A novel role for Greatwall kinase in recovery from DNA damage

Activation of the DNA damage response (DDR) is critical for genomic integrity and tumor suppression. The occurrence of DNA damage quickly evokes the DDR through ATM/ATR-dependent signal transduction, which promotes DNA repair and activates the checkpoint to halt cell cycle progression (Halazonetis et al., 2008; Motoyama and Naka, 2004; Zhou and Elledge, 2000). The "turn off" process of the DDR upon satisfaction of DNA repair, also known as "checkpoint recovery", involves deactivation of DDR elements, but the mechanism is poorly understood. Greatwall kinase (Gwl) has been identified as a key element in the G2/M transition (Archambault et al., 2007; Jackson, 2006; Zhao et al., 2008; Yu et al., 2004; Yu et al., 2006; Zhao et al., 2006) and helps maintain M phase through inhibition of PP2A/B55δ (Burgess et al., 2010; Castilho et al., 2009; Goldberg, 2010; Lorca et al., 2010; Vigneron et al., 2009), the principal phosphatase for Cdk-phosphorylated substrates. Here we show that Gwl also promotes recovery from DNA damage and is itself directly inhibited by the DNA damage response (DDR). In Xenopus egg extracts, immunodepletion of Gwl increased the DDR to damaged DNA, whereas addition of wild type, but not kinase dead Gwl, inhibited the DDR. The removal of damaged DNA from egg extracts leads to recovery from checkpoint arrest and entry into mitosis, a process impaired by Gwl depletion and enhanced by Gwl over-expression. Moreover, activation of Cdk1 after the removal of damaged DNA is regulated by Gwl. Collectively, these results defines Gwl as a new regulator of the DDR, which plays an important role in recovery from DNA     

Early human dispersals into the Iberian Peninsula: a comment on Martínez et al.(2010) and Garcia et al. (2011)

Garcia et al. (2011) recently discussed early human dispersals into the Iberian Peninsula, describing several putative lithic artifacts (Martínez et al., 2010) recovered from layer 7 of the Vallpara díssection (Madurell-Malapeira et al., 2010) in Terrassa (Vallès-Penedès Basin, Catalonia, Spain). According to the authors' opinion, such evidence (1) fills a gap in the chronology of early human occupation in Iberia, (2) indicates that these populations had primary and early access to carcasses, and (3) confirms that early human populations were equipped with advanced cultural traits enabling them to survive in unfavourable climatic conditions. We argue below that the record of human activity at Vallparadís (Martínez et al., 2010;Garcia et al., 2011) is doubtful and even that if confirmed, a chronological gap would remain (contra Garcia et al., 2011). Additional remarks on assertions by these authors on the Vallparadís geology, taphonomy and paleonvironment are also provided.     

Cell fate plug and play: direct reprogramming and induced pluripotency

Building on the discovery that MyoD expression reprograms fibroblasts into muscle, three papers (Vierbuchen et al., 2010; Ieda et al., 2010; Szabo et al., 2010) recently reported the reprogramming of fibroblasts into neurons, cardiomyocytes, and blood cell progenitors without first passing the cells through a pluripotent state. Here we discuss the advantages and challenges of harnessing this direct reprogramming method for regenerative medicine.     

华南特马豆克期笔石地层分带及全球对比

特马豆克阶是奥陶系底部第一个阶,笔石是特马豆克阶高分辨率地层划分与对比的重要化石类群。江南斜坡带是我国早奥陶世特马豆克期漂浮笔石分异度和丰度最高的相区之一,位于该区的湖南益阳南坝剖面,发育有完整的上特马豆克阶笔石地层,特马豆克阶-弗洛阶界线附近地层连续,上特马豆克阶笔石地层研究已取得较大进展,但下特马豆克阶地层缺乏系统研究。近年来,通过对该剖面笔石标本的不间断采集,新识别出下特马豆克阶笔石带Rhabdinopora flabelliformis parabola带。到目前为止,湖南益阳南坝剖面特马豆克阶可以识别出5个笔石带,自下而上依次为:Rhabdinopora flabelliformis parabola带、Adelograptus tenellus带、Aorograptus victoriae带、Araneograptus murrayi带以及Hunnegraptus copiosus带。基于目前已识别出的笔石带,参考国内外同期笔石地层资料,本文详细讨论华南特马豆克期笔石带序列,并与国内外同期地层进行精确对比。     

iPSCs: induced back to controversy

Several recent reports (Mayshar et?al., 2010; Laurent et?al., 2011; Lister et?al., 2011; Gore et?al., 2011; Hussein et?al., 2011) uncover genetic and epigenetic alterations in induced pluripotent stem cells, stimulating debate about their future. However, will these important findings really impact what we hope to gain?     

浙江天台盆地晚白垩世恐龙蛋新类型(英文)

浙江天台盆地上白垩统赖家组和赤城山组是我国最重要的恐龙蛋化石产出地层之一。近年来,我们对天台盆地陆相红层中的恐龙蛋化石层位进行了详细厘定,对恐龙蛋类型进行了系统描述,并对前人报道的一些属种进行了分类订正。研究显示,天台恐龙蛋化石群基本上可分为7蛋科、12蛋属和15蛋种,代表了我国晚白垩世早期的恐龙蛋化石组合。本文简要报道了主要产自天台盆地赤城山组的双塘似蜂窝蛋(新蛋属、新修订种)、木鱼山半蜂窝蛋(新蛋属、新蛋种)、国清寺副蜂窝蛋(新修订种)、天台棱柱形蛋(新修订种)和张头槽马赛克蛋(新蛋属、新修订种)等3新蛋属、5新蛋种和修订种的主要鉴定特征,并建立一新蛋科——似蜂窝蛋科。     

Sinoatrial node pacemaker cells:cardiomyocyte-or neuron-like cells?

The sinoatrial node(SAN)is the headquarter of heartbeat throughout our lifetime(Lakatta et al.,2010;Cingolani et al.,2018;Peters et al.,2020).Every beat of the heart is triggered by a bioelectric pulse spontaneously released by SAN pacemaker cells(SANPCs)(Yaniv et al.,2014;Yavari et al.,2017).In adult human heart,the SAN is a crescent-shaped structure of 1-2 cm long and 0.5 cm wide,which is located at the junction of the superior vena cava and the right atrium and lies along the sulcus terminalis(John et al.,2016).However,the nature of SANPCs remains incompletely known.In general,SANPCs have long been considered as specialized cardiomyocytes(Van Eif et al.,2018;Linscheid et al.,2019;Galang et al.,2020;).However,SANPCs do not have myofibril and T-tube,thus not sharing the contractility property of cardiomyocytes(Satoh,2003;Protze et al.,2017).Interestingly,SANPCs share some electrophysiolog-ical characteristics with neurons:excitability and conductiv-ity.In addition,SANPCs have their intrinsic autonomic rhythm,while neurons also possess the intrinsic ability to generate spontaneous electrical impulses(Lisman et al.,2018).Whether SANPCs are neuron-like cells that reside in the heart remains enigmatic in the field.     

Epigenetic Variations in Plant Hybrids and Their Potential Roles in Heterosis

Heterosis,one of the most important biological phenomena,refers to the phenotypic superiority of a hybrid over its genetically diverse parents with respect to many traits such as biomass,growth rate and yield.Despite its successful application in breeding and agronomic production of many crop and animal varieties,the molecular basis of heterosis remains elusive.The classic genetic explanations for heterosis centered on three hypotheses:dominance (Davenport,1908;Bruce,1910;Keeble and Pellew,1910;Jones,1917),overdominance (East,1908;Shull,1908) and epistasis (Powers,1944;Yu et al.,1997).However,these hypotheses are largely conceptual and not connected to molecular principles,and are therefore insufficient to explain the molecular basis of heterosis (Birchler et al.,2003).Recently,many studies have explored the molecular mechanism of heterosis in plants at a genome-wide level.These studies suggest that global differential gene expression between hybrids and parental lines potentially contributes to heterosis in plants (e.g.,Swanson-Wagner et al.,2006;Zhang et al.,2008;Wei et al.,2009;Song et al.,2010).Research suggests that genetic components,including cis-acting elements and trans-acting factors,are critical regulators of differential gene expression in hybrids (Hochholdinger and Hoecker,2007;Springer and Stupar,2007;Zhang et al.,2008).However,other research indicates that epigenetic components,the regulators of chromatin states and genome activity,also have the potential to impact heterosis (e.g.,Ha et al.,2009;He et al.,2010;Groszmann et al.,2011;Barber et al.,2012;Chodavarapu et al.,2012;Greaves et al.,2012a;Shen et al.,2012).     

Immune plexins and semaphorins: old proteins,new immune functions

Plexins and semaphorins are a large family of proteins that are involved in cell movement and response. The importance of plexins and semaphorins has been emphasized by their discovery in many organ systems including the nervous (Nkyimbeng-Takwi and Chapoval, 2011; McCormick and Leipzig, 2012; Yaron and Sprinzak, 2012), epithelial (Miao et al., 1999; Fujii et al., 2002), and immune systems (Takamatsu and Kumanogoh, 2012) as well as diverse cell processes including angiogenesis (Serini et al., 2009; Sakurai et al., 2012), embryogenesis (Perala et al., 2012), and cancer (Potiron et al., 2009; Micucci et al., 2010). Plexins and semaphorins are transmembrane proteins that share a conserved extracellular semaphorin domain (Hota and Buck, 2012). The plexins and semaphorins are divided into four and eight subfamilies respectively based on their structural homology. Semaphorins are relatively small proteins containing the extracellular semaphorin domain and short intracellular tails. Plexins contain the semaphorin domain and long intracellular tails (Hota and Buck, 2012). The majority of plexin and semaphorin research has focused on the nervous system, particularly the developing nervous system, where these proteins are found to mediate many common neuronal cell processes including cell movement, cytoskeletal rearrangement, and signal transduction (Choi et al., 2008; Takamatsu et al., 2010). Their roles in the immune system are the focus of this review.     

The special delivery of a tail-anchored protein: why it pays to use a dedicated courier

The membrane-spanning C-terminal regions in tail-anchored proteins must be recognized and delivered posttranslationally to the endoplasmic reticulum or mitochondrial membrane. A paper in this issue of Molecular Cell (Wang et?al., 2010) and another recent report (Mariappan et?al., 2010) delineate early steps in this pathway.     

New ways to make old walls: bacterial surprises

Two papers in this issue of Cell (Paradis-Bleau et?al., 2010 and Typas et?al., 2010) report that the lipoproteins LpoA and LpoB are required for the synthesis of cell walls in Escherichia coli. Attached to the bacterial outer membrane, these new cell wall components regulate penicillin-binding proteins located at the inner membrane.     

Moment arms of the human digital flexors

For the extrinsic hand flexors (flexor digitorum profundus, FDP; flexor digitorum superficialis, FDS; flexor pollicis longus, FPL), moment arm corresponds to the tendon's distance from the center of the metacarpalphalangeal (MP), proximal interphalangeal (PIP), or distal interphalangeal (DIP) joint. The clinical value of establishing accurate moment arms has been highlighted for biomechanical modeling, the development of robotic hands, designing rehabilitation protocols, and repairing flexor tendon pulleys (Brand et al., 1975; An et al., 1983; Thompson and Giurintano, 1989; Deshpande et al., 2010; Wu et al., 2010). In this study, we define the moment arms for all of the extrinsic flexor tendons of the hand across all digital joints for all digits in cadaveric hands.     

Human rhinovirus C infection is associated with asthma in children determined by xTAG respiratory viral panel FAST

<正>Dear Editor,Cumulative evidence supports the role of early-life viral infections,especially respiratory syncytial virus(RSV)and human rhinovirus(HRV),as major antecedents of childhood asthma(Lemanske,2002;Jackson et al.,2008).In this study,the x TAG respiratory viral panel FAST(RVP FAST)assay,a multiplex polymerase chain reaction(PCR)-based method(Arens et al.,2010;BaladaLlasat et al.,2011;Gharabaghi et al.,2011;Selvaraju,2012),was used to investigate the association of infec-     

Genetic insights into age-related macular degeneration: controversies addressing risk, causality, and therapeutics

Age-related macular degeneration (AMD) is a common condition among the elderly population that leads to the progressive central vision loss and serious compromise of quality of life for its sufferers. It is also one of the few disorders for whom the investigation of its genetics has yielded rich insights into its diversity and causality and holds the promise of enabling clinicians to provide better risk assessments for individuals as well as to develop and selectively deploy new therapeutics to either prevent or slow the development of disease and lessen the threat of vision loss. The genetics of AMD began initially with the appreciation of familial aggregation and increase risk and expanded with the initial association of APOE variants with the disease. The first major breakthroughs came with family-based linkage studies of affected (and discordant) sibs, which identified a number of genetic loci and led to the targeted search of the 1q31 and 10q26 loci for associated variants. Three of the initial four reports for the CFH variant, Y402H, were based on regional candidate searches, as were the two initial reports of the ARMS2/HTRA1 locus variants. Case-control association studies initially also played a role in discovering the major genetic variants for AMD, and the success of those early studies have been used to fuel enthusiasm for the methodology for a number of diseases. Until 2010, all of the subsequent genetic variants associated with AMD came from candidate gene testing based on the complement factor pathway. In 2010, several large-scale genome-wide association studies (GWAS) identified genes that had not been previously identified. Much of this historical information is available in a number of recent reviews (Chen et al., 2010b; Deangelis et al., 2011; Fafowora and Gorin, 2012b; Francis and Klein, 2011; Kokotas et al., 2011). Large meta analysis of AMD GWAS has added new loci and variants to this collection (Chen et al., 2010a; Kopplin et al., 2010; Yu et al., 2011). This paper will focus on the ongoing controversies that are confronting AMD genetics at this time, rather than attempting to summarize this field, which has exploded in the past 5 years.     

187 Plucking the high hanging fruit: a systematic approach for targeting protein interfaces

Development of specific ligands for protein targets that help decode the complexities of protein–protein interaction networks is a key goal for the field of chemical biology. Despite the emergence of powerful in silico and experimental high-throughput screening strategies, the discovery of synthetic ligands that selectively modulate protein–protein interactions remains a challenge for the chemical biologists. Proteins often utilize small folded domains for recognition of other biomolecules. The basic hypothesis guiding our research is that by mimicking these domains, we can modulate the function of a particular protein with metabolically-stable synthetic molecules (Raj et al., 2013). This presentation will discuss computational approaches (Bullock et al., 2011; Jochim & Arora, 2010) to identify targetable interfaces along with synthetic methods (Patgiri et al., 2008; Tosovska & Arora, 2010) to develop protein domain mimics (PDMs) as modulators of intracellular protein–protein interactions (Henchey et al., 2010; Patgiri et al., 2011).     

Roles of Tet2 in meiosis,fertility and reproductive aging

Dear Editor, Ten-eleven translocation(Tet)enzymes play important roles in DNA demethylation involved in various biological pro-cesses including stem cell pluripotency and differentiation,and tumorigenesis(Dawlaty et al.,2013;Wu and Zhang,2017).Tet2 deficiency or mutation leads to severe hematopoietic defects or myeloid malignancies in mice(Delhommeau et al.,2009;Ko et al.,2010;Moran-Crusio et al.,2011).Restoration of TET2 blocks aberrant self-re-newal and leukemia progression in patients possessing TET2 mutations(Cimmino et al.,2017).DNA methylation-based biomarkers,or"epigenetic clocks",link developmental and maintenance processes to biological aging(Horvath and Raj,2018).Interestingly,age-associated TET2 mutations have been found to drive myeloid dysfunction,cancer and cardiovascular disease(review(Ferrone et al.,2020)).Nevertheless,there has been lack of direct evidence demonstrating that Tet2 mutations or deficiency can actually accelerate aging.     

Testing the level of ant activity associated with quorum sensing: an empirical approach leading to the establishment and test of a null-model (response to the comment of Richardson et al.)

In a paper in this journal (Nouvellet et al., 2010), we presented results from experiments on the behaviour of the Pharaoh's ant, Monomorium pharaonis, along with a substantial statistical and theoretical analysis of the results. In a minor part of our paper, we compared our results with the related work of Richardson et al. (2010a). These authors have subsequently commented on our interpretation of their work (Richardson et al., 2011). In this Letter we respond to the comments of Richardson et al. (2011), and give detailed arguments why we stand by our original conclusions.     

64 Hoogsteen or not Hoogsteen? Iodine-125 radioprobing of the p53-induced DNA deformations

Radioprobing is suitable for tracing the DNA and RNA trajectories in nucleoprotein complexes in solution. The method is based on the analysis of the single-strand breaks produced by decay of iodine-125 incorporated in the C5 position of cytosine (Karamychev et al., 1999, 2012). Here, we used radioprobing to study the conformation of DNA in complex with the DNA binding domain (DBD) of the tumor-suppressor protein p53. Two recently crystallized DNA-p53 DBD complexes have different conformations of the CATG motifs: one with the Hoogsteen A:T pairs (Kitayner et al., 2010) and the other with the Watson–Crick pairs (Chen et al., 2010). The two complexes differ in the sequence of the central YYY|RRR junction: the first one has the C|G step and the second has the T|A step. Thus, it is interesting to apply the radioprobing method to the two DNA sequences used in crystallography to see if the local changes (T|A to C|G) in the center of the p53 response element would produce significant distortions in the CATG motifs. To this aim, the iodine-containing cytosine was incorporated in the duplexes containing p53-binding sites, in one of the two CATG motifs and the frequencies of DNA breaks were analyzed. Frequencies of breaks are negatively correlated with the iodine–sugar distances, thus, one can evaluate the changes in these distances upon DNA binding to a protein. The radioprobing distances obtained for both DNA sequences proved to be consistent with the Watson–Crick structure observed by Chen et al. (2010). We did not find any evidence of the Hoogsteen A:T base pair formation in the DNA-p53 DBD complexes in solution using our radioprobing method. The most significant changes in the break frequency distributions were detected in the central segment of the p53 binding site, YYY|RRR, which are consistent with an increase in DNA twisting in this region and local DNA bending and sliding (Nagaich et al., 1999). We interpret these p53-induced DNA deformations in the context of p53 binding to nucleosomal DNA (Sahu et al., 2010).     

Hypoxic culture and in vivo inflammatory environments affect the assumption of pericyte characteristics by human adipose and bone marrow progenitor cells

Previous studies have shown that exposure to a hypoxic in vitro environment increases the secretion of pro-angiogenic growth factors by human adipose-derived stromal cells (hASCs) [Cao Y, et al., Biochem Biophys Res Commun 332: 370-379, 2005; Kokai LE, et al., Plast Reconstr Surg 116: 1453-1460, 2005; Park BS, et al., Biomed Res (Tokyo) 31: 27-34, 2010; Rasmussen JG, et al., Cytotherapy 13: 318-328, 2010; Rehman J, et al., Circulation 109: 1292-1298, 2004]. Previously, it has been demonstrated that hASCs can differentiate into pericytes and promote microvascular stability and maintenance during angiogenesis in vivo (Amos PJ, et al., Stem Cells 26: 2682-2690, 2008; Traktuev DO, et al., Circ Res 102: 77-85, 2008). In this study, we tested the hypotheses that angiogenic induction can be increased and pericyte differentiation decreased by pretreatment of hASCs with hypoxic culture and that hASCs are similar to human bone marrow-derived stromal cells (hBMSCs) in these regards. Our data confirms previous studies showing that hASCs: 1) secrete pro-angiogenic proteins, which are upregulated following culture in hypoxia, and 2) migrate up gradients of PDGF-BB in vitro, while showing for the first time that a rat mesenteric model of angiogenesis induced by 48/80 increases the propensity of both hASCs and hBMSCs to assume perivascular phenotypes following injection. Moreover, culture of both cell types in hypoxia before injection results in a biphasic vascular length density response in this model of inflammation-induced angiogenesis. The effects of hypoxia and inflammation on the phenotype of adult progenitor cells impacts both the therapeutic and the basic science applications of the cell types, as hypoxia and inflammation are common features of natural and pathological vascular compartments in vivo.