Loss of symmetric cell division of apical neural progenitors drives DENND5A-related developmental and epileptic encephalopathy.

Developmental and epileptic encephalopathies (DEEs) feature altered brain development, developmental delay and seizures, with seizures exacerbating developmental delay. Here we identify a cohort with biallelic variants in DENND5A, encoding a membrane trafficking protein, and develop animal models with phenotypes like the human syndrome. We demonstrate that DENND5A interacts with Pals1/MUPP1, components of the Crumbs apical polarity complex required for symmetrical division of neural progenitor cells. Human induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell division with an inherent propensity to differentiate into neurons. These phenotypes result from misalignment of the mitotic spindle in apical neural progenitors. Cells lacking DENND5A orient away from the proliferative apical domain surrounding the ventricles, biasing daughter cells towards a more fate-committed state, ultimately shortening the period of neurogenesis. This study provides a mechanism for DENND5A-related DEE that may be generalizable to other developmental conditions and provides variant-specific clinical information for physicians and families

Validation Of 13 Hot And Potentially Terrestrial TESS Planets

The James Webb Space Telescope will be able to probe the atmospheres and surface properties of hot, terrestrial planets via emission spectroscopy. We identify 18 potentially terrestrial planet candidates detected by the Transiting Exoplanet Survey Satellite (TESS) that would make ideal targets for these observations. These planet candidates cover a broad range of planet radii (Rp ∼ 0.6–2.0R⊕) and orbit stars of various magnitudes (Ks = 5.78–10.78, V = 8.4–15.69) and effective temperatures (Teff ∼ 3000–6000 K). We use ground-based observations collected through the TESS Follow-up Observing Program (TFOP) and two vetting tools—DAVE and TRICERATOPS—to assess the reliabilities of these candidates as planets. We validate 13 planets: TOI-206 b, TOI-500 b, TOI-544 b, TOI-833 b, TOI-1075 b, TOI-1411 b, TOI-1442 b, TOI-1693 b, TOI-1860 b, TOI-2260 b, TOI-2411 b, TOI-2427 b, and TOI-2445 b. Seven of these planets (TOI-206 b, TOI-500 b, TOI-1075 b, TOI-1442 b, TOI-2260 b, TOI-2411 b, and TOI-2445 b) are ultra-short-period planets. TOI-1860 is the youngest (133 ± 26 Myr) solar twin with a known planet to date. TOI-2260 is a young (321 ± 96 Myr) G dwarf that is among the most metal-rich ([Fe/H] = 0.22 ± 0.06 dex) stars to host an ultra-short-period planet. With an estimated equilibrium temperature of ∼2600 K, TOI-2260 b is also the fourth hottest known planet with Rp \u3c 2 R⊕

Purinergic signalling and immune cells

This review article provides a historical perspective on the role of purinergic signalling in the regulation of various subsets of immune cells from early discoveries to current understanding. It is now recognised that adenosine 5'-triphosphate (ATP) and other nucleotides are released from cells following stress or injury. They can act on virtually all subsets of immune cells through a spectrum of P2X ligand-gated ion channels and G protein-coupled P2Y receptors. Furthermore, ATP is rapidly degraded into adenosine by ectonucleotidases such as CD39 and CD73, and adenosine exerts additional regulatory effects through its own receptors. The resulting effect ranges from stimulation to tolerance depending on the amount and time courses of nucleotides released, and the balance between ATP and adenosine. This review identifies the various receptors involved in the different subsets of immune cells and their effects on the function of these cells

Testing masting mechanisms of boreal forest species at different stand densities

Mast seeding is considered a reproductive trait resulting from several potential evolutionary forces. Although the mechanisms driving reproduction have been thoroughly investigated and discussed, their relative importance and possible coexistence remain an open question. Seed rain abundance and viability of balsam fir Abies balsamea, white spruce Picea glauca, and white birch Betula papyrifera were monitored during 1994-2007 along a chronosequence of developmental stages at different densities represented by four stands in the boreal forest of Quebec, Canada. The aim of the study was to verify whether seeding temporal dynamics and abundance were affected by stand density, and to test the causal relationships between the hypotheses of pollination efficiency and predator satiation. Seed rain abundance varied substantially among years and species, with the highest values being observed in 1994 and 1996, and attaining up to 28.2 × 10 3 seeds m -2 year -1. However, the annual dynamics of seed production was similar in the three sites with the higher densities. The greater proportions of germinating and dead seeds were observed in white birch, while balsam fir showed an average of 11.2% of damaged seeds, which were infected by larvae. The conifer species had the higher proportions of empty seeds. The causal models tested on balsam fir demonstrated that seed rain abundance influenced the amount of both viable and larval-infected seeds, although no causal relationship existed between these last two variables. The comparable and synchronous seed rain abundances observed among sites demonstrated that stand density can significantly affect the reproduction of trees, probably by limiting the access to resources, but not the annual dynamics of seeding. Pollination efficiency and predator satiation are important forces in the reproductive effort of trees and could be not mutually exclusive because both these mechanisms of natural selection synergistically coexist in driving the seeding dynamics of balsam fir

Towards a Framework for Steering Safety Performance: A Review of the Literature on Leading Indicators

While remarkable progress has been made recently to improve the state of occupational safety, the number of occupational accidents is still unacceptable. In addition, the organizational costs related to these safety problems in the workplace are staggering. Therefore, effective strategies are needed to guide the continuous improvement of safety performance. Common approaches include setting safety goals, identifying the key activities/interventions to reach those goals, and evaluating performance. The most challenging and fundamental issue within these approaches is evaluating safety performance. While it has been a focus of safety professionals, concerns still exist among researchers with regard to how safety performance can be appropriately and accurately measured to improve decision support systems. Recently, researchers in the field of safety have begun directing efforts towards new approaches for measuring safety performance by addressing leading indicators. However, because of its nature and utility, the ideas and concepts of leading indicators have remained unclear. In an effort to overcome this challenge, this study attempts to distinguish between the two common aspects of safety performance, observable activities and outcomes. The importance of using leading indicators for steering safety performance is then highlighted. In order to meet these objectives, the results chain model, which has been introduced by several researchers for outlining the program development, is employed. The elements of the results chain model are then interrelated with relevant safety concepts. As a result, the relationship between the leading and lagging indicators and safety performance is identified. A set of leading indicators that predict safety performance is proposed. Further, the important implications of this study for both academic communities and practitioners are discussed as well