/midbrain positional identities, FGF-dependent neural induction is associated with strong posteriorization towards hindbrain/spinal cord fates. We also demonstrate that Wnt/β-catenin signalling is activated during neural induction and promotes acquisition of neural fates posterior to forebrain. Therefore, inhibition of this pathway is needed for efficient forebrain specification. Finally, we provide evidence that the levels of Activin/Nodal and BMP signalling have a marked influence on further forebrain patterning and that constitutive inhibition of these pathways represses expression of eye field genes. These results show that the key mechanisms controlling neural patterning in model vertebrate species are preserved in adherent, chemically defined hESC cultures and reveal new insights into the signals regulating eye field specification.
human embryonic stem cells; neuroectoderm; anteroposterior patterning; forebrain; eye field
Red blood cell (RBC) levels of eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA, the omega-3 index, expressed as a percent of total fatty acids) are inversely related to risk for cardiovascular disease (CVD). Although several mechanisms underlying this relationship have been proposed, understanding the associations between the omega-3 index and markers of CVD in the community can shed additional light on this question. The objectives of this study were to define the relations between the omega-3 index and clinical factors and to determine the heritability of the omega-3 index.
RBC samples (n = 3196) drawn between 2005 and 2008 from participants in the Framingham Study [Examination 8 of the Offspring cohort plus Examination 3 of the Omni (minorities) cohort] were analyzed for fatty acid composition by gas chromatography.
The mean (SD) omega-3 index was 5.6% (1.7%). In multivariable regression models, the factors significantly and directly associated with the omega-3 index were age, female sex, higher education, fish oil supplementation, dietary intake of EPA + DHA, aspirin use, lipid pharmacotherapy, and LDL-cholesterol. Factors inversely associated were Offspring cohort, heart rate, waist girth, triglycerides and smoking. The total explained variability in the omega-3 index for the fully adjusted model was 73%, which included major components due to heritability (24%), EPA + DHA intake (25%), and fish oil supplementation (15%).
The variability in the omega-3 index is determined primarily by dietary and genetic factors. An increased omega-3 index is associated with a generally cardioprotective risk factor milieu.
Epidemiology; Cardiovascular disease; Risk factors; Omega-3 fatty acids; Erythrocytes; Heritability
To determine the extent to which levels of membrane eicosapentaenoic (EPA)+docosahexaenoic acids (DHA) (the omega-3 index) were associated with depression in patients with acute coronary syndrome (ACS). Depression is associated with worse cardiovascular (CV) outcomes in patients with ACS. Reduced levels of blood cell membrane omega-3 (n-3) fatty acids (FAs), an emerging risk factor for both CV disease and depression, may help to explain the link between depression and adverse CV outcomes.
We measured membrane FA composition in 759 patients with confirmed ACS. The analysis included not only EPA and DHA but also the n-6 FAs linoleic and arachidonic acids (LA and AA). Depressive symptoms were measured with the Patient Health Questionnaire-9 (PHQ). Multivariable linear regression was used to adjust for demographic and clinical characteristics.
There was a significant inverse relationship between the n-3 index and depressive symptoms (PHQ) in the fully adjusted model (p = .034). For every 4.54% point rise in the n-3 index, there was a 1-point decline in depressive symptoms. In contrast to the n-3 FAs, membrane levels of the n-6 FAs LA and AA were not different between depressed and nondepressed ACS patients.
We found an inverse relationship between the n-3 index and the prevalence of depressive symptoms in patients with ACS. Therefore, this study supports the hypothesis that reduced n-3 FA tissue levels are a common and potentially modifiable link between depression and adverse CV outcomes.
depression; acute coronary syndrome; omega-3 fatty acids
How synaptic neuropil is formed within the CNS is poorly understood. The retinal inner plexiform layer (IPL) is positioned between the cell bodies of amacrine cells (ACs) and retinal ganglion cells (RGCs). It consists of bipolar cell (BC) axon terminals that synapse on the dendrites of ACs and RGCs intermingled with projections from Müller glia (MG). We examined whether any of these cellular processes are specifically required for the formation of the IPL. Using genetic and pharmacological strategies, we eliminated RGCs, ACs, and MG individually or in combination. Even in the absence of all of these partner cells, an IPL-like neuropil consisting of only BC axon terminals still forms, complete with presynaptic specializations and sublaminar organization. Previous studies have shown that an IPL can form in the complete absence of BCs; therefore, we conclude that neither presynaptic nor postsynaptic processes are individually essential for the formation of this synaptic neuropil.
► Bipolar cells are among the first cell types to colonize the nascent IPL ► Presynaptic BCs can autonomously build an IPL-like neuropil ► The BC-only neuropil exhibits sublaminar structure and presynaptic specializations ► No single contributing cell type is essential for the formation of the IPL
There has been little work on the cellular requirements for the formation of synaptic neuropil. In studying the development of the retinal inner plexiform layer (IPL), Harris and colleagues demonstrate that the axons of retinal interneurons, bipolar cells, will form a neuropil in the absence of all partner cells in vivo. These results suggest that neuropil formation in the vertebrate CNS may not require interactions between cell types but instead may result from the coordinated action of multiple autonomously stratifying cell types.
Unlike healthy adult tissues, cancers produce energy mainly by aerobic glycolysis instead of oxidative phosphorylation1. This adaptation, called the Warburg effect, may be a feature of all dividing cells, both normal and cancerous2, or it may be specific to cancers3. Whether in a normally growing tissue during development, proliferating and postmitotic cells produce energy in fundamentally different ways is not known. Here we show in the embryonic Xenopus retina in vivo, that dividing progenitor cells depend less on oxidative phosphorylation for ATP production than non-dividing differentiated cells, and instead use glycogen to fuel aerobic glycolysis. The transition from glycolysis to oxidative phosphorylation is connected to the cell differentiation process. Glycolysis is indispensable for progenitor proliferation and biosynthesis, even when it is not used for ATP production. These results suggest that the Warburg effect can be a feature of normal proliferation in vivo, and that the regulation of glycolysis and oxidative phosphorylation is critical for normal development.
In a recent study, we showed that the combination of aspirin plus the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) synergistically inhibited platelet function. As aspirin, EPA, and DHA have demonstrated anti-inflammatory properties, we hypothesized that the ingestion of EPA and DHA, with and without aspirin, would reduce plasma levels of inflammatory cytokines and angiogenesis factors more than aspirin alone and before aspirin was ingested.
Using multiplex technology, we investigated the effects of aspirin (single-dose 650 mg on day 1), EPA+DHA (3.4 g/d for days 2-29), and aspirin with EPA+DHA (day 30) on plasma levels of inflammatory cytokines and angiogenesis factors in healthy adults.
Aspirin alone had no effect on any factor versus baseline, but EPA+DHA, with and without aspirin, significantly reduced concentrations of 8 of 9 factors. Although EPA+DHA plus aspirin reduced concentrations of a subset of the factors compared to baseline, neither aspirin alone nor the combination significantly reduced the level of any analyte more robustly than EPA+DHA alone.
These data suggest that EPA+DHA has more pronounced down-regulatory effects on inflammation and angiogenesis than aspirin. The implications of these findings for the use of combined therapy for cardiovascular disease remain to be clarified.
eicosapentaenoic acid; docosahexaenoic acid; lipid mediators; fatty acids; angiogenesis; hemostasis; platelet function; cytokines; aspirin
Studies of depressed psychiatric patients have shown that antidepressant efficacy can be increased by augmentation with omega-3 fatty acids (FAs). The purpose of this study was to determine whether omega-3 augmentation improves the response to sertraline in patients with major depression and documented coronary heart disease (CHD). One hundred twenty-two patients with major depression and CHD were given 50 mg/day of sertraline (Zoloft™) and randomized in double-blind fashion to 2g/day of omega-3 (Lovaza™) or to corn oil placebo capsules. Adherence to the medication regimen was 97% in both groups for both medications. The levels of omega-3 (percent DHA+EPA in red blood cells) were nearly identical between the groups at baseline; the level changed during the intervention phase in the omega-3 arm to the expected level, but it remained stable in the placebo arm. Neither weekly Beck Depression Inventory (BDI-II) scores (p = .38) nor pre-post BDI-II scores (p = .44) differed between the omega-3 and placebo groups. The rates of depression remission (BDI-II ≤ 8) and response (>50% reduction in BDI-II from baseline) were also nearly identical. In conclusion, this trial yielded no evidence that omega-3 augmentation increases the efficacy of sertraline for comorbid major depression in CHD. Whether higher doses of omega-3, longer treatment, or the use of omega-3 as a monotherapy can improve depression in patients with stable heart disease remains to be determined.
A fundamental question in developmental neuroscience is how a collection of progenitor cells proliferates and differentiates to create a brain of the appropriate size and cellular composition. To address this issue, we devised lineage-tracing assays in developing zebrafish embryos to reconstruct entire retinal lineage progressions in vivo and thereby provide a complete quantitative map of the generation of a vertebrate CNS tissue from individual progenitors. These lineage data are consistent with a simple model in which the retina is derived from a set of equipotent retinal progenitor cells (RPCs) that are subject to stochastic factors controlling lineage progression. Clone formation in mutant embryos reveals that the transcription factor Ath5 acts as a molecular link between fate choice and mode of cell division, giving insight into the elusive molecular mechanisms of histogenesis, the conserved temporal order by which neurons of different types exit the cell cycle.
► Method for full live lineage tracing of retinal cells in vivo ► Demonstration that retinal clone growth is representative of retinal growth ► A stochastic model accurately predicts clone growth from equipotent progenitors ► Links between mode of cell division and cell fate help explain histogenesis
A key question in developmental neuroscience is how a collection of progenitors proliferates and differentiates to create a brain of the consistent size and composition. He et al. use lineage tracing to reconstruct the full retinal lineages in vivo and propose a model for stochastic control of lineage progression.
This study involves a reanalysis of data from a randomized controlled trial to examine whether child-parent psychotherapy (CPP), an empirically based treatment focusing on the mother-child relationship as the vehicle for child improvement, is efficacious for children who experienced multiple traumatic and stressful life events (TSEs).
Participants comprised 75 preschool-aged children and their mothers referred to treatment following the child’s exposure to domestic violence. Dyads were randomly assigned to CPP or to a comparison group that received monthly case management plus referrals to community services and were assessed at intake, posttest, and 6-month follow-up. Treatment effectiveness was examined by level of child TSE risk exposure (<4 risks versus 4+ TSEs).
For children in the 4+ risk group, those who received CPP showed significantly greater improvements in PTSD and depression symptoms, PTSD diagnosis, number of co-occurring diagnoses, and behavior problems compared to those in the comparison group. CPP children with <4 risks showed greater improvements in symptoms of PTSD than those in the comparison group. Mothers of children with 4+ TSEs in the CPP group showed greater reductions in symptoms of PTSD and depression than those randomized to the comparison condition. Analyses of 6-month follow-up data suggest improvements were maintained for the high risk group.
The data provide evidence that CPP is effective in improving outcomes for children who experienced four or more TSEs and had positive effects for their mothers as well.
Numerous studies show that exposure to childhood trauma and adversity has negative consequences for later physical and mental health, but few interventions have been specifically evaluated to determine their effectiveness for children who experienced multiple TSEs. The findings suggest that including the mother as an integral participant in the child’s treatment may be particularly effective in the treatment of young children exposed to multiple risks.
The use of zone-doubled Fresnel zone plates for sub-20 nm spatial resolution in full-field transmission X-ray microscopy and tomography at the hard X-ray regime (8–10 keV) is demonstrated.
Full-field transmission X-ray microscopy is a unique non-destructive technique for three-dimensional imaging of specimens at the nanometer scale. Here, the use of zone-doubled Fresnel zone plates to achieve a spatial resolution better than 20 nm in the hard X-ray regime (8–10 keV) is reported. By obtaining a tomographic reconstruction of a Ni/YSZ solid-oxide fuel cell, the feasibility of performing three-dimensional imaging of scientifically relevant samples using such high-spatial-resolution Fresnel zone plates is demonstrated.
Fresnel zone plate; hard X-rays; full-field transmission X-ray microscopy; solid-oxide fuel cell
Omega-3 fatty acids have multiple cardiovascular benefits, but may also inhibit platelet aggregation and increase bleeding risk. If this platelet inhibition is clinically meaningful, patients with the highest omega-3 indices (red blood cell eicosapentaenoic [EPA] plus docosahexaenoic acid [DHA]), which reflect long-term omega-3 fatty acid intake, should be at the greatest bleeding risk. We studied 1,523 patients from 24 US centers who had their omega-3 index assessed at the time of AMI. The rates of serious bleeding (TIMI major or minor) and mild-moderate bleeding (TIMI minimal) were identified in patients with low (<4%), intermediate (4–8%) and high (>8%) omega-3 indices. There were no differences in bleeding across omega-3 index categories. After multivariable adjustment, there remained no association between the omega-3 index and either serious (per 2% increase: RR 1.03, 95% CI 0.90–1.19) or mild-moderate (per 2% increase: RR 1.02, 95% CI 0.85–1.23) bleeding. In conclusion, we found no relationship between the omega-3 index and bleeding in this large, multicenter cohort of AMI patients, suggesting that concerns about bleeding should not preclude use of omega-3 supplements or increased fish consumption when clinically indicated.
myocardial infarction; bleeding; fatty acids; omega-3; eicosapentaenoic acids; docosahexaenoic acids; outcomes
When neurons exit the cell cycle after their terminal mitosis, they detach from the apical surface of the neuroepithelium. Despite the fact that this detachment is crucial for further neurogenesis and neuronal migration, the underlying mechanisms are still not understood. Here, taking advantage of the genetics and imaging possibilities of the zebrafish retina as a model system, we show by knock down experiments that the guidance molecule Slit1b as well as its receptor Robo3 are required for apical retraction of retinal ganglion cells (RGCs). In contrast, N-cadherin seems to be responsible for maintenance of apical attachment as expression of dominant-negative N-cadherin causes RGCs to lose apical attachments prematurely and rescues retraction in slit1b morphants. These results suggest that Slit-Robo signaling downregulates N-cadherin activity to allow apical retraction in newly generated RGCs.
zebrafish; retinal ganglion cell; slit/robo; cadherin; apical retraction
Transforming growth factor beta-1 (TGF-β1) is an important genetic modifier of lung disease severity in cystic fibrosis (CF), yet the mechanism behind this disease association remains unknown. Initial steps in the investigation of the relationship between TGF-β1 and CF lung disease include determining the most appropriate available biospecimen for TGF-β1 protein measurement.
In hospitalized pediatric CF patients, plasma TGF-β1 is increased in association with clinical parameters of lung disease severity.
Serum and plasma were obtained pre- and post intravenous antibiotic therapy in pediatric CF patients hospitalized for a pulmonary exacerbation. Total TGF-β1, measured via ELISA, was compared with markers of lung disease, including airway microbiology, lung function and response to therapy.
Forty CF children were studied, 15 of whom underwent bronchoalveolar lavage (BAL) at the time of admission. Plasma TGF-β1 positively correlated with BAL fluid TGF-β1 (r = .59, p < .05). Admission plasma TGF-β1 was increased in subjects positive for Pseudomonas aeruginosa (p = .014) and was inversely associated with diminished lung function (p < .038) after therapy. Treatment with antibiotics significantly decreased plasma TGF-β1 (p < .001). Serum TGF-β1 was not associated with plasma TGF-β1, BALF TGF-β1 or these clinical parameters of lung disease.
In pediatric CF, plasma (but not serum) TGF-β1 is increased in association with Pseudomonas infection and lung disease, and is reduced in response to therapy. These findings emphasize the importance of optimizing biospecimen selection for future studies investigating the role of TGF-β1 in CF lung disease.
Genetic modifiers; airway remodeling; lung disease; bronchoalveolar lavage fluid; blood; serum