Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration

RNA exosomes are multi-subunit complexes conserved throughout evolution and are emerging as the major cellular machinery for processing, surveillance and turnover of a diverse spectrum of coding and noncoding RNA substrates essential for viability. By exome sequencing, we discovered recessive mutations in EXOSC3 (encoding exosome component 3) in four siblings with infantile spinal motor neuron disease, cerebellar atrophy, progressive microcephaly and profound global developmental delay, consistent with pontocerebellar hypoplasia type 1 (PCH1; MIM 607596). We identified mutations in EXOSC3 in an additional 8 of 12 families with PCH1. Morpholino knockdown of exosc3 in zebrafish embryos caused embryonic maldevelopment, resulting in small brain size and poor motility, reminiscent of human clinical features, and these defects were largely rescued by co-injection with wild-type but not mutant exosc3 mRNA. These findings represent the first example of an RNA exosome core component gene that is responsible for a human disease and further implicate dysregulation of RNA processing in cerebellar and spinal motor neuron maldevelopment and degeneration.     

Vesicles carrying nuclear material in matureCyprinus carpio erythrocytes

Zusammenfassung Chromatinhaltige feulgenpositive Bläschen wurden im Cytoplasma der Erythrocyten vonCyprinus carpio gefunden. Sie haben ihren Ursprung in den unmittelbar an der Kernmembran anliegenden Mitochondrien, die während der Chromatinaufnahme allmählich ihre Struktur verlieren.

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The authors wish to thank Mrs.Vera Mondin Weisz and Mr.C. A. Gonçalves Silva for their technical assistance and Mrs.Sibylle Heller for her editorial aid and translation. This research has been supported by the Conselho Nacional de Pesquisas (Proc. No. 10112/71) and Fundo Especial de Despesas do Instituto Butantan.     

Interferon production by sendai virus-treated hamster and monkey cells

Résumé On présente une étude comparée sur la production d'interféron par les cellules non-transformées et tumorales de hamster ainsi que par les cellules de singe, après leur traîtement par le virus Sendai inactivé. Les cellules tumorales ne produisent pas l'interféron sous l'action du virus sendai. Les cellules non-transformées cessent de produire ou de libérer l'interféron, dans leur milieu de culture, en moins de 24 h après l'enlèvement du virus Sendai de ce milieu.

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Supported by a Fellowship from The Medical Research Council of Canada. We thank Mr.L. Guerin for supplying some of the culture material used, Dr.E. Perry for his support and discussions, and Dr.J. C. N. Westwood for his support. Our present address is: Department of Tumor Biology, Karolinska Institutet, 104 01 Stockholm 60 (Sweden).     

An aqueous extract of Liu Wei Di Huang Wan alters the labeling of blood constituents with Technetium-99m

The Liu Wei Di Huang Wan is a formula of a traditional Chinese medicine that is used to treat asthma patients and has been shown to have several important properties,such as antioxidant and free radical scavenging activities.The influence of an extract of Liu Wei Di Huang Wan on the labeling of blood constituents with technetium-99m was investigated.Anticoagulated blood(Wistar rats) was incubated with the extract,stannous chloride and technetium-99m,as sodium pertechnetate.Samples were centrifuged and aliquots of plasma and blood cells were separated and precipitated with trichloroacetic acid,to obtain soluble and insoluble fractions of the blood constituents.The percentage of radioactivity(%ATI) in all the fractions was determined.The analysis of the results shows that the extract at the highest concentration used(70 mg/mL) decreased significantly(P<0.05) the %ATI(from 96.48 ± 1.19 to 54.46 ± 7.38) on blood cells compartment,(from 81.11 ± 4.15 to 61.33 ± 4.74) on insoluble fractions of blood cells and(from 65.91 ± 2.44 to 13.15 ± 3.62) on insoluble fractions of plasma.In conclusion,the results suggest that the substances present on this extract can alter this labeling process,probably due to(i) redox properties(antioxidant and chelator activities) and/or(ii) specific actions in the binding sites where the 99mTc would be bound on the blood constituents.As a consequence,precaution is suggested on the interpretation of the nuclear medicine results from performed with blood constituents labeled with 99m Tc in patients that have undertaken LWDHW,although the current findings were obtained in experimental animal models.     

Coupling of agonist binding to channel gating in an ACh-binding protein linked to an ion channel

Neurotransmitter receptors from the Cys-loop superfamily couple the binding of agonist to the opening of an intrinsic ion pore in the final step in rapid synaptic transmission. Although atomic resolution structural data have recently emerged for individual binding and pore domains, how they are linked into a functional unit remains unknown. Here we identify structural requirements for functionally coupling the two domains by combining acetylcholine (ACh)-binding protein, whose structure was determined at atomic resolution, with the pore domain from the serotonin type-3A (5-HT3A) receptor. Only when amino-acid sequences of three loops in ACh-binding protein are changed to their 5-HT3A counterparts does ACh bind with low affinity characteristic of activatable receptors, and trigger opening of the ion pore. Thus functional coupling requires structural compatibility at the interface of the binding and pore domains. Structural modelling reveals a network of interacting loops between binding and pore domains that mediates this allosteric coupling process.     

More than just scanning: the importance of cap-independent mRNA translation initiation for cellular stress response and cancer

The scanning model for eukaryotic mRNA translation initiation states that the small ribosomal subunit, along with initiation factors, binds at the cap structure at the 5′ end of the mRNA and scans the 5′ untranslated region (5′UTR) until an initiation codon is found. However, under conditions that impair canonical cap-dependent translation, the synthesis of some proteins is kept by alternative mechanisms that are required for cell survival and stress recovery. Alternative modes of translation initiation include cap- and/or scanning-independent mechanisms of ribosomal recruitment. In most cap-independent translation initiation events there is a direct recruitment of the 40S ribosome into a position upstream, or directly at, the initiation codon via a specific internal ribosome entry site (IRES) element in the 5′UTR. Yet, in some cellular mRNAs, a different translation initiation mechanism that is neither cap- nor IRES-dependent seems to occur through a special RNA structure called cap-independent translational enhancer (CITE). Recent evidence uncovered a distinct mechanism through which mRNAs containing N ⁶-methyladenosine (m⁶A) residues in their 5′UTR directly bind eukaryotic initiation factor 3 (eIF3) and the 40S ribosomal subunit in order to initiate translation in the absence of the cap-binding proteins. This review focuses on the important role of cap-independent translation mechanisms in human cells and how these alternative mechanisms can either act individually or cooperate with other cis-acting RNA regulons to orchestrate specific translational responses triggered upon several cellular stress states, and diseases such as cancer. Elucidation of these non-canonical mechanisms reveals the complexity of translational control and points out their potential as prospective novel therapeutic targets.     

Mechanisms regulating dendritic arbor patterning

The nervous system is populated by diverse types of neurons, each of which has dendritic trees with strikingly different morphologies. These neuron-specific morphologies determine how dendritic trees integrate thousands of synaptic inputs to generate different firing properties. To ensure proper neuronal function and connectivity, it is necessary that dendrite patterns are precisely controlled and coordinated with synaptic activity. Here, we summarize the molecular and cellular mechanisms that regulate the formation of cell type-specific dendrite patterns during development. We focus on different aspects of vertebrate dendrite patterning that are particularly important in determining the neuronal function; such as the shape, branching, orientation and size of the arbors as well as the development of dendritic spine protrusions that receive excitatory inputs and compartmentalize postsynaptic responses. Additionally, we briefly comment on the implications of aberrant dendritic morphology for nervous system disease.