Nucleoporins build the nuclear pore complex (NPC), which, as sole gate for nuclear-cytoplasmic exchange, is of outmost importance for normal cell function. Defects in the process of nucleocytoplasmic transport or in its machinery have been frequently described in human diseases, such as cancer and neurodegenerative disorders, but only in a few cases of developmental disorders. Here we report biallelic mutations in the nucleoporin NUP88 as a novel cause of lethal fetal akinesia deformation sequence (FADS) in two families. FADS comprises a spectrum of clinically and genetically heterogeneous disorders with congenital malformations related to impaired fetal movement. We show that genetic disruption of nup88 in zebrafish results in pleiotropic developmental defects reminiscent of those seen in affected human fetuses, including locomotor defects as well as defects at neuromuscular junctions. Phenotypic alterations become visible at distinct developmental stages, both in affected human fetuses and in zebrafish, whereas early stages of development are apparently normal. The zebrafish phenotypes caused by nup88 deficiency are rescued by expressing wild-type Nup88 but not the disease-linked mutant forms of Nup88. Furthermore, using human and mouse cell lines as well as immunohistochemistry on fetal muscle tissue, we demonstrate that NUP88 depletion affects rapsyn, a key regulator of the muscle nicotinic acetylcholine receptor at the neuromuscular junction. Together, our studies provide the first characterization of NUP88 in vertebrate development, expand our understanding of the molecular events causing FADS, and suggest that variants in NUP88 should be investigated in cases of FADS.
The expression of the hBCAT proteins is significantly elevated in AD brain. This may modulate glutamate production and toxicity, and thereby play a role in the pathogenesis of the disease.
The bacteriophage vB_SenS-Ent1 (Ent1) is a member of the family Siphoviridae of tailed bacteriophages and infects a broad range of serovars of the enteric pathogen Salmonella enterica. The virion particle is composed of an icosahedral head 64 nm in diameter and a flexible, non-contractile tail of 116 ¾ 8.5 nm possessing terminal fibres. The adsorption rate constant at 37 6C is 6.73 ¾ 10 "9 ml min "1 . Latent and eclipse periods are 25 and 20 min, respectively, and the burst size is 35 progeny particles per cell after 35 min at 37 6C. Sequencing revealed a circularly permuted, 42 391 bp dsDNA genome containing 58 ORFs organized into four major transcriptional units. Comparisons with the genome sequences of other bacteriophages revealed a high level of nucleotide sequence identity and shared orthologous proteins with the Salmonella phages SETP3, SE2 and KS7 (SS3e) and the Escherichia phages K1G, K1H, K1ind1 and K1ind3. INTRODUCTIONSalmonellae are Gram-negative, facultatively anaerobic, non-sporulating and generally motile bacilli that are causative agents of typhoid fever, gastroenteritis and enteric fever in both humans and animals. The species Salmonella enterica is classified into five subspecies by differential biochemistry and further subdivided into serotypes based upon serology of the lipopolysaccharide (LPS) (O) and flagellar (H) antigens (Grimont & Weill, 2007). Epidemiological surveillance data present serovars of Salmonella enterica subspecies enterica as prominent aetiological agents of bacterial food-borne disease worldwide (ECDC, 2010;Scallan et al., 2011). Non-typhoidal infections by Salmonella serovars other than Typhi and Paratyphi are generally self-limiting, with clinical manifestations ranging from mild to severe gastroenteritis. In a small proportion of cases, further complications arise, including bacteraemia, gastrointestinal bleeding and focal infections (Acheson & Hohmann, 2001). Transmission to humans is primarily associated with the ingestion of a wide variety of contaminated food products, but may also arise by contact with animals, contaminated water and infected individuals (Hanning et al., 2009). In the USA, the economic burden associated with medical care and lost productivity due to salmonellosis is estimated at several billion dollars annually (Voetsch et al., 2004).All Salmonella phages reported thus far belong to the order Caudovirales (tailed phages) and represent three families: the Siphoviridae, Podoviridae and Myoviridae. Of these, only a small fraction are lytic, whilst the majority are capable of a temperate life cycle (Kropinski et al., 2007). Lysogeny is widespread among strains of Salmonella and most, if not all, harbour prophages. To date, the complete genome sequences of 36 Salmonella phages are publicly available, representing just 3.97 % (35/880) of all available bacteriophage genome sequences. With an estimated 10 31 bacteriophages existing in the environment (Suttle, 2005;Whitman et al., 1998), current knowledge is limited regarding the identification and characte...
These studies indicate that hBCAT may play a role in the stress response of the cell as a novel redox chaperone, which, if compromised, may result in protein misfolding, creating aggregates as a key feature in neurodegenerative conditions such as Alzheimer's disease.
Herein, we report a hybrid polyoxometalate organic–inorganic compound, Na2[(HGMP)2Mo5O15]⋅7 H2O (1; where GMP=guanosine monophosphate), which spontaneously assembles into a structure with dimensions that are strikingly similar to those of the naturally occurring left‐handed Z‐form of DNA. The helical parameters in the crystal structure of the new compound, such as rise per turn and helical twist per dimer, are nearly identical to this DNA conformation, allowing a close comparison of the two structures. Solution circular dichroism studies show that compound 1 also forms extended secondary structures in solution. Gel electrophoresis studies demonstrate the formation of non‐covalent adducts with natural plasmids. Thus we show a route by which simple hybrid inorganic–organic monomers, such as compound 1, can spontaneously assemble into a double helix without the need for a covalently connected linear sequence of nucleic acid base pairs.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.