The RNA-binding protein ATX-2 regulates cytokinesis through PAR-5 and ZEN-4

The spindle midzone harbors both microtubules and proteins necessary for furrow formation and the completion of cytokinesis. However, the mechanisms that mediate the temporal and spatial recruitment of cell division factors to the spindle midzone and midbody remain unclear. Here we describe a mechanism governed by the conserved RNA-binding protein ATX-2/Ataxin-2, which targets and maintains ZEN-4 at the spindle midzone. ATX-2 does this by regulating the amount of PAR-5 at mitotic structures, particularly the spindle, centrosomes, and midbody. Preventing ATX-2 function leads to elevated levels of PAR-5, enhanced chromatin and centrosome localization of PAR-5-GFP, and ultimately a reduction of ZEN-4-GFP at the spindle midzone. Codepletion of ATX-2 and PAR-5 rescued the localization of ZEN-4 at the spindle midzone, indicating that ATX-2 mediates the localization of ZEN-4 upstream of PAR-5. We provide the first direct evidence that ATX-2 is necessary for cytokinesis and suggest a model in which ATX-2 facilitates the targeting of ZEN-4 to the spindle midzone by mediating the posttranscriptional regulation of PAR-5

The minibrain kinase homolog, mbk-2, is required for spindle positioning and asymmetric cell division in early C. elegans embryos

AbstractIn the newly fertilized Caenorhabditis elegans zygote, cytoplasmic determinants become localized asymmetrically along the anterior–posterior (A–P) axis of the embryo. The mitotic apparatus then orients so as to cleave the embryo into anterior and posterior blastomeres that differ in both size and developmental potential. Here we describe a role for MBK-2, a member of the Dyrk family of protein kinases, in asymmetric cell division in C. elegans. In mbk-2 mutants, the initial mitotic spindle is misplaced and cytoplasmic factors, including the germline-specific protein PIE-1, are mislocalized. Our findings support a model in which MBK-2 down-regulates the katanin-related protein MEI-1 to control spindle positioning and acts through distinct, as yet unknown factors, to control the localization of cytoplasmic determinants. These findings in conjunction with work from Schizosaccharomyces pombe indicate a possible conserved role for Dyrk family kinases in the regulation of spindle placement during cell division

Fate specification and tissue-specific cell cycle control of the <i>Caenorhabditis elegans</i> intestine

Coordination between cell fate specification and cell cycle control in multicellular organisms is essential to regulate cell numbers in tissues and organs during development, and its failure may lead to oncogenesis. In mammalian cells, as part of a general cell cycle checkpoint mechanism, the F-box protein β-transducin repeat-containing protein (β-TrCP) and the Skp1/Cul1/F-box complex control the periodic cell cycle fluctuations in abundance of the CDC25A and B phosphatases. Here, we find that the Caenorhabditis elegans β-TrCP orthologue LIN-23 regulates a progressive decline of CDC-25.1 abundance over several embryonic cell cycles and specifies cell number of one tissue, the embryonic intestine. The negative regulation of CDC-25.1 abundance by LIN-23 may be developmentally controlled because CDC-25.1 accumulates over time within the developing germline, where LIN-23 is also present. Concurrent with the destabilization of CDC-25.1, LIN-23 displays a spatially dynamic behavior in the embryo, periodically entering a nuclear compartment where CDC-25.1 is abundant

A Mathematical Model of Mitotic Exit in Budding Yeast: The Role of Polo Kinase

Cell cycle progression in eukaryotes is regulated by periodic activation and inactivation of a family of cyclin–dependent kinases (Cdk's). Entry into mitosis requires phosphorylation of many proteins targeted by mitotic Cdk, and exit from mitosis requires proteolysis of mitotic cyclins and dephosphorylation of their targeted proteins. Mitotic exit in budding yeast is known to involve the interplay of mitotic kinases (Cdk and Polo kinases) and phosphatases (Cdc55/PP2A and Cdc14), as well as the action of the anaphase promoting complex (APC) in degrading specific proteins in anaphase and telophase. To understand the intricacies of this mechanism, we propose a mathematical model for the molecular events during mitotic exit in budding yeast. The model captures the dynamics of this network in wild-type yeast cells and 110 mutant strains. The model clarifies the roles of Polo-like kinase (Cdc5) in the Cdc14 early anaphase release pathway and in the G-protein regulated mitotic exit network

Diversification of the Caenorhabditis heat shock response by Helitron transposable elements.

Heat Shock Factor 1 (HSF-1) is a key regulator of the heat shock response (HSR). Upon heat shock, HSF-1 binds well-conserved motifs, called Heat Shock Elements (HSEs), and drives expression of genes important for cellular protection during this stress. Remarkably, we found that substantial numbers of HSEs in multiple Caenorhabditis species reside within Helitrons, a type of DNA transposon. Consistent with Helitron-embedded HSEs being functional, upon heat shock they display increased HSF-1 and RNA polymerase II occupancy and up-regulation of nearby genes in C. elegans. Interestingly, we found that different genes appear to be incorporated into the HSR by species-specific Helitron insertions in C. elegans and C. briggsae and by strain-specific insertions among different wild isolates of C. elegans. Our studies uncover previously unidentified targets of HSF-1 and show that Helitron insertions are responsible for rewiring and diversifying the Caenorhabditis HSR

Status, trends and future dynamics of biodiversity and ecosystems underpinning nature's contributions to people

Biodiversity at the species and ecosystem levels is currently under multiple threats almost everywhere in the Asia-Pacific region, and in many areas the situation is now critical (well established). Of the various ecosystems, lowland evergreen forests, alpine ecosystems, limestone karsts, inland wetlands, and estuarine and coastal habitats are most threatened (well established). Genetic diversity within species, both wild and domestic, is also decreasing in many cases as a result of decreasing ranges (established but incomplete). In several countries there has been a small increase in the forest cover which is mostly attributed to monoculture forestry plantations and enabling policies of the governments. Forest fires associated with rapid loss of forest cover is leading to enormous environmental and socio-economic loss (well established) {3.2.1; 3.2.2; 3.2.3; 3.2.4; 3.2.5; 3.3.1}. There has been a steady decline in the populations of large vertebrates due to poaching and illegal trade in wildlife parts and products in the Asia-Pacific region (well established). As a result, most of these species now survive only in the best-managed protected areas (well established). Widespread loss of large vertebrates has had a measureable impact on several forest functions and services, including seed dispersal (established but incomplete). Australia has the highest rate of mammal extinction (>10 per cent) of any continent globally. Bird extinctions on individual Pacific islands range from 15.4 per cent to 87.5 per cent for those with good fossil records, and these extinctions have resulted in the loss of many ecological functions previously performed by birds (well established). Besides wildlife, there is a massive regional trade in timber, traditional medicines and other products (well established). Without adequate protection, remediation and proper policies, the current decline in biodiversity and nature's contributions to people on land, in freshwaters, and in the sea will threaten the quality of life of future generations in the Asia-Pacific region {3.2.1.1; 3.2.1.2; 3.2.1.4; 3.2.1.7; 3.2.2.1; 3.3.1} With the current rate of human population growth, expansion of urban industrial environments, transformation of agriculture in favour of high yielding varieties, transforming forests to uniform plantations of oil palm, rubber or timber trees, the biodiversity and nature's contributions to people in the Asia-Pacific region are likely to be adversely affected in the coming decades (well established). It is predicted that most of the biodiversity in the next few decades may be confined to protected areas or in places where the local communities have taken the lead in local level conservation in lieu of economic incentives and equitable compensation by the stake-holders. Unprecedented increase in human population of the Asia-Pacific region has stressed the fragile ecosystems to their limits; while arable cropping has been extended to sites which were not entirely suitable for it, resulting in soil degradation and erosion (well established) {3.2.1.1; 3.2.1.2; 3.2.1.5; 3.2.2.2; 3.2.2.4; 3.3; 3.3.1; 3.3.6; 3.4}. Freshwater ecosystems in the Asia-Pacific region support more than 28 per cent of aquatic and semi-aquatic species but nearly 37 per cent of these species are threatened due to anthropogenic and climatic drivers (well established). Cumulative impacts of global warming and damming of rivers in some of the river basins will have significant negative impacts on fish production and environmental flows (well established). Likewise, degradation of wetlands has had severe negative impacts on migratory waterfowl, fish production and local livelihoods (well established). However, there are scientific data gaps on the current status of biodiversity and nature's contributions to people in most of the river basins, inland wetlands and peatlands of the region {3.2.2.1; 3.2.2.2; 3.2.2.3; 3.2.2.4}. Coastal and marine habitats are likewise threatened due to commercial aquaculture, overfishing, and pollution affecting biodiversity and nature's contributions to people (well established). Detailed analyses of fisheries production in the region have shown severe decline in recent decades. It is projected that if unsustainable fishing practices continue, there could be no exploitable stocks of fish by as early as 2048. This could lead to trophic cascades and collapse of marine ecosystems (established but incomplete). Loss of seagrass beds which forms main diet of several threatened species such as dugong is a major concern (well established). There is a need to conduct systematic and region-wide assessment of fisheries stocks and coastal habitat in the region to aid conservation, management and restoration. {3.1.3.1; 3.2.3.3; 3.2.3.6; 3.2.4.6; 3.4}. Mangrove ecosystems in the Asia-Pacific region are most diverse in the world. They support a rich biodiversity and provide a range of provisioning, regulating and supporting services, which are crucial for the livelihood of local communities (well established). Both mangrove and intertidal habitats form a buffer from siltation for offshore coral reefs protection hence affecting productivity of reefs including seagrass. However, up to 75 per cent of the mangroves have been degraded or converted in recent decades (well established). The conversion of mangroves to aquaculture, rice, oil palm, and other land-use changes is leading to the loss of the buffer between sea and land which can reduce the impact of natural disasters such as cyclones and tsunamis. It is projected that rise in sea level due to global warming would pose the biggest threat to mangroves, thereby affecting nature's contributions to people especially in Bangladesh, Philippines, New Zealand, Viet Nam and China (well established) {3.2.3.1; 3.2.3.2; 3.3.4}. There has been a steady increase in the number, abundance and impacts of invasive alien species in the Asia-Pacific region, negatively affecting native biodiversity, ecosystem functioning and socio-cultural environments (well established). The total annual loss caused by invasive alien species has been estimated at US$35.5 billion in SE Asia and US$9B in Australia. Costs to agriculture due to invasive alien species are likewise immense in the region {3.2.1.1; 3.2.1.2; 3.2.1.4; 3.2.1.5; 3.2.1.6; 3.2.1.7; 3.2.2.1; 3.2.2.2; 3.2.2.3; 3.2.3.6; 3.3.5}. There has been a nearly 30 per cent decline in biocultural diversity in the Asia-Pacific region since the 1970s (well established). Decline of linguistic diversity has been catastrophic in the indigenous Australian and Trans-New Guinean families, as a result of a shifting away from small indigenous languages towards larger, national or regional languages (well established). Linguistic and biological diversity often coincide in the Asia-Pacific region and parallel strategies need to be developed for their conservation. National conservation priorities should take into consideration the bioculturally rich areas that are facing great threats {3.2.5; 3.2.5.2; 3.2.5.4; 3.4}. Protected Area coverage in the Asia-Pacific region has increased substantially since last three decades. Despite this progress, however, at least 75 per cent of Key Biodiversity Areas remain unprotected, suggesting that the region is not on track to conserve areas of particular importance for biodiversity, as called for under Aichi Target 11 (well established). Oceania has the highest overall Protected Area coverage in the region. North-East Asia has the highest proportion of Key Biodiversity Areas covered by Protected Areas, but only 1 per cent of its marine area is protected (well established) {3.2.5.6; 3.2.6; 3.2.6.1}. The Asia-Pacific region has high levels of endemism, and some 25 per cent of the region’s endemic species are facing high extinction risks as per the IUCN Red List. Endemic species in some subregions face an extinction risk as high as 46 per cent of endemic species threatened in South Asia (well established). South-East Asia has the greatest number of threatened species and the fastest increases in extinction risk (Red List Index) in the Asia-Pacific region. North Asian endemic species extinction risk is also higher than the regional average; the high percentage of Data Deficient species (36 per cent) indicates that more research and conservation action are needed for endemic species in this subregion (well established) {3.2.1; 3.2.2; 3.2.6.2; 3.3.4}. Some aspects of biodiversity have recently started to recover in several countries in the Asia-Pacific region (established but incomplete). This recovery has resulted from various changes, including population concentration in cities, increased agricultural production per unit area, increasing conservation awareness among citizens, and the enabling policies of the governments. Future trends of biodiversity in the Asia-Pacific region will largely depend on whether other countries will follow this recovering trajectory by stabilizing land/sea use change, manage their natural resources sustainably, and cooperating with each other in meeting the Aichi Targets and the Sustainable Development Goals {3.2.1.5; 3.2.3.5; 3.3.1; 3.3.3; 3.3.6}. Given that the scientific information on the status and trends of biodiversity and nature's contributions to people is not available uniformly across all ecosystems and habitats in the region, the national governments are encouraged to initiate systematic documentation and monitoring of health of ecosystems and ecosystem flows (established but incomplete). Saving terrestrial fauna especially big mammals and other fauna that require large roaming areas such as Orangutans, proboscis monkey, hornbills, tigers, Sumatran rhinoceros, gaurs and Asian elephants can be done by connecting large tracts of forests with wildlife corridors or through rehabilitation projects; the same goes for coastal and marine, freshwater and other ecosystems in the region {3.2.1.1; 3.2.2.4; 3.3.4; 3.4}

Fragilities Caused by Dosage Imbalance in Regulation of the Budding Yeast Cell Cycle

Cells can maintain their functions despite fluctuations in intracellular parameters, such as protein activities and gene expression levels. This commonly observed biological property of cells is called robustness. On the other hand, these parameters have different limitations, each reflecting the property of the subsystem containing the parameter. The budding yeast cell cycle is quite fragile upon overexpression of CDC14, but is robust upon overexpression of ESP1. The gene products of both CDC14 and ESP1 are regulated by 1∶1 binding with their inhibitors (Net1 and Pds1), and a mathematical model predicts the extreme fragility of the cell cycle upon overexpression of CDC14 and ESP1 caused by dosage imbalance between these genes. However, it has not been experimentally shown that dosage imbalance causes fragility of the cell cycle. In this study, we measured the quantitative genetic interactions of these genes by performing combinatorial “genetic tug-of-war” experiments. We first showed experimental evidence that dosage imbalance between CDC14 and NET1 causes fragility. We also showed that fragility arising from dosage imbalance between ESP1 and PDS1 is masked by CDH1 and CLB2. The masking function of CLB2 was stabilization of Pds1 by its phosphorylation. We finally modified Chen's model according to our findings. We thus propose that dosage imbalance causes fragility in biological systems

The opposite effects of fluvoxamine and sertraline in the treatment of psychotic major depression: a case report

<p>Abstract</p> <p>Background</p> <p>Psychotic major depression is a clinical subtype of major depressive disorder. A number of clinical studies have demonstrated the efficacy of the combination of an antidepressant (for example, a tricyclic antidepressant or selective serotonin reuptake inhibitor (SSRI)) and an atypical antipsychotic or electroconvulsive therapy (ECT) in treating psychotic major depression. In several studies, monotherapy of SSRIs such as fluvoxamine has been shown to be effective in the treatment of psychotic major depression.</p> <p>Methods</p> <p>We report on a 36-year-old Japanese woman in whom fluvoxamine (a SSRI with sigma-1 receptor agonist) and sertraline (a SSRI with sigma-1 receptor antagonist) showed the opposite effects on psychotic symptoms in the treatment of psychotic major depression.</p> <p>Results</p> <p>Symptoms of depression and psychosis in the patient who was non-respondent to antipsychotic drugs improved after fluvoxamine monotherapy. At 3 years later, a switch to sertraline from fluvoxamine dramatically worsened the psychotic symptoms in the patient. Then, a switch back to fluvoxamine from sertraline improved these symptoms 1 week after fluvoxamine treatment.</p> <p>Conclusion</p> <p>Doctors should consider the monotherapy of sigma-1 receptor agonist fluvoxamine as an alternative approach to treating psychotic major depression.</p

Neurochemical Changes in the Mouse Hippocampus Underlying the Antidepressant Effect of Genetic Deletion of P2X7 Receptors.

Recent investigations have revealed that the genetic deletion of P2X7 receptors (P2rx7) results in an antidepressant phenotype in mice. However, the link between the deficiency of P2rx7 and changes in behavior has not yet been explored. In the present study, we studied the effect of genetic deletion of P2rx7 on neurochemical changes in the hippocampus that might underlie the antidepressant phenotype. P2X7 receptor deficient mice (P2rx7-/-) displayed decreased immobility in the tail suspension test (TST) and an attenuated anhedonia response in the sucrose preference test (SPT) following bacterial endotoxin (LPS) challenge. The attenuated anhedonia was reproduced through systemic treatments with P2rx7 antagonists. The activation of P2rx7 resulted in the concentration-dependent release of [3H]glutamate in P2rx7+/+ but not P2rx7-/- mice, and the NR2B subunit mRNA and protein was upregulated in the hippocampus of P2rx7-/- mice. The brain-derived neurotrophic factor (BDNF) expression was higher in saline but not LPS-treated P2rx7-/- mice; the P2rx7 antagonist Brilliant blue G elevated and the P2rx7 agonist benzoylbenzoyl ATP (BzATP) reduced BDNF level. This effect was dependent on the activation of NMDA and non-NMDA receptors but not on Group I metabotropic glutamate receptors (mGluR1,5). An increased 5-bromo-2-deoxyuridine (BrdU) incorporation was also observed in the dentate gyrus derived from P2rx7-/- mice. Basal level of 5-HT was increased, whereas the 5HIAA/5-HT ratio was lower in the hippocampus of P2rx7-/- mice, which accompanied the increased uptake of [3H]5-HT and an elevated number of [3H]citalopram binding sites. The LPS-induced elevation of 5-HT level was absent in P2rx7-/- mice. In conclusion there are several potential mechanisms for the antidepressant phenotype of P2rx7-/- mice, such as the absence of P2rx7-mediated glutamate release, elevated basal BDNF production, enhanced neurogenesis and increased 5-HT bioavailability in the hippocampus

Downregulation of the anaphase-promoting complex (APC)7 in invasive ductal carcinomas of the breast and its clinicopathologic relationships

INTRODUCTION: The anaphase-promoting complex (APC) is a multiprotein complex with E3 ubiquitin ligase activity, which is required for the ubiquitination of securin and cyclin-B. Moreover, the mitotic spindle checkpoint is activated if APC activation is prevented. In addition, several APC-targeting molecules such as securin, polo-like kinase, aurora kinase, and SnoN have been reported to be oncogenes. Therefore, dysregulation of APC may be associated with tumorigenesis. However, the clinical significance and the involvement of APC in tumorigenesis have not been investigated. METHODS: The expression of APC7 was immunohistochemically investigated in 108 invasive ductal carcinomas of the breast and its relationship with clinicopathologic parameters was examined. The expression of APC7 was defined as positive when the summed scores of staining intensities (0 to 3+) and stained proportions (0 to 3+) exceeded 3+. RESULTS: Positive APC7 expression was less frequent than its negative expression when histologic (P = 0.009) or nuclear grade (P = 0.009), or mitotic number (P = 0.0016) was elevated. The frequency of APC7 negative expression was higher in high Ki-67 or aneuploid groups than in low Ki-67 or diploid groups. CONCLUSION: These data show that loss of APC7 expression is more common in breast carcinoma cases with poor prognostic parameters or malignant characteristics. They therefore suggest that dysregulation of APC activity, possibly through downregulation of APC7, may be associated with tumorigenesis in breast cancer