NFATc1 controls the cytotoxicity of CD8+ T cells

NFAT nuclear translocation has been shown to be required for CD8+ T cell cytokine production in response to viral infection. Here the authors show NFATc1 controls the cytotoxicity and metabolic switching of activated CD8+ T cells required for optimal response to bacteria and tumor cells

Self-oligomerization regulates stability of survival motor neuron protein isoforms by sequestering an SCF^Slmb degron

Spinal muscular atrophy (SMA) is caused by homozygous mutations in human SMN1. Expression of a duplicate gene (SMN2) primarily results in skipping of exon 7 and production of an unstable protein isoform, SMNΔ7. Although SMN2 exon skipping is the principal contributor to SMA severity, mechanisms governing stability of survival motor neuron (SMN) isoforms are poorly understood. We used a Drosophila model system and label-free proteomics to identify the SCFSlmb ubiquitin E3 ligase complex as a novel SMN binding partner. SCFSlmb interacts with a phosphor degron embedded within the human and fruitfly SMN YG-box oligomerization domains. Substitution of a conserved serine (S270A) interferes with SCFSlmb binding and stabilizes SMNΔ7. SMA-causing missense mutations that block multimerization of full-length SMN are also stabilized in the degron mutant background. Overexpression of SMNΔ7S270A, but not wild-type (WT) SMNΔ7, provides a protective effect in SMA model mice and human motor neuron cell culture systems. Our findings support a model wherein the degron is exposed when SMN is monomeric and sequestered when SMN forms higher-order multimers

The Relationship of Within-Host Multiplication and Virulence in a Plant-Virus System

Background. Virulence does not represent any obvious advantage to parasites. Most models of virulence evolution assume that virulence is an unavoidable consequence of within-host multiplication of parasites, resulting in trade-offs between within-host multiplication and between-host transmission fitness components. Experimental support for the central assumption of this hypothesis, i.e., for a positive correlation between within-host multiplication rates and virulence, is limited for plant-parasite systems. Methodology/Principal Findings. We have addressed this issue in the system Arabidopsis thaliana-Cucumber mosaic virus (CMV). Virus multiplication and the effect of infection on plant growth and on viable seed production were quantified for 21 Arabidopsis wild genotypes infected by 3 CMV isolates. The effect of infection on plant growth and seed production depended of plant architecture and length of postembryonic life cycle, two genetically-determined traits, as well as on the time of infection in the plant's life cycle. A relationship between virus multiplication and virulence was not a general feature of this host-parasite system. This could be explained by tolerance mechanisms determined by the host genotype and operating differently on two components of plant fitness, biomass production and resource allocation to seeds. However, a positive relationship between virus multiplication and virulence was detected for some accessions with short life cycle and high seed weight to biomass ratio, which show lower levels of tolerance to infection. Conclusions/Significance. These results show that genotype-specific tolerance mechanisms may lead to the absence of a clear relationship between parasite multiplication and virulence. Furthermore, a positive correlation between parasite multiplication and virulence may occur only in some genotypes and/or environmental conditions for a given host-parasite system. Thus, our results challenge the general validity of the trade-off hypothesis for virulence evolution, and stress the need of considering the effect of both the host and parasite genotypes in analyses of host-parasite interactions. © 2007 Pagán et al.Ministerio de Educación y Ciencia, Spain.Peer Reviewe

The Relationship of Within-Host Multiplication and Virulence in a Plant-Virus System

Background. Virulence does not represent any obvious advantage to parasites. Most models of virulence evolution assume that virulence is an unavoidable consequence of within-host multiplication of parasites, resulting in trade-offs between within-host multiplication and between-host transmission fitness components. Experimental support for the central assumption of this hypothesis, i.e., for a positive correlation between within-host multiplication rates and virulence, is limited for plant-parasite systems. Methodology/Principal Findings. We have addressed this issue in the system Arabidopsis thaliana-Cucumber mosaic virus (CMV). Virus multiplication and the effect of infection on plant growth and on viable seed production were quantified for 21 Arabidopsis wild genotypes infected by 3 CMV isolates. The effect of infection on plant growth and seed production depended of plant architecture and length of postembryonic life cycle, two genetically-determined traits, as well as on the time of infection in the plant's life cycle. A relationship between virus multiplication and virulence was not a general feature of this host-parasite system. This could be explained by tolerance mechanisms determined by the host genotype and operating differently on two components of plant fitness, biomass production and resource allocation to seeds. However, a positive relationship between virus multiplication and virulence was detected for some accessions with short life cycle and high seed weight to biomass ratio, which show lower levels of tolerance to infection. Conclusions/Significance. These results show that genotype-specific tolerance mechanisms may lead to the absence of a clear relationship between parasite multiplication and virulence. Furthermore, a positive correlation between parasite multiplication and virulence may occur only in some genotypes and/or environmental conditions for a given host-parasite system. Thus, our results challenge the general validity of the trade-off hypothesis for virulence evolution, and stress the need of considering the effect of both the host and parasite genotypes in analyses of host-parasite interactions. © 2007 Pagán et al.Ministerio de Educación y Ciencia, Spain.Peer Reviewe

Inhibition of Apoptosis Blocks Human Motor Neuron Cell Death in a Stem Cell Model of Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is a genetic disorder caused by a deletion of the survival motor neuron 1 gene leading to motor neuron loss, muscle atrophy, paralysis, and death. We show here that induced pluripotent stem cell (iPSC) lines generated from two Type I SMA subjects–one produced with lentiviral constructs and the second using a virus-free plasmid–based approach–recapitulate the disease phenotype and generate significantly fewer motor neurons at later developmental time periods in culture compared to two separate control subject iPSC lines. During motor neuron development, both SMA lines showed an increase in Fas ligand-mediated apoptosis and increased caspase-8 and-3 activation. Importantly, this could be mitigated by addition of either a Fas blocking antibody or a caspase-3 inhibitor. Together, these data further validate this human stem cell model of SMA, suggesting that specific inhibitors of apoptotic pathways may be beneficial for patients

Early Alterations in Hippocampal Circuitry and Theta Rhythm Generation in a Mouse Model of Prenatal Infection: Implications for Schizophrenia

Post-mortem studies suggest that GABAergic neurotransmission is impaired in schizophrenia. However, it remains unclear if these changes occur early during development and how they impact overall network activity. To investigate this, we used a mouse model of prenatal infection with the viral mimic, polyriboinosinic–polyribocytidilic acid (poly I∶C), a model based on epidemiological evidence that an immune challenge during pregnancy increases the prevalence of schizophrenia in the offspring. We found that prenatal infection reduced the density of parvalbumin- but not somatostatin-positive interneurons in the CA1 area of the hippocampus and strongly reduced the strength of inhibition early during postnatal development. Furthermore, using an intact hippocampal preparation in vitro, we found reduced theta oscillation generated in the CA1 area. Taken together, these results suggest that redistribution in excitatory and inhibitory transmission locally in the CA1 is associated with a significant alteration in network function. Furthermore, given the role of theta rhythm in memory, our results demonstrate how a risk factor for schizophrenia can affect network function early in development that could contribute to cognitive deficits observed later in the disease

Virus Adaptation by Manipulation of Host's Gene Expression

Viruses adapt to their hosts by evading defense mechanisms and taking over cellular metabolism for their own benefit. Alterations in cell metabolism as well as side-effects of antiviral responses contribute to symptoms development and virulence. Sometimes, a virus may spill over from its usual host species into a novel one, where usually will fail to successfully infect and further transmit to new host. However, in some cases, the virus transmits and persists after fixing beneficial mutations that allow for a better exploitation of the new host. This situation would represent a case for a new emerging virus. Here we report results from an evolution experiment in which a plant virus was allowed to infect and evolve on a naïve host. After 17 serial passages, the viral genome has accumulated only five changes, three of which were non-synonymous. An amino acid substitution in the viral VPg protein was responsible for the appearance of symptoms, whereas one substitution in the viral P3 protein the epistatically contributed to exacerbate severity. DNA microarray analyses show that the evolved and ancestral viruses affect the global patterns of host gene expression in radically different ways. A major difference is that genes involved in stress and pathogen response are not activated upon infection with the evolved virus, suggesting that selection has favored viral strategies to escape from host defenses

Ancient Nursery Area for the Extinct Giant Shark Megalodon from the Miocene of Panama

BACKGROUND: As we know from modern species, nursery areas are essential shark habitats for vulnerable young. Nurseries are typically highly productive, shallow-water habitats that are characterized by the presence of juveniles and neonates. It has been suggested that in these areas, sharks can find ample food resources and protection from predators. Based on the fossil record, we know that the extinct Carcharocles megalodon was the biggest shark that ever lived. Previous proposed paleo-nursery areas for this species were based on the anecdotal presence of juvenile fossil teeth accompanied by fossil marine mammals. We now present the first definitive evidence of ancient nurseries for C. megalodon from the late Miocene of Panama, about 10 million years ago. METHODOLOGY/PRINCIPAL FINDINGS: We collected and measured fossil shark teeth of C. megalodon, within the highly productive, shallow marine Gatun Formation from the Miocene of Panama. Surprisingly, and in contrast to other fossil accumulations, the majority of the teeth from Gatun are very small. Here we compare the tooth sizes from the Gatun with specimens from different, but analogous localities. In addition we calculate the total length of the individuals found in Gatun. These comparisons and estimates suggest that the small size of Gatun's C. megalodon is neither related to a small population of this species nor the tooth position within the jaw. Thus, the individuals from Gatun were mostly juveniles and neonates, with estimated body lengths between 2 and 10.5 meters. CONCLUSIONS/SIGNIFICANCE: We propose that the Miocene Gatun Formation represents the first documented paleo-nursery area for C. megalodon from the Neotropics, and one of the few recorded in the fossil record for an extinct selachian. We therefore show that sharks have used nursery areas at least for 10 millions of years as an adaptive strategy during their life histories