Plk4 Regulates Centriole Asymmetry and Spindle Orientation in Neural Stem Cells

Defects in mitotic spindle orientation (MSO) disrupt the organization of stem cell niches impacting tissue morphogenesis and homeostasis. Mutations in centrosome genes reduce MSO fidelity, leading to tissue dysplasia and causing several diseases such as microcephaly, dwarfism, and cancer. Whether these mutations perturb spindle orientation solely by affecting astral microtubule nucleation or whether centrosome proteins have more direct functions in regulatingMSO is unknown. To investigate this question, we analyzed the consequences of deregulating Plk4 (the master centriole duplication kinase) activity in Drosophila asymmetrically dividing neural stem cells. We found that Plk4 functions upstream of MSO control, orchestrating centriole symmetry breaking and consequently centrosome positioning. Mechanistically, we show that Plk4 acts through Spd2 phosphorylation, which induces centriole release from the apical cortex. Overall, this work not only reveals a role for Plk4 in regulating centrosome function but also links the centrosome biogenesis machinery with the MSO apparatus.ERC starting grant CentroStemCancer [242598]; Institut Curie; CNRS; NCI [P30CA23074]; NIGMS [R01 GM110166, GM126035]; FRM; IC; FRM installation grant; ATIP grantOpen access articleThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Dry Eye Diseases and Ocular Surgery: Practical Guidelines for Canadian Eye Care Practitioners

In 2014, the Canadian Dry Eye Disease Consensus Panel published Guidelines for screening, diagnosis and management of dry eye diseases (DED). These did not address the implications of DED for individuals who are being considered for or have recently undergone ocular surgery. DED is common in certain surgical cohorts, and the perisurgical setting poses specific challenges, both because surgery can complicate preexisting DED and because symptomatic and non-symptomatic DED place the patient at risk of poor surgical outcomes. The Consensus Panel has developed this Addendum to the 2014 Guidelines to offer guidance on DED care before and after ocular surgery

Ankyrin G restricts ion channel diffusion at the axonal initial segment before the establishment of the diffusion barrier

Ion channel immobilization by ankyrin G is regulated by casein kinase 2 in immature hippocampal neurons

CMB-S4 Science Book, First Edition

This book lays out the scientific goals to be addressed by the next-generation ground-based cosmic microwave background experiment, CMB-S4, envisioned to consist of dedicated telescopes at the South Pole, the high Chilean Atacama plateau and possibly a northern hemisphere site, all equipped with new superconducting cameras. CMB-S4 will dramatically advance cosmological studies by crossing critical thresholds in the search for the B-mode polarization signature of primordial gravitational waves, in the determination of the number and masses of the neutrinos, in the search for evidence of new light relics, in constraining the nature of dark energy, and in testing general relativity on large scales

Lignes directrices pratiques pour les professionnels canadiens des soins oculovisuels concernant la sécheresse oculaire et la chirurgie de l’œil

En 2014, le Groupe de consensus canadien sur la sécheresse oculaire a publié un document intitulé Dépistage, diagnostic et prise en charge de la sécher-esse oculaire : guide pratique à l’intention des optométristes canadiens. Ce guide pratique ne traitait pas des répercussions de la sécheresse oculaire chez les personnes en voie de subir une intervention chirurgicale de l’œil ou ayant récemment subi ce genre d’intervention. La sécheresse oculaire est courante dans certaines cohortes ayant subi une intervention chirurgicale, et le contexte périopératoire pose des problèmes précis; d’une part parce qu’une intervention chirurgicale peut compliquer une sécheresse oculaire préexistante et, d’autre part, parce la sécheresse oculaire symptomatique et asymptomatique expose le patient au risque d’obtenir des résultats chirur-gicaux médiocres. Le groupe de consensus a élaboré cet addenda au guide pratique de 2014 pour offrir des conseils sur les soins relatifs à la sécheresse oculaire avant et après une intervention chirurgicale aux yeux

A Cell-Based Small Molecule Screening Method for Identifying Inhibitors of Epithelial-Mesenchymal Transition in Carcinoma

Epithelial Mesenchymal Transition (EMT) is a crucial mechanism for carcinoma progression, as it provides routes for in situ carcinoma cells to dissociate and become motile, leading to localized invasion and metastatic spread. Targeting EMT therefore represents an important therapeutic strategy for cancer treatment. The discovery of oncogene addiction in sustaining tumor growth has led to the rapid development of targeted therapeutics. Whilst initially optimized as anti-proliferative agents, it is likely that some of these compounds may inhibit EMT initiation or sustenance, since EMT is also modulated by similar signaling pathways that these compounds were designed to target. We have developed a novel screening assay that can lead to the identification of compounds that can inhibit EMT initiated by growth factor signaling. This assay is designed as a high-content screening assay where both cell growth and cell migration can be analyzed simultaneously via time-course imaging in multi-well plates. Using this assay, we have validated several compounds as viable EMT inhibitors. In particular, we have identified compounds targeting ALK5, MEK, and SRC as potent inhibitors that can interfere with EGF, HGF, and IGF-1 induced EMT signaling. Overall, this EMT screening method provides a foundation for improving the therapeutic value of recently developed compounds in advanced stage carcinoma

Ectodermal Influx and Cell Hypertrophy Provide Early Growth for All Murine Mammary Rudiments, and Are Differentially Regulated among Them by Gli3

Mammary gland development starts in utero with one or several pairs of mammary rudiments (MRs) budding from the surface ectodermal component of the mammalian embryonic skin. Mice develop five pairs, numbered MR1 to MR5 from pectoral to inguinal position. We have previously shown that Gli3Xt-J/Xt-J mutant embryos, which lack the transcription factor Gli3, do not form MR3 and MR5. We show here that two days after the MRs emerge, Gli3Xt-J/Xt-J MR1 is 20% smaller, and Gli3Xt-J/Xt-J MR2 and MR4 are 50% smaller than their wild type (wt) counterparts. Moreover, while wt MRs sink into the underlying dermis, Gli3Xt-J/Xt-J MR4 and MR2 protrude outwardly, to different extents. To understand why each of these five pairs of functionally identical organs has its own, distinct response to the absence of Gli3, we determined which cellular mechanisms regulate growth of the individual MRs, and whether and how Gli3 regulates these mechanisms. We found a 5.5 to 10.7-fold lower cell proliferation rate in wt MRs compared to their adjacent surface ectoderm, indicating that MRs do not emerge or grow via locally enhanced cell proliferation. Cell-tracing experiments showed that surface ectodermal cells are recruited toward the positions where MRs emerge, and contribute to MR growth during at least two days. During the second day of MR development, peripheral cells within the MRs undergo hypertrophy, which also contributes to MR growth. Limited apoptotic cell death counterbalances MR growth. The relative contribution of each of these processes varies among the five MRs. Furthermore, each of these processes is impaired in the absence of Gli3, but to different extents in each MR. This differential involvement of Gli3 explains the variation in phenotype among Gli3Xt-J/Xt-J MRs, and may help to understand the variation in numbers and positions of mammary glands among mammals

Receiver development for BICEP Array, a next-generation CMB polarimeter at the South Pole

A detection of curl-type (B-mode) polarization of the primary CMB would be direct evidence for the inflationary paradigm of the origin of the Universe. The Bicep/Keck Array (BK) program targets the degree angular scales, where the power from primordial B-mode polarization is expected to peak, with ever-increasing sensitivity and has published the most stringent constraints on inflation to date. Bicep Array (BA) is the Stage-3 instrument of the BK program and will comprise four Bicep3-class receivers observing at 30/40, 95, 150 and 220/270 GHz with a combined 32,000+ detectors; such wide frequency coverage is necessary for control of the Galactic foregrounds, which also produce degree-scale B-mode signal. The 30/40 GHz receiver is designed to constrain the synchrotron foreground and has begun observing at the South Pole in early 2020. By the end of a 3-year observing campaign, the full Bicep Array instrument is projected to reach σr between 0.002 and 0.004, depending on foreground complexity and degree of removal of B-modes due to gravitational lensing (delensing). This paper presents an overview of the design, measured on-sky performance and calibration of the first BA receiver. We also give a preview of the added complexity in the time-domain multiplexed readout of the 7,776-detector 150 GHz receiver

Observing low elevation sky and the CMB Cold Spot with BICEP3 at the South Pole

BICEP3 is a 520 mm aperture on-axis refracting telescope at the South Pole, which observes the polarization of the cosmic microwave background (CMB) at 95 GHz to search for the B-mode signal from inflationary gravitational waves. In addition to this main target, we have developed a low-elevation observation strategy to extend coverage of the Southern sky at the South Pole, where BICEP3 can quickly achieve degree-scale E-mode measurements over a large area. An interesting E-mode measurement is probing a potential polarization anomaly around the CMB Cold Spot. During the austral summer seasons of 2018-19 and 2019-20, BICEP3 observed the sky with a flat mirror to redirect the beams to various low elevation ranges. The preliminary data analysis shows degree-scale E-modes measured with high signal-to-noise ratio