Analysis of the mitotic exit control system using locked levels of stable mitotic cyclin

Cyclin‐dependent kinase (Cdk) both promotes mitotic entry (spindle assembly and anaphase) and inhibits mitotic exit (spindle disassembly and cytokinesis), leading to an elegant quantitative hypothesis that a single cyclin oscillation can function as a ratchet to order these events. This ratchet is at the core of a published ODE model for the yeast cell cycle. However, the ratchet model requires appropriate cyclin dose–response thresholds. Here, we test the inhibition of mitotic exit in budding yeast using graded levels of stable mitotic cyclin (Clb2). In opposition to the ratchet model, stable levels of Clb2 introduced dose‐dependent delays, rather than hard thresholds, that varied by mitotic exit event. The ensuing cell cycle was highly abnormal, suggesting a novel reason for cyclin degradation. Cdc14 phosphatase antagonizes Clb2–Cdk, and Cdc14 is released from inhibitory nucleolar sequestration independently of stable Clb2. Thus, Cdc14/Clb2 balance may be the appropriate variable for mitotic regulation. Although our results are inconsistent with the aforementioned ODE model, revision of the model to allow Cdc14/Clb2 balance to control mitotic exit corrects these discrepancies, providing theoretical support for our conclusions.     

Life history predicts advancement of avian spring migration in response to climate change

An increasing number of studies demonstrate that plant and animal phenologies such as the timing of bird migration have been advancing over the globe, likely as a result of climate change. Even closely related species differ in their phenological responses, and the sources of this variation are poorly established. We used a large, standardized dataset of first arrival dates (FAD) of migratory birds to test the effects of phylogenetic relationships and various life-history and ecological traits on the degree to which different species adapt to climate change by earlier migration in spring. Using the phylogenetic comparative method, we found that the advancement of FAD was greater in species with more generalized diet, shorter migration distance, more broods per year, and less extensive prebreeding molt. In turn, we found little evidence that FAD trends were influenced by competition for mating (polygamy or extra-pair paternity) and breeding opportunities (cavity nests). Our findings were robust to several potentially confounding effects. These evolutionary correlations, coupled with the low levels of phylogenetic dependence we found, indicate that avian migration phenology adapts to climate change as a species-specific response. Our results suggest that the degree of this response is fundamentally shaped by constraints and selection pressures of the species' life history, and less so by the intensity of sexual selection.     

The ubiquitin ligase activity in the DDB2 and CSA complexes is differentially regulated by the COP9 signalosome in response to DNA damage

Nucleotide excision repair (NER) is a major cellular defense against the carcinogenic effects of ultraviolet light from the sun. Mutational inactivation of NER proteins, like DDB and CSA, leads to hereditary diseases such as xeroderma pigmentosum (XP) and Cockayne syndrome (CS). Here, we show that DDB2 and CSA are each integrated into nearly identical complexes via interaction with DDB1. Both complexes contain cullin 4A and Roc1 and display ubiquitin ligase activity. They also contain the COP9 signalosome (CSN), a known regulator of cullin-based ubiquitin ligases. Strikingly, CSN differentially regulates ubiquitin ligase activity of the DDB2 and CSA complexes in response to UV irradiation. Knockdown of CSN with RNA interference leads to defects in NER. These results suggest that the distinct UV response of the DDB2 and CSA complexes is involved in diverse mechanisms of NER.     

Targeted proteomic study of the cyclin-Cdk module

The cell division cycle of the yeast S. cerevisiae is driven by one Cdk (cyclin-dependent kinase), which becomes active when bound to one of nine cyclin subunits. Elucidation of Cdk substrates and other Cdk-associated proteins is essential for a full understanding of the cell cycle. Here, we report the results of a targeted proteomics study using affinity purification coupled to mass spectrometry. Our study identified numerous proteins in association with particular cyclin-Cdk complexes. These included phosphorylation substrates, ubiquitination-degradation proteins, adaptors, and inhibitors. Some associations were previously known, and for others, we confirmed their specificity and biological relevance. Using a hypothesis-driven mass spectrometric approach, we also mapped in vivo phosphorylation at Cdk consensus motif-containing peptides within several cyclin-associated candidate Cdk substrates. Our results demonstrate that this approach can be used to detect a host of transient and dynamic protein associations within a biological module.     

Interrogation of Functional Cell-Surface Markers Identifies CD151 Dependency in High-Grade Serous Ovarian Cancer

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长春市儿童医院1998～2001年婴幼儿杯状病毒腹泻流行病学研究

人类杯状病毒(human calicivirus,HuCV)是引起儿童和成人非菌性胃肠炎的主要病原之一.为了掌握HuCV在我国的流行情况,1998年7月至2001年6月,从长春市儿童医院2343例5岁以下腹泻患儿中共收集粪便标本1264份,其中1056份来自2135例住院患儿.对轮状病毒检测为阴性的588份标本,经多价酶免疫试验(EIA)和两组引物反转录-聚合酶链反应(RT-PCR)检测HuCV,202份为阳性,其中住院患儿标本178份,HuCV检出率为16.9%.HuCV腹泻以2岁以下儿童为主(占96%),流行高峰季节为11月至次年3月.选择17株HuCV进行分子鉴定,15株属GⅡ-4群,1株属GⅡ-3群,另1株属GⅠ-2群,表明GⅡ-4群HuCV是我国流行的优势株.根据HuCV住院患儿的监测资料初步估计,HuCV腹泻住院率约为0.5‰～2.4‰.讨论了长春地区HuCV的流行趋势和疾病负担.以上结果为我国HuCV腹泻的预防和控制提供了科学依据.     

Bonafide,type-specific human papillomavirus persistence among HIV-positive pregnant women: predictive value for cytological abnormalities,a longitudinal cohort study

This study investigated the rate of human papillomavirus (HPV) persistence,associated risk factors, and predictors of cytological alteration outcomes in acohort of human immunodeficiency virus-infected pregnant women over an 18-monthperiod. HPV was typed through L1 gene sequencing in cervical smearscollected during gestation and at 12 months after delivery. Outcomes were defined asnonpersistence (clearance of the HPV in the 2nd sample), re-infection (detection ofdifferent types of HPV in the 2 samples), and type-specific HPV persistence (the sameHPV type found in both samples). An unfavourable cytological outcome was consideredwhen the second exam showed progression to squamous intraepithelial lesion or highsquamous intraepithelial lesion. Ninety patients were studied. HPV DNA persistenceoccurred in 50% of the cases composed of type-specific persistence (30%) orre-infection (20%). A low CD4⁺T-cell count at entry was a risk factor fortype-specific, re-infection, or HPV DNA persistence. The odds ratio (OR) was almostthree times higher in the type-specific group when compared with the re-infectiongroup (OR = 2.8; 95% confidence interval: 0.43-22.79). Our findings show thatbonafide (type-specific) HPV persistence is a stronger predictor for the developmentof cytological abnormalities, highlighting the need for HPV typing as opposed to HPVDNA testing in the clinical setting.     

超声治疗动脉粥样硬化性心血管疾病研究进展

超声干预治疗动脉粥样硬化性心血管疾病（atherosclerotic cardiovascular disease,ASCVD）是一种非侵入性治疗方法，其应用于临床治疗的前景广阔。超声波在身体组织中产生的机械、空化及生化等一系列作用可以有效清除血管中的斑块或血栓。但是，安全性是超声疗法应用于临床中亟需解决的首要问题。超声波在身体组织中的传播会引起组织损伤。另外，安全处理因超声刺激而产生的斑块或血栓碎片也是超声疗法应用中面临的挑战。除了确保安全性，合理制定治疗方案及治疗参数从而提高超声疗法疗效是超声疗法应用于临床中有待解决的重要问题。本文结合近年来超声干预治疗动脉粥样硬化性心血管疾病方面的各种临床、动物及体外模型实验研究结果，综述了超声干预治疗的机制、不同治疗方法和治疗参数的效果、如何确保安全性，以及提高超声疗法疗效需解决的一系列问题，进而提出可能的解决方案。     

Phosphorylation of gamma-tubulin regulates microtubule organization in budding yeast.

gamma-Tubulin is essential for microtubule nucleation in yeast and other organisms; whether this protein is regulated in vivo has not been explored. We show that the budding yeast gamma-tubulin (Tub4p) is phosphorylated in vivo. Hyperphosphorylated Tub4p isoforms are restricted to G1. A conserved tyrosine near the carboxy terminus (Tyr445) is required for phosphorylation in vivo. A point mutation, Tyr445 to Asp, causes cells to arrest prior to anaphase. The frequency of new microtubules appearing in the SPB region and the number of microtubules are increased in tub4-Y445D cells, suggesting this mutation promotes microtubule assembly. These data suggest that modification of gamma-tubulin is important for controlling microtubule number, thereby influencing microtubule organization and function during the yeast cell cycle.