The murine stk gene product, a transmembrane protein tyrosine kinase, is a receptor for macrophage-stimulating protein.

Macrophage-stimulating protein (MSP) was originally identified as an inducer of murine resident peritoneal macrophage responsiveness to chemoattractants. We recently showed that the product of RON, a protein tyrosine kinase cloned from a human keratinocyte library, is the receptor for MSP. Similarity of murine stk to RON led us to determine if the stk gene product is the murine receptor for MSP. Radiolabeled MSP could bind to NIH 3T3 cells transfected with murine stk cDNA (3T3/stk). Binding was saturable and was inhibited by unlabeled MSP but not by structurally related proteins, including hepatocyte growth factor and plasminogen. Specific binding to STK was demonstrated by cross-linking of 125I-labeled MSP to membrane proteins of 3T3/stk cells, which resulted in a protein complex with a molecular mass of 220 kDa. This radiolabeled complex comprised 125I-MSP and STK, since it could be immunoprecipitated by antibodies to the STK beta chain. Binding of MSP to stk cDNA-transfected cells induced tyrosine phosphorylation of the 150-kDa STK beta chain within 1 min and caused increased motile activity. These results establish the murine stk gene product as a specific transmembrane protein tyrosine kinase receptor for MSP. Inasmuch as the stk cDNA was cloned from a hematopoietic stem cell, our data suggest that in addition to macrophages and keratinocytes, a cell in the hematopoietic lineage may also be a target for MSP.

Sammlung aller bekannten Denk- Schau- anderer Münzen des durchleuchtigsten Pfalzbaierischen Hauses aus dem uralten Wittelsbachischen Geschlechte. Von der Ludwigischen oder Baierischen Linie insbesondere. 1.Stük.

Mode of access: Internet.

卫星星座覆盖性能分析及仿真研究

卫星星座是指由多颗卫星按一定形状构成的可提供一定覆盖性能的系统，可以通过多星协作来完成通讯、气象、导航、定位、侦察、预警、监视等各方面的任务。作为卫星星座的重要性能指标，对地覆盖性能一直广受关注，随着卫星星座应用领域不断扩展，卫星星座的对空覆盖性能日益受到重视。因此本文围绕卫星星座覆盖性能的相关问题进行研究。 卫星轨道动力学是卫星星座覆盖性能分析的基础，也是对卫星星座进行仿真分析的基础。本文在分析轨道动力学原理的基础上，推导了J2000坐标系下卫星运动方程、星下点计算方程，完成了仿真算法实现，用STK验证，结果吻合较好，为星座覆盖性能仿真分析打下了基础。 本文系统地研究了星座对地覆盖分析中的解析法和数值仿真法（包括视函数法和地心角法），在此基础上提出了载荷与星下点重合和偏离两种情况下卫星对地瞬时覆盖面积的解析方法。根据地心角法原理，结合卫星的载荷特性，推导了卫星对空间球面的覆盖判据，给出了卫星星座对空间的覆盖分析方法。 为了对星座的覆盖性能进行定量评估，本文系统地提出了一组覆盖性能指标，包括覆盖重数、覆盖时间、覆盖时间百分比、覆盖面积百分比、间隙时间百分比、间隙面积百分比的最大、最小和平均值等，给出了各项性能指标的意义与计算方法，用于评价其覆盖品质。 在上述工作的基础上，本文设计并实现了星座覆盖性能仿真系统，通过对典型星座的覆盖性能进行仿真分析，明确了影响星座对地覆盖性能的因素，验证了对地和对空间覆盖分析方法及指标的合理性，得出的结论可以用于星座设计和星座优化等，此外，对空间应用设计也有一定的参考价值。

Genome-wide survey of putative serine/threonine protein kinases in cyanobacteria

Background: Serine/threonine kinases (STKs) have been found in an increasing number of prokaryotes, showing important roles in signal transduction that supplement the well known role of two-component system. Cyanobacteria are photoautotrophic prokaryotes able to grow in a wide range of ecological environments, and their signal transduction systems are important in adaptation to the environment. Sequence information from several cyanobacterial genomes offers a unique opportunity to conduct a comprehensive comparative analysis of this kinase family. In this study, we extracted information regarding Ser/Thr kinases from 21 species of sequenced cyanobacteria and investigated their diversity, conservation, domain structure, and evolution. Results: 286 putative STK homologues were identified. STKs are absent in four Prochlorococcus strains and one marine Synechococcus strain and abundant in filamentous nitrogen-fixing cyanobacteria. Motifs and invariant amino acids typical in eukaryotic STKs were conserved well in these proteins, and six more cyanobacteria- or bacteria-specific conserved residues were found. These STK proteins were classified into three major families according to their domain structures. Fourteen types and a total of 131 additional domains were identified, some of which are reported to participate in the recognition of signals or substrates. Cyanobacterial STKs show rather complicated phylogenetic relationships that correspond poorly with phylogenies based on 16S rRNA and those based on additional domains. Conclusion: The number of STK genes in different cyanobacteria is the result of the genome size, ecophysiology, and physiological properties of the organism. Similar conserved motifs and amino acids indicate that cyanobacterial STKs make use of a similar catalytic mechanism as eukaryotic STKs. Gene gain-and-loss is significant during STK evolution, along with domain shuffling and insertion. This study has established an overall framework of sequence-structure-function interactions for the STK gene family, which may facilitate further studies of the role of STKs in various organisms.

Genome-wide survey of putative serine/threonine protein kinases in cyanobacteria

Background: Serine/threonine kinases (STKs) have been found in an increasing number of prokaryotes, showing important roles in signal transduction that supplement the well known role of two-component system. Cyanobacteria are photoautotrophic prokaryotes able to grow in a wide range of ecological environments, and their signal transduction systems are important in adaptation to the environment. Sequence information from several cyanobacterial genomes offers a unique opportunity to conduct a comprehensive comparative analysis of this kinase family. In this study, we extracted information regarding Ser/Thr kinases from 21 species of sequenced cyanobacteria and investigated their diversity, conservation, domain structure, and evolution. Results: 286 putative STK homologues were identified. STKs are absent in four Prochlorococcus strains and one marine Synechococcus strain and abundant in filamentous nitrogen-fixing cyanobacteria. Motifs and invariant amino acids typical in eukaryotic STKs were conserved well in these proteins, and six more cyanobacteria- or bacteria-specific conserved residues were found. These STK proteins were classified into three major families according to their domain structures. Fourteen types and a total of 131 additional domains were identified, some of which are reported to participate in the recognition of signals or substrates. Cyanobacterial STKs show rather complicated phylogenetic relationships that correspond poorly with phylogenies based on 16S rRNA and those based on additional domains. Conclusion: The number of STK genes in different cyanobacteria is the result of the genome size, ecophysiology, and physiological properties of the organism. Similar conserved motifs and amino acids indicate that cyanobacterial STKs make use of a similar catalytic mechanism as eukaryotic STKs. Gene gain-and-loss is significant during STK evolution, along with domain shuffling and insertion. This study has established an overall framework of sequence-structure-function interactions for the STK gene family, which may facilitate further studies of the role of STKs in various organisms.

螺旋藻丝氨酸/苏氨酸激酶基因家族的克隆与表达分析

螺旋藻（Spirulina)，是丝状不形成异型胞的蓝藻，由于其所蕴涵的高品质营养成分而成为一属具有重要经济价值的微藻。丝氨酸/苏氨酸激酶（serine/threonine kinases，STK）系统在螺旋藻的信号转导中发挥了重要作用。螺旋藻生活环境复杂，其中温度是中国北方温带地区螺旋藻大规模养殖的主要限制性因素。本文克隆了一条螺旋藻STK基因，并初步从STK激酶基因家族的角度探索了螺旋藻对高温环境的适应。主要结果如下： 1. 构建了插入片段为1-2kb的螺旋藻基因组文库。基于该文库用简并引物PCR的方法得到了一条螺旋藻STK基因5'端长度为504bp的基因组序列。 2．以本实验室构建的螺旋藻基因组草图为基础，在基因组水平上研究了螺旋藻STK基因家族的特点。发现螺旋藻草图中STK基因家族共包含33个基因，这些基因基于蛋白结构域分析可以分为三大类群。序列保守性分析发现，螺旋藻STK激酶具有与真核STK激酶相同的保守域，此外螺旋藻STK激酶还具有特有的保守氨基酸。 3．在中国北方温带地区，螺旋藻大规模养殖的主要限制性因素是温度。由于北方地区温度较低，螺旋藻规模养殖普遍存在年养殖期较短的问题，造成设备浪费，若采用加温措施又增加养殖成本；而在夏季晴天中午，又存在高温胁迫的问题。跨膜蛋白是信号转导的第一阶段，因此我们设置了不同温度来诱导螺旋藻，对其中7个跨膜STK基因进行半定量RT-PCR分析，结果显示STK2103在不同温度下表达量不同，推测该蛋白参与了螺旋藻温度相关的信号转导过程。 本文将基础研究与实验验证相结合，为螺旋藻的信号转导研究提供了线索。

两种蓝藻真核型Ser/Thr激酶基因功能的初步验证

Ser/Thr蛋白激酶（serine/threonine kinases，STK）在真核生物的信号转导通路中具有重要作用，而且已经成为对抗肿瘤、结核等多种人类疾病的药物作用靶点。上世纪九十年代，有研究发现STK在原核生物的信号转导中也发挥重要作用。本论文以聚球藻PCC7942（Synechococcus sp. PCC7942）和钝顶螺旋藻（Spirulina platensis）为材料，对几个真核型的Ser/Thr蛋白激酶基因的功能进行了初步验证。 蓝藻兼具细菌和植物的特点，具有成熟的转化体系，为真核生物基因功能的研究提供了新的模式宿主。聚球藻PCC7942是一种单细胞的淡水蓝藻，具有天然的外源DNA转化系统，是蓝藻分子遗传学研究的模式生物。通过基因敲除及表达差异分析发现聚球藻PCC7942中的Ser/Thr蛋白激酶stk196参与高温胁迫的信号传递。钝顶螺旋藻是原核丝状蓝藻，由于其蕴涵高品质营养成分而成为一类具有重要经济价值的微藻，该研究利用半定量RT-PCR方法，分析四个具有跨膜结构域的Ser/Thr蛋白激酶在正常生长温度下和经低温、高温诱导后表达量的变化情况，发现stk2103在低温诱导后的表达量降低，高温诱导后的表达量升高，提示该基因的表达可能参与了钝顶螺旋藻对温度的适应。 蓝藻中真核型Ser/Thr蛋白激酶功能的研究为我们进一步研究真核生物的Ser/Thr蛋白激酶功能提供了借鉴，并对植物抗逆胁迫的研究提供重要的理论依据。

Genetic Predictors of Clinical Outcomes in Non-Small Cell Lung Cancer Patients

Lung cancer is the leading cause of cancer-related mortality in the US. Emerging evidence has shown that host genetic factors can interact with environmental exposures to influence patient susceptibility to the diseases as well as clinical outcomes, such as survival and recurrence. We aimed to identify genetic prognostic markers for non-small cell lung cancer (NSCLC), a major (85%) subtype of lung cancer, and also in other subgroups. With the fast evolution of genotyping technology, genetic association studies have went through candidate gene approach, to pathway-based approach, to the genome wide association study (GWAS). Even in the era of GWAS, pathway-based approach has its own advantages on studying cancer clinical outcomes: it is cost-effective, requiring a smaller sample size than GWAS easier to identify a validation population and explore gene-gene interactions. In the current study, we adopted pathway-based approach focusing on two critical pathways - miRNA and inflammation pathways. MicroRNAs (miRNA) post-transcriptionally regulate around 30% of human genes. Polymorphisms within miRNA processing pathways and binding sites may influence patients’ prognosis through altered gene regulation. Inflammation plays an important role in cancer initiation and progression, and also has shown to impact patients’ clinical outcomes. We first evaluated 240 single nucleotide polymorphisms (SNPs) in miRNA biogenesis genes and predicted binding sites in NSCLC patients to determine associations with clinical outcomes in early-stage (stage I and II) and late-stage (stage III and IV) lung cancer patients, respectively. First, in 535 early-stage patients, after correcting multiple comparisons, FZD4:rs713065 (hazard ratio [HR]:0.46, 95% confidence interval [CI]:0.32-0.65) showed a significant inverse association with survival in early stage surgery-only patients. SP1:rs17695156 (HR:2.22, 95% CI:1.44-3.41) and DROSHA:rs6886834 (HR:6.38, 95% CI:2.49-16.31) conferred increased risk of progression in the all patients and surgery-only populations, respectively. FAS:rs2234978 was significantly associated with improved survival in all patients (HR:0.59, 95% CI:0.44-0.77) and in the surgery plus chemotherapy populations (HR:0.19, 95% CI:0.07-0.46).. Functional genomics analysis demonstrated that this variant creates a miR-651 binding site resulting in altered miRNA regulation of FAS, providing biological plausibility for the observed association. We then analyzed these associations in 598 late-stage patients. After multiple comparison corrections, no SNPs remained significant in the late stage group, while the top SNP NAT1:rs15561 (HR=1.98, 96%CI=1.32-2.94) conferred a significantly increased risk of death in the chemotherapy subgroup. To test the hypothesis that genetic variants in the inflammation-related pathways may be associated with survival in NSCLC patients, we first conducted a three-stage study. In the discovery phase, we investigated a comprehensive panel of 11,930 inflammation-related SNPs in three independent lung cancer populations. A missense SNP (rs2071554) in HLA-DOB was significantly associated with poor survival in the discovery population (HR: 1.46, 95% CI: 1.02-2.09), internal validation population (HR: 1.51, 95% CI: 1.02-2.25), and external validation (HR: 1.52, 95% CI: 1.01-2.29) population. Rs2900420 in KLRK1 was significantly associated with a reduced risk for death in the discovery (HR: 0.76, 95% CI: 0.60-0.96) and internal validation (HR: 0.77, 95% CI: 0.61-0.99) populations, and the association reached borderline significance in the external validation population (HR: 0.80, 95% CI: 0.63-1.02). We also evaluated these inflammation-related SNPs in NSCLC patients in never smokers. Lung cancer in never smokers has been increasingly recognized as distinct disease from that in ever-smokers. A two-stage study was performed using a discovery population from MD Anderson (411 patients) and a validation population from Mayo Clinic (311 patients). Three SNPs (IL17RA:rs879576, BMP8A:rs698141, and STK:rs290229) that were significantly associated with survival were validated (pCD74:rs1056400 and CD38:rs10805347) were borderline significant (p=0.08) in the Mayo Clinic population. In the combined analysis, IL17RA:rs879576 resulted in a 40% reduction in the risk for death (p=4.1 × 10-5 [p=0.61, heterogeneity test]). We also validated a survival tree created in MD Anderson population in the Mayo Clinic population. In conclusion, our results provided strong evidence that genetic variations in specific pathways that examined (miRNA and inflammation pathways) influenced clinical outcomes in NSCLC patients, and with further functional studies, the novel loci have potential to be translated into clinical use.

Täysipainoinen osallistuminen integraatioon välttämätöntä. Elinkeinoelämän valmistautuminen Länsi-Euroopan yhdentymiskehitykseen 1987–1992

Pro gradu -tutkielmani tarkastelee Suomen elinkeinoelämän etujärjestöjen, Teollisuuden Keskusliiton (TKL) ja Suomen Työnantajain Keskusliiton (STK) valmistautumista Länsi-Euroopan integraation syvenemiseen vuosina 1987–1992. Tutkimukseni perustuu Elinkeinoelämän keskusarkiston TKL:a, STK:a ja näiden yhteisorganisaatioita käsittelevään arkistomateriaaliin. Tutkimukseni metodina on historiantutkimuksen lähdekritiikki. Suomen kauppapoliittinen ympäristö oli vahvassa murroksessa 1980-luvun puolivälistä syvenemään alkaneen Euroopan yhdentymiskehityksen ja hiipuvan idänkaupan vuoksi. Samaa aikakautta kuvasivat nopea teknologinen kehitys, itäblokin murtuminen, maailmankaupan vapautuminen ja Suomen kansainvälistyminen. Suomen osallistumista länsi-integraatioon rajoitti merkittävällä tavalla Suomen ja Neuvostoliiton välinen YYA-sopimus, ja Suomen harjoittama puolueettomuuspolitiikka. Ennen keväällä 1992 jätettyä EY-jäsenyyshakemusta Suomi oli pyrkinyt osallistumaan Länsi-Euroopan taloudelliseen integraatioon, mutta välttämään poliittista integraatiota ulkopoliittisista rajoitteista johtuen. Elinkeinoelämä pyrki valmistautumaan integraatioon läheisessä yhteistyössä Suomen valtionjohdon kanssa. Elinkeinoelämän etujärjestöt tiedostivat hyvin Suomen ulkopolitiikan virallisen linjan, joka muuttui merkittävällä tavalla vasta Neuvostoliiton kaaduttua joulukuussa 1991. Suomen kauppapoliittinen asema riippui pitkälti Neuvostoliitosta. Tutkimukseni näkökulmana on elinkeinoelämän etujärjestöjen tahto vaikuttaa Suomen osallistumiseen Länsi-Euroopan integraatioprosessiin. 1980-luvun puolivälin jälkeen yhä vahvemmin läntiseen kauppaan nojanneen Suomen teollisuuden ja työnantajien etujärjestöt aktivoituivat seuraamaan ja vaikuttamaan yhdentymiskehitykseen eriasteisesti. Integraatioseuranta ja yhdentymiskehitykseen vaikuttaminen pitivät sisällään asiantuntijavierailuja, muistioiden laatimista, kirjeenvaihtoa ja tapaamisia Suomen valtiojohdon, EY-komission johtajien, EY- ja EFTA-maiden teollisuusjärjestöjen ja virkamiesjohdon kanssa, integraatioseminaarien järjestämistä ja julkisen keskustelun muokkaamista integraatiomyönteiseen suuntaan eri keinoin. Teollisuuden ja työnantajien etujärjestöt pitivät länsi-integraatioon osallistumista välttämättömänä taloudellisen kilpailukyvyn turvaamiseksi Suomen päämarkkina-alueilla Länsi-Euroopassa. Integraation toivottiin vauhdittavan Suomen rakennemuutosta sekä avaavan suojattuja kotimarkkina-aloja kilpailulle.