Deprotection of centromeric cohesin at meiosis II requires APC/C activity but not kinetochore tension

Genome haploidization involves sequential loss of cohesin from chromosome arms and centromeres during two meiotic divisions. At centromeres, cohesin's Rec8 subunit is protected from separase cleavage at meiosis I and then deprotected to allow its cleavage at meiosis II. Protection of centromeric cohesin by shugoshin-PP2A seems evolutionarily conserved. However, deprotection has been proposed to rely on spindle forces separating the Rec8 protector from cohesin at metaphase II in mammalian oocytes and on APC/C-dependent destruction of the protector at anaphase II in yeast. Here, we have activated APC/C in the absence of sister kinetochore biorientation at meiosis II in yeast and mouse oocytes, and find that bipolar spindle forces are dispensable for sister centromere separation in both systems. Furthermore, we show that at least in yeast, protection of Rec8 by shugoshin and inhibition of separase by securin are both required for the stability of centromeric cohesin at metaphase II. Our data imply that related mechanisms preserve the integrity of dyad chromosomes during the short metaphase II of yeast and the prolonged metaphase II arrest of mammalian oocytes

The Evaluation of Optic Nerves Using 7 Tesla 'Silent' Zero Echo Time Imaging in Patients with Leber's Hereditary Optic Neuropathy with or without Idebenone Treatment

Magnetic Resonance Imaging (MRI) of the Optic Nerve is difficult due to the fine extended nature of the structure, strong local magnetic field distortions induced by anatomy, and large motion artefacts associated with eye movement. To address these problems we used a Zero Echo Time (ZTE) MRI sequence with an Adiabatic SPectral Inversion Recovery (ASPIR) fat suppression pulse which also imbues the images with Magnetisation Transfer contrast. We investigated an application of the sequence for imaging the optic nerve in subjects with Leber's hereditary optic neuropathy (LHON). Of particular note is the sequence's near-silent operation, which can enhance image quality of the optic nerve by reducing the occurrence of involuntary saccades induced during Magnetic Resonance (MR) scanning

Searching for life with rovers: exploration methods and science results from the 2004 field campaign of the “Life in the Atacama” project and applications to future Mars Missions

LITA develops and field tests a long-range automated rover and a science payload to search for microbial life in the Atacama. The Atacama's evolution provides a unique training ground for designing and testing exploration strategies and life detection methods for the search for life on Mars

Nonsense-Mediated mRNA Decay Modulates Immune Receptor Levels to Regulate Plant Antibacterial Defense

SummaryNonsense-mediated mRNA decay (NMD) is a conserved eukaryotic RNA surveillance mechanism that degrades aberrant mRNAs. NMD impairment in Arabidopsis is linked to constitutive immune response activation and enhanced antibacterial resistance, but the underlying mechanisms are unknown. Here we show that NMD contributes to innate immunity in Arabidopsis by controlling the turnover of numerous TIR domain-containing, nucleotide-binding, leucine-rich repeat (TNL) immune receptor-encoding mRNAs. Autoimmunity resulting from NMD impairment depends on TNL signaling pathway components and can be triggered through deregulation of a single TNL gene, RPS6. Bacterial infection of plants causes host-programmed inhibition of NMD, leading to stabilization of NMD-regulated TNL transcripts. Conversely, constitutive NMD activity prevents TNL stabilization and impairs plant defense, demonstrating that host-regulated NMD contributes to disease resistance. Thus, NMD shapes plant innate immunity by controlling the threshold for activation of TNL resistance pathways

Stress-Induced GSK3 Regulates the Redox Stress Response by Phosphorylating Glucose-6-Phosphate Dehydrogenase in Arabidopsis.

Diverse stresses such as high salt conditions cause an increase in reactive oxygen species (ROS), necessitating a redox stress response. However, little is known about the signaling pathways that regulate the antioxidant system to counteract oxidative stress. Here, we show that a Glycogen Synthase Kinase3 from Arabidopsis thaliana (ASKα) regulates stress tolerance by activating Glc-6-phosphate dehydrogenase (G6PD), which is essential for maintaining the cellular redox balance. Loss of stress-activated ASKα leads to reduced G6PD activity, elevated levels of ROS, and enhanced sensitivity to salt stress. Conversely, plants overexpressing ASKα have increased G6PD activity and low levels of ROS in response to stress and are more tolerant to salt stress. ASKα stimulates the activity of a specific cytosolic G6PD isoform by phosphorylating the evolutionarily conserved Thr-467, which is implicated in cosubstrate binding. Our results reveal a novel mechanism of G6PD adaptive regulation that is critical for the cellular stress response

Arabidopsis MKS1 Is Involved in Basal Immunity and Requires an Intact N-terminal Domain for Proper Function

Innate immune signaling pathways in animals and plants are regulated by mitogen-activated protein kinase (MAPK) cascades. MAP kinase 4 (MPK4) functions downstream of innate immune receptors via a nuclear substrate MKS1 to regulate the activity of the WRKY33 transcription factor, which in turn controls the production of anti-microbial phytoalexins.We investigate the role of MKS1 in basal resistance and the importance of its N- and C-terminal domains for MKS1 function. We used the information that mks1 loss-of-function partially suppresses the mpk4 loss-of-function phenotype, and that transgenic expression of functional MKS1 in mpk4/mks1 double mutants reverted the mpk4 dwarf phenotype. Transformation of mks1/mpk4 with mutant versions of MKS1 constructs showed that a single amino acid substitution in a putative MAP kinase docking domain, MKS1-L32A, or a truncated MKS1 version unable to interact with WRKY33, were deficient in reverting the double mutant to the mpk4 phenotype. These results demonstrate functional requirement in MKS1 for the interaction with MPK4 and WRKY33. In addition, nuclear localization of MKS1 was shown to depend on an intact N-terminal domain. Furthermore, loss-of-function mks1 mutants exhibited increased susceptibility to strains of Pseudomonas syringae and Hyaloperonospora arabidopsidis, indicating that MKS1 plays a role in basal defense responses.Taken together, our results indicate that MKS1 function and subcellular location requires an intact N-terminus important for both MPK4 and WRKY33 interactions

Characteristics associated with significantly worse quality of life in mycosis fungoides/Sezary syndrome from the Prospective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) study

Background Mycosis fungoides (MF) and Sezary Syndrome (SS) are the most common cutaneous T-cell lymphomas. MF/SS is accompanied by considerable morbidity from pain, itching and disfigurement. Aim To identify factors associated with poorer health-related quality of life (HRQoL) in patients newly diagnosed with MF/SS. Methods Patients enrolled into Prospective Cutaneous Lymphoma International Prognostic Index (PROCLIPI; an international observational study in MF/SS) had their HRQoL assessed using the Skindex-29 questionnaire. Skindex-29 scores were analysed in relation to patient- and disease-specific characteristics. Results The study population consisted of 237 patients [60 center dot 3% male; median age 60 years, (interquartile range 49-70)], of whom 179 had early MF and 58 had advanced MF/SS. In univariate analysis, HRQoL, as measured by Skindex-29, was worse in women, SS, late-stage MF, those with elevated lactate dehydrogenase, alopecia, high modified Severity Weighted Assessment Tool and confluent erythema. Linear regression models only identified female gender (beta = 8 center dot 61; P = 0 center dot 003) and alopecia (beta = 9 center dot 71, P = 0 center dot 02) as independent predictors of worse global HRQoL. Item-level analysis showed that the severe impairment in symptoms [odds ratio (OR) 2 center dot 14, 95% confidence interval (CI) 1 center dot 19-3 center dot 89] and emotions (OR 1 center dot 88, 95% CI 1 center dot 09-3 center dot 27) subscale scores seen in women was caused by more burning/stinging, pruritus, irritation and greater feelings of depression, shame, embarrassment and annoyance with their diagnosis of MF/SS. Conclusions HRQoL is significantly more impaired in newly diagnosed women with MF/SS and in those with alopecia. As Skindex-29 does not include existential questions on cancer, which may cause additional worry and distress, a comprehensive validated cutaneous T-cell lymphoma-specific questionnaire is urgently needed to more accurately assess disease-specific HRQoL in these patients.Peer reviewe

Potential Tumor Suppressor NESG1 as an Unfavorable Prognosis Factor in Nasopharyngeal Carcinoma

BACKGROUND:Recently we identified nasopharyngeal epithelium specific protein 1 (NESG1) as a potential tumor suppressor in nasopharyngeal carcinoma (NPC). The purpose of this study is to investigate the involvement of NESG1 in tumor progression and prognosis of human NPC. METHODOLOGY/PRINCIPAL FINDINGS:NESG1 protein expression in NPC was examined. Survival analysis was performed using Kaplan-Meier method. The effect of NESG1 on cell proliferation, migration, and invasion were also investigated. RESULTS:NESG1 expression was downregulated in atypical hyperplasia and NPC samples compared to normal and squamous nasopharynx tissues. Reduced protein expression was negatively associated with the status of NPC progression. Patients with lower NESG1 expression had a shorter overall survival and disease-free time than did patients with higher NESG1 expression. Multivariate analysis suggested NESG1 expression as an independent prognostic indicator for NPC patient survival. Proliferation, migration, and invasion ability were significantly increased in cell lines following lentiviral-mediated shRNA suppression of NESG1 expression. Microarray analysis indicated that NESG1 participated in multiple pathways, including MAPK signaling and cell cycle regulation. Finally, DNA methylation microarray examination revealed a lack of hypermethylation at the NESG1 promoter, suggesting other mechanisms are involved in suppressing NESG1 expression in NPC. CONCLUSION:Our studies are the first to demonstrate that decreased NESG1 expression is an unfavorable prognostic factor for NPC