Omega-3 fatty acid ethyl esters have well-known triglyceride-lowering properties and were shown >30 years ago to inhibit platelet function. With the recent US Food and Drug Administration (FDA) ...approval of these agents for treating severe triglyceride elevations, concerns about excess bleeding naturally arise. However, an objective assessment of the evidence for clinically significant bleeding reveals that such concerns are unfounded. As such, the benefits of triglyceride lowering with omega-3 fatty acids more than outweigh any theoretical risks for increased bleeding.
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.
ABSTRACT The total number of globular clusters (GCs) in a galaxy rises continuously with the galaxy luminosity L, while the relative number of galaxies decreases with L following the Schechter ...function. The product of these two very nonlinear functions gives the relative number of GCs contained by all galaxies at a given L. It is shown that GCs, in this universal sense, are most commonly found in galaxies within a narrow range around L . In addition, blue (metal-poor) GCs outnumber the red (metal-richer) ones globally by 4 to 1 when all galaxies are added, pointing to the conclusion that the earliest stages of galaxy formation were especially favorable to forming massive, dense star clusters.
•Nutrition-based interventions to reduce COVID-19 morbidity/mortality are needed.•The Omega-3 Index (O3I) was measured in banked blood from 100 COVID-19 patients.•Risk for death was analyzed as a ...function of quartiles (Q) of the O3I.•Patients in Q4 (O3I ≥ 5.7%) vs. Q1–3 were 75% less likely to die (p = 0.07).•These pilot data suggest that a higher O3I may lower risk for death from COVID-19.
Very-long chain omega-3 fatty acids (EPA and DHA) have anti-inflammatory properties that may help reduce morbidity and mortality from COVID-19 infection. We conducted a pilot study in 100 patients to test the hypothesis that RBC EPA+DHA levels (the Omega-3 Index, O3I) would be inversely associated with risk for death by analyzing the O3I in banked blood samples drawn at hospital admission. Fourteen patients died, one of 25 in quartile 4 (Q4) (O3I ≥5.7%) and 13 of 75 in Q1–3. After adjusting for age and sex, the odds ratio for death in patients with an O3I in Q4 vs Q1–3 was 0.25, p = 0.07. Although not meeting the classical criteria for statistical significance, this strong trend suggests that a relationship may indeed exist, but more well-powered studies are clearly needed.
Multipotent retinal progenitors undergo a varied number of divisions to produce clones of heterogeneous sizes and cell types. We describe the transition from a proliferating progenitor to a ...differentiated postmitotic cell and discuss how controls of proliferation operate within individual cells as well as in the whole tissue. We discuss how extracellular and intracellular signaling, transcriptional regulation, cell cycle kinetics, interkinetic nuclear migration, orientation of cell division, and epigenetic modifications all interact to regulate a progenitor's transition from division to differentiation. We also propose some directions for future research.
Next-generation sequencing has identified actionable genetic aberrations in intrahepatic cholangiocarcinomas (iCCA), including the fibroblast growth factor receptor 2 (FGFR2) fusions. Derazantinib ...(ARQ 087), an orally bioavailable, multi-kinase inhibitor with potent pan-FGFR activity, has shown preliminary therapeutic activity against FGFR2 fusion-positive iCCA.
This multicentre, phase 1/2, open-label study enrolled adult patients with unresectable iCCA with FGFR2 fusion, who progressed, were intolerant or not eligible to first-line chemotherapy (NCT01752920). Subjects received derazantinib in continuous daily doses. Tumour response was assessed according to RECIST 1.1 every 8 weeks.
Twenty-nine patients (18 women/11 men; median age, 58.7 years), 2 treatment-naive and 27 who progressed after at least one prior systemic therapy, were enrolled. Overall response rate was 20.7%, disease control rate was 82.8%. Estimated median progression-free survival was 5.7 months (95% CI: 4.04-9.2 months). Treatment-related adverse events (AE) were observed in 27 patients (93.1%, all grades), including asthenia/fatigue (69.0%), eye toxicity (41.4%), and hyperphosphatemia (75.9%). Grade ≥ 3 AEs occurred in 8 patients (27.6%).
Derazantinib demonstrated encouraging anti-tumour activity and a manageable safety profile in patients with advanced, unresectable iCCA with FGFR2 fusion who progressed after chemotherapy. A pivotal trial of derazantinib in iCCA is ongoing (NCT03230318).
Radiative feedback is an important consequence of cluster formation in giant molecular clouds (GMCs) in which newly formed clusters heat and ionize their surrounding gas. The process of cluster ...formation, and the role of radiative feedback, has not been fully explored in different GMC environments. We present a suite of simulations which explore how the initial gravitational boundedness, and radiative feedback, affect cluster formation. We model the early evolution (<5 Myr) of turbulent, 106 M⊙ clouds with virial parameters ranging from 0.5 to 5. To model cluster formation, we use cluster sink particles, coupled to a raytracing scheme, and a custom subgrid model which populates a cluster via sampling an initial mass function (IMF) with an efficiency of 20 per cent per free-fall time. We find that radiative feedback only decreases the cluster particle formation efficiency by a few per cent. The initial virial parameter plays a much stronger role in limiting cluster formation, with a spread of cluster formation efficiencies of 37–71 per cent for the most unbound to the most bound model. The total number of clusters increases while the maximum mass cluster decreases with an increasing initial virial parameter, resulting in steeper mass distributions. The star formation rates in our cluster particles are initially consistent with observations but rise to higher values at late times. This suggests that radiative feedback alone is not responsible for dispersing a GMC over the first 5 Myr of cluster formation.
How the site of axon emergence is specified during neural development is not understood. Previous studies disagree on the relative importance of intrinsic and extrinsic mechanisms. The axons of ...retinal ganglion cells (RGCs) emerge basally in vivo, yet because RGCs develop from polarized neuroepithelial cells within a polarized environment, disentangling intrinsic and extrinsic influences is a challenge. We use time-lapse imaging to demonstrate that Laminin acting directly on RGCs is necessary and sufficient to orient axon emergence in vivo. Laminin contact with the basal processes of newborn RGCs prevents the cells from entering a stochastic Stage 2 phase, directs the rapid accumulation of the early axonal marker Kif5c560-YFP, and leads to the formation of axonal growth cones. These results suggest that contact-mediated cues may be critical for the site of axon emergence and account for the differences in cellular behavior observed in vitro and in vivo.
Display omitted
► Axon emergence from RGCs is stochastic in vitro, but is highly directed in vivo ► Laminin is necessary for in vivo behavior and prevents in vitro-like behavior ► Contact with Laminin is sufficient to transform a neurite to an axon in vivo ► Laminin contact directs microtubule changes, leading to axon formation
•Pregnant women with ‘low’ omega-3 blood levels have higher risk for early preterm birth.•DHA supplementation during pregnancy can reduce premature birth rates in higher risk individuals.•There is no ...agreed upon blood DHA level that would define what ‘low’ omega-3 status is.•Blood DHA levels from 6 pregnancy studies were converted to a common DHA metric for comparison.•Having a standardized metric for ‘low’ DHA status is needed for use in clinical practice.
Recent trials in pregnant women on the effects of supplemental DHA on early preterm birth (ePTB) risk have shown that there is a maternal blood docosahexaenoic acid (DHA) level below which risk for ePTB was increased and supplemental DHA was effective at reducing risk. However, DHA levels were expressed in different terms across these trials making cross study comparisons impossible. The purposes of this study were 1) to report interlaboratory conversion factors from study-specific metrics to a common metric, red blood cell (RBC) DHA measured by OmegaQuant Analytics (OQA), and 2) to translate reported pre- and post-treatment DHA levels from these trials into a RBC DHA for comparison. Data from five published and one unpublished study are included. Across these studies, the effects on RBC DHA levels after supplementation with 0, 200, 600, 800 and 1000 mg of DHA were (as a% change from baseline): 0 mg, no change; 200 mg, 15–20% increase; 600 mg, 55–60% increase; 800 mg, 13–65% increase; and 1000 mg, 51% increase. Standardization of fatty acid analysis and reporting and a target omega-3 or DHA level for identifying those for which higher dose DHA supplementation is indicated to prevent ePTB are needed for clinical use.
PDF
