BubR1 acetylation at prometaphase is required for modulating APC/C activity and timing of mitosis

Regulation of BubR1 is central to the control of APC/C activity. We have found that BubR1 forms a complex with PCAF and is acetylated at lysine 250. Using mass spectrometry and acetylated BubR1-specific antibodies, we have confirmed that BubR1 acetylation occurs at prometaphase. Importantly, BubR1 acetylation was required for checkpoint function, through the inhibition of ubiquitin-dependent BubR1 degradation. BubR1 degradation began before the onset of anaphase. It was noted that the pre-anaphase degradation was regulated by BubR1 acetylation. Degradation of an acetylation-mimetic form, BubR1–K250Q, was inhibited and chromosome segregation in cells expressing BubR1–K250Q was markedly delayed. By contrast, the acetylation-deficient mutant, BubR1–K250R, was unstable, and mitosis was accelerated in BubR1–K250R-expressing cells. Furthermore, we found that APC/C–Cdc20 was responsible for BubR1 degradation during mitosis. On the basis of our collective results, we propose that the acetylation status of BubR1 is a molecular switch that converts BubR1 from an inhibitor to a substrate of the APC/C complex, thus providing an efficient way to modulate APC/C activity and mitotic timing

A massive proto-cluster of galaxies at a redshift of z {\approx} 5.3

Massive clusters of galaxies have been found as early as 3.9 Billion years (z=1.62) after the Big Bang containing stars that formed at even earlier epochs. Cosmological simulations using the current cold dark matter paradigm predict these systems should descend from "proto-clusters" - early over-densities of massive galaxies that merge hierarchically to form a cluster. These proto-cluster regions themselves are built-up hierarchically and so are expected to contain extremely massive galaxies which can be observed as luminous quasars and starbursts. However, observational evidence for this scenario is sparse due to the fact that high-redshift proto-clusters are rare and difficult to observe. Here we report a proto-cluster region 1 billion years (z=5.3) after the Big Bang. This cluster of massive galaxies extends over >13 Mega-parsecs, contains a luminous quasar as well as a system rich in molecular gas. These massive galaxies place a lower limit of >4x10^11 solar masses of dark and luminous matter in this region consistent with that expected from cosmological simulations for the earliest galaxy clusters.Comment: Accepted to Nature, 16 Pages, 6 figure

A probit- log- skew-normal mixture model for repeated measures data with excess zeros, with application to a cohort study of paediatric respiratory symptoms

<p>Abstract</p> <p>Background</p> <p>A zero-inflated continuous outcome is characterized by occurrence of "excess" zeros that more than a single distribution can explain, with the positive observations forming a skewed distribution. Mixture models are employed for regression analysis of zero-inflated data. Moreover, for repeated measures zero-inflated data the clustering structure should also be modeled for an adequate analysis.</p> <p>Methods</p> <p>Diary of Asthma and Viral Infections Study (DAVIS) was a one year (2004) cohort study conducted at McMaster University to monitor viral infection and respiratory symptoms in children aged 5-11 years with and without asthma. Respiratory symptoms were recorded daily using either an Internet or paper-based diary. Changes in symptoms were assessed by study staff and led to collection of nasal fluid specimens for virological testing. The study objectives included investigating the response of respiratory symptoms to respiratory viral infection in children with and without asthma over a one year period. Due to sparse data daily respiratory symptom scores were aggregated into weekly average scores. More than 70% of the weekly average scores were zero, with the positive scores forming a skewed distribution. We propose a random effects probit/log-skew-normal mixture model to analyze the DAVIS data. The model parameters were estimated using a maximum marginal likelihood approach. A simulation study was conducted to assess the performance of the proposed mixture model if the underlying distribution of the positive response is different from log-skew normal.</p> <p>Results</p> <p>Viral infection status was highly significant in both probit and log-skew normal model components respectively. The probability of being symptom free was much lower for the week a child was viral positive relative to the week she/he was viral negative. The severity of the symptoms was also greater for the week a child was viral positive. The probability of being symptom free was smaller for asthmatics relative to non-asthmatics throughout the year, whereas there was no difference in the <it>severity </it>of the symptoms between the two groups.</p> <p>Conclusions</p> <p>A positive association was observed between viral infection status and both the probability of experiencing any respiratory symptoms, and their severity during the year. For DAVIS data the random effects probit -log skew normal model fits significantly better than the random effects probit -log normal model, endorsing our parametric choice for the model. The simulation study indicates that our proposed model seems to be robust to misspecification of the distribution of the positive skewed response.</p

Nanostring-based multigene assay to predict recurrence for gastric cancer patients after surgery

10.1371/journal.pone.0090133PLoS ONE93-POLN

Oncoprotein HCCR-1 expression in breast cancer is well correlated with known breast cancer prognostic factors including the HER2 overexpression, p53 mutation, and ER/PR status

<p>Abstract</p> <p>Background</p> <p>Oncoprotein HCCR-1 functions as a negative regulator of the p53 and contributes breast tumorigenesis. The serum HCCR-1 assay is useful in diagnosing breast cancer and mice transgenic for HCCR developed breast cancers. But it is unknown how <it>HCCR-1 </it>contributes to human breast tumorigenesis.</p> <p>Methods</p> <p>Oncogene HCCR-1 expression levels were determined in normal breast tissues, breast cancer tissues and cancer cell lines. We examined whether HCCR-1 protein expression in breast cancer is related to different biological characteristics, including ER, PR, p53 genotype, and HER2 status in 104 primary breast cancer tissues using immunohistochemical analyses.</p> <p>Results</p> <p>HCCR-1 was upregulated in breast cancer cells and tissues compared with normal breast tissues. In this study, overexpression of HCCR-1 was well correlated with known breast cancer prognostic markers including the presence of steroid receptors (ER and PR), p53 mutation and high HER2 overexpression. HCCR-1 was not detected in the ER-negative, PR-negative, p53 negative and low HER2 breast cancer tissues. These data indicate that the level of HCCR-1 in breast cancer tissues is relatively well correlated with known breast cancer factors, including the HER2 overexpression, p53 mutation, and ER/PR status.</p> <p>Conclusion</p> <p>Determination of HCCR-1 levels as options for HER2 testing is promising although it needs further evaluation.</p

Area-level poverty and preterm birth risk: A population-based multilevel analysis

<p>Abstract</p> <p>Background</p> <p>Preterm birth is a complex disease with etiologic influences from a variety of social, environmental, hormonal, genetic, and other factors. The purpose of this study was to utilize a large population-based birth registry to estimate the independent effect of county-level poverty on preterm birth risk. To accomplish this, we used a multilevel logistic regression approach to account for multiple co-existent individual-level variables and county-level poverty rate.</p> <p>Methods</p> <p>Population-based study utilizing Missouri's birth certificate database (1989–1997). We conducted a multilevel logistic regression analysis to estimate the effect of county-level poverty on PTB risk. Of 634,994 births nested within 115 counties in Missouri, two levels were considered. Individual-level variables included demographics factors, prenatal care, health-related behavioral risk factors, and medical risk factors. The area-level variable included the percentage of the population within each county living below the poverty line (US census data, 1990). Counties were divided into quartiles of poverty; the first quartile (lowest rate of poverty) was the reference group.</p> <p>Results</p> <p>PTB < 35 weeks occurred in 24,490 pregnancies (3.9%). The rate of PTB < 35 weeks was 2.8% in counties within the lowest quartile of poverty and increased through the 4^thquartile (4.9%), p < 0.0001. High county-level poverty was significantly associated with PTB risk. PTB risk (< 35 weeks) was increased for women who resided in counties within the highest quartile of poverty, adjusted odds ratio (_adjOR) 1.18 (95% CI 1.03, 1.35), with a similar effect at earlier gestational ages (< 32 weeks), _adjOR 1.27 (95% CI 1.06, 1.52).</p> <p>Conclusion</p> <p>Women residing in socioeconomically deprived areas are at increased risk of preterm birth, above other underlying risk factors. Although the risk increase is modest, it affects a large number of pregnancies.</p

Influences of the G2350A polymorphism in the ACE Gene on cardiac structure and function of ball game players

<p>Abstract</p> <p>Background</p> <p>Except for the I/D polymorphism in the angiotensin I-converting enzyme (ACE) gene, there were few reports about the relationship between other genetic polymorphisms in this gene and the changes in cardiac structure and function of athletes. Thus, we investigated whether the G2350A polymorphism in the <it>ACE </it>gene is associated with the changes in cardiac structure and function of ball game players. Total 85 healthy ball game players were recruited in this study, and they were composed of 35 controls and 50 ball game players, respectively. Cardiac structure and function were measured by 2-D echocardiography, and the G2350A polymorphism in the <it>ACE </it>gene analyzed by the SNaPshot method.</p> <p>Results</p> <p>There were significant differences in left ventricular mass index (LVmassI) value among each sporting discipline studied. Especially in the athletes of basketball disciplines, indicated the highest LVmassI value than those of other sporting disciplines studied (p < 0.05). However, there were no significant association between any echocardiographic data and the G2350A polymorphism in the <it>ACE </it>gene in the both controls and ball game players.</p> <p>Conclusions</p> <p>Our data suggests that the G2350A polymorphism in the <it>ACE </it>gene may not significantly contribute to the changes in cardiac structure and function of ball game players, although sporting disciplines of ball game players may influence the changes in LVmassI value of these athletes. Further studies using a larger sample size and other genetic markers in the <it>ACE </it>gene will be needed.</p

Anti-tumor effect of Liqi, a traditional Chinese medicine prescription, in tumor bearing mice

<p>Abstract</p> <p>Background</p> <p><it>Liqi</it>, an herbal preparation used in traditional Chinese medicine, has been used to treat cancer in China for centuries. We investigated the anti-tumor effects of liqi and their mechanisms in mice that had been xenografted with tumors.</p> <p>Methods</p> <p>Sarcoma 180 tumor, Lewis lung carcinoma, and SGC-7901 cells were implanted in BALB/c mice, C57BL/6 mice, and BALB/c nude mice, respectively. Liqi was administered to subgroups of these mice. The tumor weight and size were measured. Cell cycle analysis and T lymphocyte subsets were determined by flow cytometry. The activity of NK cells and TNF was tested using cytotoxicity assay on YAC-1 cells and L929 cells, respectively, and the activity of IL-2 was tested with an IL-2-dependent CTLL-2 cell proliferation assay. Platelet aggregation was monitored by measuring electric impedance, and the levels of thromboxane A2 (TXA₂) and prostacyclin (PGI₂) in blood were measured by ¹²⁵I-TXB₂and ¹²⁵I-Keto-PGF_1αradioimmunoassay.</p> <p>Results</p> <p>The results showed that liqi inhibited tumor growth in tumor-implanted mice and arrested the cell proliferation in the G0/G1 phase and reduced the portion of cells in S and G2/M phase for SGC-7901 cells. Liqi increased the activity of NK cells and TNF-α, stimulated IL-2 production and activity, and regulated T lymphocyte subpopulations. Liqi inhibited the Lewis lung carcinoma metastasis by inhibiting platelet aggregation and normalizing the balance between TXA₂and PGI₂.</p> <p>Conclusion</p> <p>All these findings demonstrated that liqi has an anti-tumor effect in vivo. The mechanism may be related to immune regulation and anticoagulation effects.</p

Mitochondria-Specific Accumulation of Amyloid β Induces Mitochondrial Dysfunction Leading to Apoptotic Cell Death

Mitochondria are best known as the essential intracellular organelles that host the homeostasis required for cellular survival, but they also have relevance in diverse disease-related conditions, including Alzheimer's disease (AD). Amyloid β (Aβ) peptide is the key molecule in AD pathogenesis, and has been highlighted in the implication of mitochondrial abnormality during the disease progress. Neuronal exposure to Aβ impairs mitochondrial dynamics and function. Furthermore, mitochondrial Aβ accumulation has been detected in the AD brain. However, the underlying mechanism of how Aβ affects mitochondrial function remains uncertain, and it is questionable whether mitochondrial Aβ accumulation followed by mitochondrial dysfunction leads directly to neuronal toxicity. This study demonstrated that an exogenous Aβ1–42 treatment, when applied to the hippocampal cell line of mice (specifically HT22 cells), caused a deleterious alteration in mitochondria in both morphology and function. A clathrin-mediated endocytosis blocker rescued the exogenous Aβ1–42-mediated mitochondrial dysfunction. Furthermore, the mitochondria-targeted accumulation of Aβ1–42 in HT22 cells using Aβ1–42 with a mitochondria-targeting sequence induced the identical morphological alteration of mitochondria as that observed in the APP/PS AD mouse model and exogenous Aβ1–42-treated HT22 cells. In addition, subsequent mitochondrial dysfunctions were demonstrated in the mitochondria-specific Aβ1–42 accumulation model, which proved indistinguishable from the mitochondrial impairment induced by exogenous Aβ1–42-treated HT22 cells. Finally, cellular toxicity was directly induced by mitochondria-targeted Aβ1–42 accumulation, which mimics the apoptosis process in exogenous Aβ1–42-treated HT22 cells. Taken together, these results indicate that mitochondria-targeted Aβ1–42 accumulation is the necessary and sufficient condition for Aβ-mediated mitochondria impairments, and leads directly to cellular death rather than along with other Aβ-mediated signaling alterations