ADAR1 Facilitates HIV-1 Replication in Primary CD4+ T Cells

Unlike resting CD4⁺ T cells, activated CD4⁺T cells are highly susceptible to infection of human immunodeficiency virus 1 (HIV-1). HIV-1 infects T cells and macrophages without activating the nucleic acid sensors and the anti-viral type I interferon response. Adenosine deaminase acting on RNA 1 (ADAR1) is an RNA editing enzyme that displays antiviral activity against several RNA viruses. Mutations in ADAR1 cause the autoimmune disorder Aicardi-Goutieères syndrome (AGS). This disease is characterized by an inappropriate activation of the interferon-stimulated gene response. Here we show that HIV-1 replication, in ADAR1-deficient CD4⁺T lymphocytes from AGS patients, is blocked at the level of protein translation. Furthermore, viral protein synthesis block is accompanied by an activation of interferon-stimulated genes. RNA silencing of ADAR1 in Jurkat cells also inhibited HIV-1 protein synthesis. Our data support that HIV-1 requires ADAR1 for efficient replication in human CD4⁺T cells.     

Apoptosis and mitotic arrest are two independent effects of the protein phosphatases inhibitor okadaic acid in K562 leukemia cells.

Treatment of human myeloid leukemia K562 cells with the serine/threonine protein phosphatases inhibitor okadaic acid induced mitotic arrest followed by apoptosis in a synchronized manner. The effect was observed at drug concentrations that inhibited the protein phosphatase type 2A but not type 1. We investigated whether apoptosis was a consequence of the preceding mitosis arrest or was induced independently by okadaic acid. We found that (1) apoptosis, but not mitotic arrest, was inhibited in cells with constitutive expression of Bcl-2; (2) pretreatment of cells with the DNA synthesis inhibitor hydroxyurea blocked the mitotic arrest but not the apoptosis mediated by okadaic acid; (3) down-regulation of c-myc gene was associated with apoptosis, but not with mitotic arrest; and (4) inhibition of protein synthesis abrogated mitotic arrest, but not apoptosis. The results suggest that inhibition of protein phosphatase 2A by okadaic acid provokes mitotic arrest and apoptosis of leukemia cells by independent mechanisms.     

Cancer‐associated mutations in VAV1 trigger variegated signaling outputs and T‐cell lymphomagenesis

Mutations in VAV1, a gene that encodes a multifunctional protein important for lymphocytes, are found at different frequencies in peripheral T‐cell lymphoma (PTCL), non‐small cell lung cancer, and other tumors. However, their pathobiological significance remains unsettled. After cataloguing 51 cancer‐associated VAV1 mutations, we show here that they can be classified in five subtypes according to functional impact on the three main VAV1 signaling branches, GEF‐dependent activation of RAC1, GEF‐independent adaptor‐like, and tumor suppressor functions. These mutations target new and previously established regulatory layers of the protein, leading to quantitative and qualitative changes in VAV1 signaling output. We also demonstrate that the most frequent VAV1 mutant subtype drives PTCL formation in mice. This process requires the concurrent engagement of two downstream signaling branches that promote the chronic activation and transformation of follicular helper T cells. Collectively, these data reveal the genetic constraints associated with the lymphomagenic potential of VAV1 mutant subsets, similarities with other PTCL driver genes, and potential therapeutic vulnerabilities.     

Exceptions to Cajal's neuron theory: communicating synapses

Ultrastructural images of some neurons and their synaptic connections, belonging to the nucleus of the periaqueductal grey substance in the domestic cat mesencephalon, are shown. The finding that some axosomatic synapses showed an open communication between the pre- and postsynaptic portion attracted our attention. In this way a continuity is made between the presynaptic bouton of one neuron (axon) and the postsynaptic portion of the other (neuronal soma). Synapses having these interneuronal communications could be denominated communicating synapses. Accepting Cajal's neuron theory and his law of neuronal independence, it is very difficult to interpret these images. We wonder if this type of communicating synapses could be the exception that proves the rule of the neuron independence.     

Drivers of beta diversity of macroinvertebrate communities in tropical forest streams

1. There has recently been increasing interest in patterns of beta diversity but we still lack a comprehensive understanding of these patterns in various regions (e.g. the tropics), ecosystems (e.g. streams) and organism groups (e.g. invertebrates). 2. Our aim was to investigate the patterns of beta diversity of stream macroinvertebrates in relation to key environmental (i.e. stream size, pH and habitat degradation) and geographical variables (i.e. latitude, longitude, altitude) in a tropical region. We surveyed a total of 8–10 riffle sites in each of 34 streams (altogether 337 riffle sites were sampled) in Peninsular Malaysia to examine variation in macroinvertebrate community composition at within‐stream and among‐stream scales. 3. Based on test of homogeneity of dispersion, we found that the streams studied differed significantly in within‐stream variation in community composition (i.e. among‐site variation of within stream beta diversity). The patterns were similar based on Bray–Curtis coefficient on abundance data, Sorensen coefficient on presence–absence data and Simpson coefficient on presence–absence data. We also found that within‐stream beta diversity was significantly related to stream size, pH and latitude, with each of these variables individually accounting for around 20% of the variation in beta diversity in simple regressions, while the total variation explained by the three significant variables amounted to around 50% in multiple regressions. By contrast, habitat degradation, longitude and altitude were not significantly related to beta diversity. We also found that the factor drainage basin accounted for much of the variation in beta diversity in general linear models, suppressing the effects of environmental variables. 4. We concluded that within‐stream beta diversity is mainly related to a combination of the identity of a drainage basin and stream environmental factors. Our findings provide important background for stream environmental assessment and conservation planning by emphasising that (i) macroinvertebrate communities within streams are not homogeneous, but show considerable beta diversity, (ii) streams differ in their degree of within‐stream beta diversity, (iii) stream size and water pH should be considered in applied contexts related to within‐stream beta diversity and (iv) historical effects may be different in different drainage basins and may affect present‐day patterns of within‐stream beta diversity.     

The Hidden Sexuality of Alexandrium Minutum: An Example of Overlooked Sex in Dinoflagellates

Dinoflagellates are haploid eukaryotic microalgae in which rapid proliferation causes dense blooms, with harmful health and economic effects to humans. The proliferation mode is mainly asexual, as the sexual cycle is believed to be rare and restricted to stressful environmental conditions. However, sexuality is key to explaining the recurrence of many dinoflagellate blooms because in many species the fate of the planktonic zygotes (planozygotes) is the formation of resistant cysts in the seabed (encystment). Nevertheless, recent research has shown that individually isolated planozygotes in the lab can enter other routes besides encystment, a behavior of which the relevance has not been explored at the population level. In this study, using imaging flow cytometry, cell sorting, and Fluorescence In Situ Hybridization (FISH), we followed DNA content and nuclear changes in a population of the toxic dinoflagellate Alexandrium minutum that was induced to encystment. Our results first show that planozygotes behave like a population with an “encystment-independent” division cycle, which is light-controlled and follows the same Light:Dark (L:D) pattern as the cycle governing the haploid mitosis. Resting cyst formation was the fate of just a small fraction of the planozygotes formed and was restricted to a period of strongly limited nutrient conditions. The diploid-haploid turnover between L:D cycles was consistent with two-step meiosis. However, the diel and morphological division pattern of the planozygote division also suggests mitosis, which would imply that this species is not haplontic, as previously considered, but biphasic, because individuals could undergo mitotic divisions in both the sexual (diploid) and the asexual (haploid) phases. We also report incomplete genome duplication processes. Our work calls for a reconsideration of the dogma of rare sex in dinoflagellates.     

Suicide inactivation of peroxidase from Chamaerops excelsa palm tree leaves

The concentration and time-dependences and the mechanism of the inactivation of Chamaerops excelsa peroxidase (CEP) by hydrogen peroxide were studied kinetically with four co-substrates (2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), guaiacol, o-dianisidine and o-phenylenediamine). The turnover number (r) of H₂O₂ required to complete the inactivation of the enzyme varied for the different substrates, the enzyme most resistant to inactivation (r = 4844) with ABTS being the most useful substrate for biotechnological applications, opening a new avenue of enquiry with this peroxidase.     

Cohesin-SA1 deficiency drives aneuploidy and tumourigenesis in mice due to impaired replication of telomeres

Cohesin is a protein complex originally identified for its role in sister chromatid cohesion, although increasing evidence portrays it also as a major organizer of interphase chromatin. Vertebrate cohesin consists of Smc1, Smc3, Rad21/Scc1 and either stromal antigen 1 (SA1) or SA2. To explore the functional specificity of these two versions of cohesin and their relevance for embryonic development and cancer, we generated a mouse model deficient for SA1. Complete ablation of SA1 results in embryonic lethality, while heterozygous animals have shorter lifespan and earlier onset of tumourigenesis. SA1-null mouse embryonic fibroblasts show decreased proliferation and increased aneuploidy as a result of chromosome segregation defects. These defects are not caused by impaired centromeric cohesion, which depends on cohesin-SA2. Instead, they arise from defective telomere replication, which requires cohesion mediated specifically by cohesin-SA1. We propose a novel mechanism for aneuploidy generation that involves impaired telomere replication upon loss of cohesin-SA1, with clear implications in tumourigenesis.