Expected Polarization of Λ\Lambda particles produced in deep inelastic polarized lepton scattering

We calculate the polarization of Lambda and Anti-Lambda particles produced in deep inelastic polarized lepton scattering. We use two models: the naive quark model and a model in which SU(3)$_F$ symmetry is used to deduce the spin structure of SU(3) octet hyperons from that of the proton. We perform the calculations for Lambda and Anti-Lambda produced directly or as decay products of $\Sigma^0$ and $\Sigma^*$.Comment: 12 pages, 1 figur

How neuronal migration contributes to the morphogenesis of the CNS: insights from the zebrafish

We used transgenic zebrafish expressing GFP or YFP in subpopulations of neurons to study the migration, homing process and axon extension of groups of CNS neurons in different regions of the zebrafish brain. We found that extensive migration takes place at all levels of the CNS and gives rise to nuclei or cell populations with specific identities. Here, we describe 4 previously unknown or only partially characterized migratory events taking place in the zebrafish telencephalon and rhombic lip, using 3 different transgenic lines, and identify the phenotypes of the cells undertaking these migrations. The migration of a subgroup of mitral cell precursors from the dorsocaudal telencephalon to the olfactory bulb, visualized in the tg(tbr1:YFP) transgenic line, is coupled with morphogenetic transformation of the dorsal telencephalon. The tg(1.4dlx5a-6a:GFP) transgenic line provides a means to analyze the migration of GABAergic interneurons from the ventral to the dorsal telencephalon, thus extending the occurrence of this migration to another vertebrate. The tg(Xeom:GFP) transgenic line provides the first demonstration of the dorsoventral migration of glutamatergic septal neurons, present in mammals and now described in fish, thus reconciling the contrasting evidence of dorsal patterning genes (tbr1, eomes) expressed in a ventral cell population. Furthermore, migration studies in the tg(1.4dlx5a-6a:GFP) and tg(Xeom:GFP) lines help determine the origin of 2 important cell populations in the fish cerebellum: projection neurons and Purkinje cells. These examples reinforce the concept that migratory events contribute to the distribution of cell types with diverse identities through the CNS and that zebrafish transgenic lines represent excellent tools to study these events. Copyrigh

Nucleophosmin leukemogenic mutant activates Wnt signaling during zebrafish development

Nucleophosmin (NPM1) is a ubiquitous multifunctional phosphoprotein with both oncogenic and tumor suppressor functions. Mutations of the NPM1 gene are the most frequent genetic alterations in acute myeloid leukemia (AML) and result in the expression of a mutant protein with aberrant cytoplasmic localization, NPMc+. Although NPMc+ causes myeloproliferation and AML in animal models, its mechanism of action remains largely unknown. Here we report that NPMc+ activates canonical Wnt signaling during the early phases of zebrafish development and determines a Wnt-dependent increase in the number of progenitor cells during primitive hematopoiesis. Coherently, the canonical Wnt pathway is active in AML blasts bearing NPMc+ and depletion of the mutant protein in the patient derived OCI-AML3 cell line leads to a decrease in the levels of active \u3b2-catenin and of Wnt target genes. Our results reveal a novel function of NPMc+ and provide insight into the molecular pathogenesis of AML bearing NPM1 mutations

Phage therapy against Pseudomonas aeruginosa infections in a cystic fibrosis zebrafish model

Cystic fibrosis (CF) is a hereditary disease due to mutations in the CFTR gene and causes mortality in humans mainly due to respiratory infections caused by Pseudomonas aeruginosa. In a previous work we used phage therapy, which is a treatment with a mix of phages, to actively counteract acute P. aeruginosa infections in mice and Galleria mellonella larvae. In this work we apply phage therapy to the treatment of P. aeruginosa PAO1 infections in a CF zebrafish model. The structure of the CFTR channel is evolutionary conserved between fish and mammals and cftr-loss-of-function zebrafish embryos show a phenotype that recapitulates the human disease, in particular with destruction of the pancreas. We show that phage therapy is able to decrease lethality, bacterial burden, and the pro-inflammatory response caused by PAO1 infection. In addition, phage administration relieves the constitutive inflammatory state of CF embryos. To our knowledge, this is the first time that phage therapy is used to cure P. aeruginosa infections in a CF animal model. We also find that the curative effect against PAO1 infections is improved by combining phages and antibiotic treatments, opening a useful therapeutic approach that could reduce antibiotic doses and time of administration

Characterization of the Regulatory Region of the Zebrafish Prep1.1 Gene: Analogies to the Promoter of the Human PREP1

Prep1 is a developmentally essential TALE class homeodomain transcription factor. In zebrafish and mouse, Prep1 is already ubiquitously expressed at the earliest stages of development, with important tissue-specific peculiarities. The Prep1 gene in mouse is developmentally essential and has haploinsufficient tumor suppressor activity [1]. We have determined the human Prep1 transcription start site (TSS) by primer extension analysis and identified, within 20 bp, the transcription start region (TSR) of the zebrafish Prep1.1 promoter. The functions of the zebrafish 5′ upstream sequences were analyzed both by transient transfections in Hela Cells and by injection in zebrafish embryos. This analysis revealed a complex promoter with regulatory sequences extending up to −1.8, possibly −5.0 Kb, responsible for tissue specific expression. Moreover, the first intron contains a conserved tissue-specific enhancer both in zebrafish and in human cells. Finally, a two nucleotides mutation of an EGR-1 site, conserved in all species including human and zebrafish and located at a short distance from the TSS, destroyed the promoter activity of the −5.0 Kb promoter. A transgenic fish expressing GFP under the −1.8 Kb zebrafish promoter/enhancer co-expressed GFP and endogenous Prep1.1 during embryonic development. In the adult fish, GFP was expressed in hematopoietic regions like the kidney, in agreement with the essential function of Prep1 in mouse hematopoiesis. Sequence comparison showed conservation from man to fish of the sequences around the TSS, within the first intron enhancer. Moreover, about 40% of the sequences spread throughout the 5 Kbof the zebrafish promoter are concentrated in the −3 to −5 Kb of the human upstream region

IRSp53 controls plasma membrane shape and polarized transport at the nascent lumen in epithelial tubules

It is unclear whether the establishment of apical\u2013basal cell polarity during the generation of epithelial lumens requires molecules acting at the plasma membrane/actin interface. Here, we show that the I-BAR-containing IRSp53 protein controls lumen formation and the positioning of the polarity determinants aPKC and podocalyxin. Molecularly, IRSp53 acts by regulating the localization and activity of the small GTPase RAB35, and by interacting with the actin capping protein EPS8. Using correlative light and electron microscopy, we further show that IRSp53 ensures the shape and continuity of the opposing plasma membrane of two daughter cells, leading to the formation of a single apical lumen. Genetic removal of IRSp53 results in abnormal renal tubulogenesis, with altered tubular polarity and architectural organization. Thus, IRSp53 acts as a membrane curvature-sensing platform for the assembly of multi-protein complexes that control the trafficking of apical determinants and the integrity of the luminal plasma membrane

Endocytic reawakening of motility in jammed epithelia

Dynamics of epithelial monolayers has recently been interpreted in terms of a jamming or rigidity transition. How cells control such phase transitions is, however, unknown. Here we show that RAB5A, a key endocytic protein, is sufficient to induce large-scale, coordinated motility over tens of cells, and ballistic motion in otherwise kinetically arrested monolayers. This is linked to increased traction forces and to the extension of cell protrusions, which align with local velocity. Molecularly, impairing endocytosis, macropinocytosis or increasing fluid efflux abrogates RAB5A-induced collective motility. A simple model based on mechanical junctional tension and an active cell reorientation mechanism for the velocity of self-propelled cells identifies regimes of monolayer dynamics that explain endocytic reawakening of locomotion in terms of a combination of large-scale directed migration and local unjamming. These changes in multicellular dynamics enable collectives to migrate under physical constraints and may be exploited by tumours for interstitial dissemination

IRSp53 controls plasma membrane shape and polarized transport at the nascent lumen in epithelial tubules

It is unclear whether the establishment of apical–basal cell polarity during the generation of epithelial lumens requires molecules acting at the plasma membrane/actin interface. Here, we show that the I-BAR-containing IRSp53 protein controls lumen formation and the positioning of the polarity determinants aPKC and podocalyxin. Molecularly, IRSp53 acts by regulating the localization and activity of the small GTPase RAB35, and by interacting with the actin capping protein EPS8. Using correlative light and electron microscopy, we further show that IRSp53 ensures the shape and continuity of the opposing plasma membrane of two daughter cells, leading to the formation of a single apical lumen. Genetic removal of IRSp53 results in abnormal renal tubulogenesis, with altered tubular polarity and architectural organization. Thus, IRSp53 acts as a membrane curvature-sensing platform for the assembly of multi-protein complexes that control the trafficking of apical determinants and the integrity of the luminal plasma membrane

Controlling the dissociation of ligands from the adenosine A(2A) receptor through modulation of salt bridge strength

Controlling the Dissociation of Ligands from the Adenosine A2A Receptor through Modulation of Salt Bridge StrengthElena Segala, Dong Guo, Robert K. Y. Cheng, Andrea Bortolato, Francesca Deflorian, Andrew S. Doré, James C. Errey, Laura H. Heitman, Adriaan P. IJzerman, Fiona H. Marshall, and Robert M. CookeHeptares Therapeutics Ltd, Biopark Broadwater Road, Welwyn Garden City AL7 3AX, U.K.Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR), Leiden University P.O. Box 9502, 2300 RA Leiden, the NetherlandsAbstractThe association and dissociation kinetics of ligands binding to proteins vary considerably, but the mechanisms behind this variability are poorly understood, limiting their utilization for drug discovery. This is particularly so for G protein-coupled receptors (GPCRs) where high resolution structural information is only beginning to emerge. Engineering the human A2A adenosine receptor has allowed structures to be solved in complex with the reference compound ZM241385 and four related ligands at high resolution. Differences between the structures are limited, with the most pronounced being the interaction of each ligand with a salt bridge on the extracellular side of the receptor. Mutagenesis experiments confirm the role of this salt bridge in controlling the dissociation kinetics of the ligands from the receptor, while molecular dynamics simulations demonstrate the ability of ligands to modulate salt bridge stability. These results shed light on a structural determinant of ligand dissociation kinetics and identify a means by which this property may be optimized.Medicinal Chemistr

Dynamic phosphorylation of Histone Deacetylase 1 by Aurora kinases during mitosis regulates zebrafish embryos development

Histone deacetylases (HDACs) catalyze the removal of acetyl molecules from histone and nonhistone substrates playing important roles in chromatin remodeling and control of gene expression. Class I HDAC1 is a critical regulator of cell cycle progression, cellular proliferation and differentiation during development; it is also regulated by many post-translational modifications (PTMs). Herein we characterize a new mitosis-specific phosphorylation of HDAC1 driven by Aurora kinases A and B. We show that this phosphorylation affects HDAC1 enzymatic activity and it is critical for the maintenance of a proper proliferative and developmental plan in a complex organism. Notably, we find that Aurora-dependent phosphorylation of HDAC1 regulates histone acetylation by modulating the expression of genes directly involved in the developing zebrafish central nervous system. Our data represent a step towards the comprehension of HDAC1 regulation by its PTM code, with important implications in unravelling its roles both in physiology and pathology