Immunoproteasome Deficiency Protects in the Retina after Optic Nerve Crush

The immunoproteasome is upregulated by disease, oxidative stress, and inflammatory cytokines, suggesting an expanded role for the immunoproteasome in stress signaling that goes beyond its canonical role in generating peptides for antigen presentation. The signaling pathways that are regulated by the immunoproteasome remain elusive. However, previous studies suggest a role for the immunoproteasome in the regulation of PTEN and NF-κB signaling. One well-known pathway upstream of NF-κB and downstream of PTEN is the Akt signaling pathway, which is responsible for mediating cellular survival and is modulated after optic nerve crush (ONC). This study investigated the role of retinal immunoproteasome after injury induced by ONC, focusing on the Akt cell survival pathway. Retinas or retinal pigment epithelial (RPE) cells from wild type (WT) and knockout (KO) mice lacking either one (LMP2) or two (LMP7 and MECL-1) catalytic subunits of the immunoproteasome were utilized in this study. We show that mRNA and protein levels of the immunoproteasome subunits are significantly upregulated in WT retinas following ONC. Mice lacking the immunoproteasome subunits show either a delayed or dampened apoptotic response as well as altered Akt signaling, compared to WT mice after ONC. Treatment of the RPE cells with insulin growth factor-1 (IGF-1) to stimulate Akt signaling confirmed that the immunoproteasome modulates this pathway, and most likely modulates parallel pathways as well. This study links the inducible expression of the immunoproteasome following retinal injury to Akt signaling, which is important in many disease pathways.     

Size matters: nest colonization patterns for twig‐nesting ants

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mTOR drives cerebrovascular,synaptic, and cognitive dysfunction in normative aging

Cerebrovascular dysfunction and cognitive decline are highly prevalent in aging, but the mechanisms underlying these impairments are unclear. Cerebral blood flow decreases with aging and is one of the earliest events in the pathogenesis of Alzheimer's disease (AD). We have previously shown that the mechanistic/mammalian target of rapamycin (mTOR) drives disease progression in mouse models of AD and in models of cognitive impairment associated with atherosclerosis, closely recapitulating vascular cognitive impairment. In the present studies, we sought to determine whether mTOR plays a role in cerebrovascular dysfunction and cognitive decline during normative aging in rats. Using behavioral tools and MRI‐based functional imaging, together with biochemical and immunohistochemical approaches, we demonstrate that chronic mTOR attenuation with rapamycin ameliorates deficits in learning and memory, prevents neurovascular uncoupling, and restores cerebral perfusion in aged rats. Additionally, morphometric and biochemical analyses of hippocampus and cortex revealed that mTOR drives age‐related declines in synaptic and vascular density during aging. These data indicate that in addition to mediating AD‐like cognitive and cerebrovascular deficits in models of AD and atherosclerosis, mTOR drives cerebrovascular, neuronal, and cognitive deficits associated with normative aging. Thus, inhibitors of mTOR may have potential to treat age‐related cerebrovascular dysfunction and cognitive decline. Since treatment of age‐related cerebrovascular dysfunction in older adults is expected to prevent further deterioration of cerebral perfusion, recently identified as a biomarker for the very early (preclinical) stages of AD, mTOR attenuation may potentially block the initiation and progression of AD.     

One genotype dominates a facultatively outcrossing plant invasion

Biological Invasions - Plant invasions are rarely homogenous. Processes such as selection, drift, gene flow, and founding events can rapidly shape the genetic diversity and spatial population...     

Changes in Species Richness,Abundance, and Composition of Arboreal Twig‐nesting Ants Along an Elevational Gradient in Coffee Landscapes

The distribution, diversity, and assembly of tropical insects have long intrigued ecologists, and for tropical ants, can be affected by competitive interactions, microhabitat requirements, dispersal, and availability and diversity of nesting sites. Arboreal twig‐nesting ants are limited by the number of hollow twigs available, especially in intensive agricultural systems. Ant diversity and abundance may shift along elevation gradients, but no studies have examined if the proportion of occupied twigs or richness of arboreal twig‐nesting ants vary with elevation. In coffee agroecosystems, there are over 40 species of arboreal twig‐nesting ants. We examined communities of twig‐nesting ants in coffee plants along an elevational gradient to answer the following questions: (1) Do species richness and colony abundance decline with elevation or show a mid‐elevation peak? (2) Does community composition change with elevation? (3) Is elevation an important predictor of change in ant abundance, richness, and relative abundance of common species? We surveyed 42 10 × 10 m plots in 2013 from 450 to1550 m elevation across a coffee landscape in Chiapas, Mexico. We sampled a total of 2211 hollow coffee twigs, 77.1 percent of which were occupied by one of 28 species of ants. Pseudomyrmex simplex was more abundant in lower elevations, whereas Pseudomyrmex ejectus dominated in high elevations. Species richness and the percent of occupied hollow twigs both peaked at mid‐elevations (800–1050 m). In sum, we found that species richness, abundance, and composition of arboreal twig‐nesting ants shift with elevation. These findings may provide important insights for understanding ant communities in coffee agroecosystems.     

Di-2-pyridylketone 4,4-Dimethyl-3-thiosemicarbazone (Dp44mT) Overcomes Multidrug Resistance by a Novel Mechanism Involving the Hijacking of Lysosomal P-Glycoprotein (Pgp)

Multidrug resistance (MDR) is a major obstacle in cancer treatment. More than half of human cancers express multidrug-resistant P-glycoprotein (Pgp), which correlates with a poor prognosis. Intriguingly, through an unknown mechanism, some drugs have greater activity in drug-resistant tumor cells than their drug-sensitive counterparts. Herein, we investigate how the novel anti-tumor agent di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) overcomes MDR. Four different cell types were utilized to evaluate the effect of Pgp-potentiated lysosomal targeting of drugs to overcome MDR. To assess the mechanism of how Dp44mT overcomes drug resistance, cellular studies utilized Pgp inhibitors, Pgp silencing, lysosomotropic agents, proliferation assays, immunoblotting, a Pgp-ATPase activity assay, radiolabeled drug uptake/efflux, a rhodamine 123 retention assay, lysosomal membrane permeability assessment, and DCF (2′,7′-dichlorofluorescin) redox studies. Anti-tumor activity and selectivity of Dp44mT in Pgp-expressing, MDR cells versus drug-sensitive cells were studied using a BALB/c nu/nu xenograft mouse model. We demonstrate that Dp44mT is transported by the lysosomal Pgp drug pump, causing lysosomal targeting of Dp44mT and resulting in enhanced cytotoxicity in MDR cells. Lysosomal Pgp and pH were shown to be crucial for increasing Dp44mT-mediated lysosomal damage and subsequent cytotoxicity in drug-resistant cells, with Dp44mT being demonstrated to be a Pgp substrate. Indeed, Pgp-dependent lysosomal damage and cytotoxicity of Dp44mT were abrogated by Pgp inhibitors, Pgp silencing, or increasing lysosomal pH using lysosomotropic bases. In vivo, Dp44mT potently targeted chemotherapy-resistant human Pgp-expressing xenografted tumors relative to non-Pgp-expressing tumors in mice. This study highlights a novel Pgp hijacking strategy of the unique dipyridylthiosemicarbazone series of thiosemicarbazones that overcome MDR via utilization of lysosomal Pgp transport activity.     

Growth and longevity in freshwater mussels: evolutionary and conservation implications

The amount of energy allocated to growth versus other functions is a fundamental feature of an organism's life history. Constraints on energy availability result in characteristic trade‐offs among life‐history traits and reflect strategies by which organisms adapt to their environments. Freshwater mussels are a diverse and imperiled component of aquatic ecosystems but little is known about their growth and longevity. Generalized depictions of freshwater mussels as ‘long‐lived and slow‐growing’ may give an unrealistically narrow view of life‐history diversity which is incongruent with the taxonomic diversity of the group and can result in development of inappropriate conservation strategies. We investigated relationships among growth, longevity, and size in 57 species and 146 populations of freshwater mussels using original data and literature sources. In contrast to generalized depictions, longevity spanned nearly two orders of magnitude, ranging from 4 to 190 years, and the von Bertalanffy growth constant, K, spanned a similar range (0.02–1.01). Median longevity and K differed among phylogenetic groups but groups overlapped widely in these traits. Longevity, K, and size also varied among populations; in some cases, longevity and K differed between populations by a factor of two or more. Growth differed between sexes in some species and males typically reached larger sizes than females. In addition, a population of Quadrula asperata exhibited two distinctly different growth trajectories. Most individuals in this population had a low‐to‐moderate value of K (0.15) and intermediate longevity (27 years) but other individuals showed extremely slow growth (K = 0.05) and reached advanced ages (72 years). Overall, longevity was related negatively to the growth rate, K, and K explained a high percentage of variation in longevity. By contrast, size and relative shell mass (g mm^?1 shell length) explained little variation in longevity. These patterns remained when data were corrected for phylogenetic relationships among species. Path analysis supported the conclusion that K was the most important factor influencing longevity both directly and indirectly through its effect on shell mass. The great variability in age and growth among and within species shows that allocation to growth is highly plastic in freshwater mussels. The strong negative relationship between growth and longevity suggests this is an important trade‐off describing widely divergent life‐history strategies. Although life‐history strategies may be constrained somewhat by phylogeny, plasticity in growth among populations indicates that growth characteristics cannot be generalized within a species and management and conservation efforts should be based on data specific to a population of interest.     

Post-genomics resources and tools for studying apicomplexan metabolism

The phylum Apicomplexa comprises over 5000 species of obligate intracellular parasites, many responsible for diseases that significantly impact human health and economics. To aid drug development programs, global sequencing initiatives are generating increasing numbers of apicomplexan genomes. The challenge is how best to exploit these resources to identify effective therapeutic targets. Because of its important role in growth and maintenance, much interest has centred on metabolism. However, in the absence of detailed biochemical data, reconstructing the metabolic potential from a fully sequenced genome remains problematic. In this review current resources and tools facilitating the metabolic reconstruction for apicomplexans are examined. Furthermore, how these datasets can be utilized to explore the metabolic capabilities of apicomplexans are discussed and targets for therapeutic intervention are prioritized.     

A phosphatase threshold sets the level of Cdk1 activity in early mitosis in budding yeast

Entry into mitosis is initiated by synthesis of cyclins, which bind and activate cyclin-dependent kinase 1 (Cdk1). Cyclin synthesis is gradual, yet activation of Cdk1 occurs in a stepwise manner: a low level of Cdk1 activity is initially generated that triggers early mitotic events, which is followed by full activation of Cdk1. Little is known about how stepwise activation of Cdk1 is achieved. A key regulator of Cdk1 is the Wee1 kinase, which phosphorylates and inhibits Cdk1. Wee1 and Cdk1 show mutual regulation: Cdk1 phosphorylates Wee1, which activates Wee1 to inhibit Cdk1. Further phosphorylation events inactivate Wee1. We discovered that a specific form of protein phosphatase 2A (PP2A(Cdc55)) opposes the initial phosphorylation of Wee1 by Cdk1. In vivo analysis, in vitro reconstitution, and mathematical modeling suggest that PP2A(Cdc55) sets a threshold that limits activation of Wee1, thereby allowing a low constant level of Cdk1 activity to escape Wee1 inhibition in early mitosis. These results define a new role for PP2A(Cdc55) and reveal a systems-level mechanism by which dynamically opposed kinase and phosphatase activities can modulate signal strength.