Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas.

Genomic instability promotes tumorigenesis and can occur through various mechanisms, including defective segregation of chromosomes or inactivation of DNA mismatch repair. Although B-cell lymphomas are associated with chromosomal translocations that deregulate oncogene expression, a mechanism for genome-wide instability during lymphomagenesis has not been described. During B-cell development, the immunoglobulin variable (V) region genes are subject to somatic hypermutation in germinal-centre B cells. Here we report that an aberrant hypermutation activity targets multiple loci, including the proto-oncogenes PIM1, MYC, RhoH/TTF (ARHH) and PAX5, in more than 50% of diffuse large-cell lymphomas (DLCLs), which are tumours derived from germinal centres. Mutations are distributed in the 5' untranslated or coding sequences, are independent of chromosomal translocations, and share features typical of V-region-associated somatic hypermutation. In contrast to mutations in V regions, however, these mutations are not detectable in normal germinal-centre B cells or in other germinal-centre-derived lymphomas, suggesting a DLCL-associated malfunction of somatic hypermutation. Intriguingly, the four hypermutable genes are susceptible to chromosomal translocations in the same region, consistent with a role for hypermutation in generating translocations by DNA double-strand breaks. By mutating multiple genes, and possibly by favouring chromosomal translocations, aberrant hypermutation may represent the major contributor to lymphomagenesis.     

经典Wnt信号通路与弥漫大B细胞淋巴瘤

弥漫性大B细胞淋巴瘤(DLBCL)的发病机制虽未完全阐明,但研究显示与信号通路表达异常有关,如经典Wnt通路。在DLBCL发病机制的研究中观察到经典Wnt通路的重要下游因子β-catenin的表达和核内定位。同时证据显示经典Wnt通路不仅与DLBCL发病机制有关,还和DLBCL临床分期密切相关,经典Wnt通路通路有可能成为治疗DLBCL潜在的有用靶点。     

FBXO6稳定表达肿瘤细胞系的构建及其亚细胞器定位

检测FBXO6在多种肿瘤细胞中的表达和定位情况并构建稳定表达FBXO6的肿瘤细胞株。运用RT-PCR方法,在人胚肾293T细胞以及9种不同来源的肿瘤细胞中,检测了FBXO6的表达情况。以载体质粒pBabe-3Flag-FBXO6-puro/pBabe-3Flag-con、包装质粒pCMV-GAG-POL及包膜质粒pCMV-VSVG用Lipofectamine2000共转染包装细胞系293T,收集病毒颗粒感染A549细胞,经嘌呤霉素筛选稳定表达细胞株,Western blot鉴定FBXO6的表达。利用激光共聚焦荧光显微镜,采用间接免疫荧光方法,检测外源性FBXO6在A549中的亚细胞定位。在10种不同来源的细胞株中,FBXO6在A549细胞中的表达最高。成功筛选出嘌呤霉素抗性细胞系A549-Con与A549-3Flag-FBXO6。Western blot方法发现A549-3Flag-FBXO6细胞系稳定表达FBXO6蛋白。间接免疫荧光发现FBXO6与内质网tracker有共定位。FBXO6在肺癌A549细胞中高度表达,构建了稳定表达FBXO6的A549细胞系,部分FBXO6分布在内质网中。     

海天背景下小目标检测跟踪方法

研究海天背景下红外图像序列中预测运动弱小目标检测跟踪的方法。通过对红外图像进行小波变换和数学形态学分析,检测所有可能目标。通过带有延迟单元的线性神经元网络对已知样本学习,采用Widrow-Hoff学习规则自适应调整神经网络参数,同时对下一帧目标轨迹进行预测,在检测到多个目标的情况下根据预测轨迹确定真实目标,提高对目标检测的准确。     

Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma

Multiple endocrine neoplasia type 1 (MEN-1) is a predisposition to hyperplasia of the parathyroid glands, and to hyperplasia or tumours of the anterior pituitary and the endocrine pancreas, and is inherited as an autosomal dominant trait. Here we map the MEN-1 locus to chromosome 11 by family studies, and demonstrate tight linkage with the human muscle phosphorylase gene. By comparing constitutional and tumour tissue genotypes of insulinomas from a pair of brothers who had inherited MEN-1 from their mother, we have shown that oncogenesis in these cases involves unmasking of a recessive mutation at this locus.     

离子液体中6-O-(11-十二烯酸)葡萄糖酯的脂肪酶催化合成及其表征

为了探索脂肪酶在离子液体中选择性地催化葡萄糖与11-十二烯酸乙酯的转酯化反应,通过不同脂肪酶在不同离子液体中进行转酯化反应,并用单因素法研究离子液体种类、温度、底物的比例、体系含水量和脂肪酶含量对反应产率的影响,优化反应条件。反应产物的结构通过红外光谱、高效液相色谱、质谱和核磁共振等表征。结果表明:脂肪酶Novozym-435在离子液体1-正丁基-3-甲基咪唑氟硼酸盐[BMIM][BF4]中,当反应温度为55℃、酶浓度20mg/mL、葡萄糖/11-十二烯酸乙酯的摩尔比1∶2、体系的水含量为2%时,获得糖酯的产率最高,Novozym-435可以重复使用7次。脂肪酶Novozym-435在离子液体[BMIM][BF4]中选择性转酯化反应的产物为6-O-(11-十二烯酸)葡萄糖单酯。     

Eukaryotic initiation factor 6 is rate-limiting in translation, growth and transformation

Cell growth and proliferation require coordinated ribosomal biogenesis and translation. Eukaryotic initiation factors (eIFs) control translation at the rate-limiting step of initiation. So far, only two eIFs connect extracellular stimuli to global translation rates: eIF4E acts in the eIF4F complex and regulates binding of capped messenger RNA to 40S subunits, downstream of growth factors, and eIF2 controls loading of the ternary complex on the 40S subunit and is inhibited on stress stimuli. No eIFs have been found to link extracellular stimuli to the activity of the large 60S ribosomal subunit. eIF6 binds 60S ribosomes precluding ribosome joining in vitro. However, studies in yeasts showed that eIF6 is required for ribosome biogenesis rather than translation. Here we show that mammalian eIF6 is required for efficient initiation of translation, in vivo. eIF6 null embryos are lethal at preimplantation. Heterozygous mice have 50% reduction of eIF6 levels in all tissues, and show reduced mass of hepatic and adipose tissues due to a lower number of cells and to impaired G1/S cell cycle progression. eIF6(+/-) cells retain sufficient nucleolar eIF6 and normal ribosome biogenesis. The liver of eIF6(+/-) mice displays an increase of 80S in polysomal profiles, indicating a defect in initiation of translation. Consistently, isolated hepatocytes have impaired insulin-stimulated translation. Heterozygous mouse embryonic fibroblasts recapitulate the organism phenotype and have normal ribosome biogenesis, reduced insulin-stimulated translation, and delayed G1/S phase progression. Furthermore, eIF6(+/-) cells are resistant to oncogene-induced transformation. Thus, eIF6 is the first eIF associated with the large 60S subunit that regulates translation in response to extracellular signals.     

The homeobox gene lim-6 is required for distinct chemosensory representations in C. elegans

The ability to discriminate between different chemical stimuli is crucial for food detection, spatial orientation and other adaptive behaviours in animals. In the nematode Caenorhabditis elegans, spatial orientation in gradients of soluble chemoattractants (chemotaxis) is controlled mainly by a single pair of chemosensory neurons. These two neurons, ASEL and ASER, are left-right homologues in terms of the disposition of their somata and processes, morphology of specialized sensory endings, synaptic partners and expression profile of many genes. However, recent gene-expression studies have revealed unexpected asymmetries between ASEL and ASER. ASEL expresses the putative receptor guanylyl cyclase genes gcy-6 and gcy-7, whereas ASER expresses gcy-5 (ref. 4). In addition, only ASEL expresses the homeobox gene lim-6, an orthologue of the human LMX1 subfamily of homeobox genes. Here we show, using laser ablation of neurons and whole-cell patch-clamp electrophysiology, that the asymmetries between ASEL and ASER extend to the functional level. ASEL is primarily sensitive to sodium, whereas ASER is primarily sensitive to chloride and potassium. Furthermore, we find that lim-6 is required for this functional asymmetry and for the ability to distinguish sodium from chloride. Thus, a homeobox gene increases the representational capacity of the nervous system by establishing asymmetric functions in a bilaterally symmetrical neuron pair.     

The Rad50 zinc-hook is a structure joining Mre11 complexes in DNA recombination and repair

The Mre11 complex (Mre11 Rad50 Nbs1) is central to chromosomal maintenance and functions in homologous recombination, telomere maintenance and sister chromatid association. These functions all imply that the linked binding of two DNA substrates occurs, although the molecular basis for this process remains unknown. Here we present a 2.2 A crystal structure of the Rad50 coiled-coil region that reveals an unexpected dimer interface at the apex of the coiled coils in which pairs of conserved Cys-X-X-Cys motifs form interlocking hooks that bind one Zn(2+) ion. Biochemical, X-ray and electron microscopy data indicate that these hooks can join oppositely protruding Rad50 coiled-coil domains to form a flexible bridge of up to 1,200 A. This suggests a function for the long insertion in the Rad50 ABC-ATPase domain. The Rad50 hook is functional, because mutations in this motif confer radiation sensitivity in yeast and disrupt binding at the distant Mre11 nuclease interface. These data support an architectural role for the Rad50 coiled coils in forming metal-mediated bridging complexes between two DNA-binding heads. The resulting assemblies have appropriate lengths and conformational properties to link sister chromatids in homologous recombination and DNA ends in non-homologous end-joining.     

TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease

B cells are important in the development of autoimmune disorders by mechanisms involving dysregulated polyclonal B-cell activation, production of pathogenic antibodies, and co-stimulation of autoreactive T cells. zTNF4 (BLyS, BAFF, TALL-1, THANK) is a member of the tumour necrosis factor (TNF) ligand family that is a potent co-activator of B cells in vitro and in vivo. Here we identify two receptors for zTNF4 and demonstrate a relationship between zTNF4 and autoimmune disease. Transgenic animals overexpressing zTNF4 in lymphoid cells develop symptoms characteristic of systemic lupus erythaematosus (SLE) and expand a rare population of splenic B-Ia lymphocytes. In addition, circulating zTNF4 is more abundant in NZBWF1 and MRL-lpr/lpr mice during the onset and progression of SLE. We have identified two TNF receptor family members, TACI and BCMA, that bind zTNF4. Treatment of NZBWF1 mice with soluble TACI-Ig fusion protein inhibits the development of proteinuria and prolongs survival of the animals. These findings demonstrate the involvement of zTNF4 and its receptors in the development of SLE and identify TACI-Ig as a promising treatment of autoimmune disease in humans.     

徐家围子登娄库组层序地层特征及有利目标预测

以层序地层学理论为指导,综合利用测井、录井、地质及地震资料,对徐家围子地区登娄库组进行了层序地层划分和对比。研究区登娄库组为一套完整的超层序,自下至上发育低水位体系域,水进体系域和高水位体系域,超层序内部进一步划分为四个三级层序(SQ1、SQ2、SQ3、SQ4),在层序框架内对沉积体系和生、储、盖组合进行分析,预测了有利勘探区带。     

改进YOLOv5的多车辆目标实时检测及跟踪算法

多车辆目标跟踪时间主要花费在车辆检测模块和对每个车辆表观特征提取模块,一般情况下,车辆检测和车辆表观特征提取是在不同的神经网络中进行的,且一张图中的车辆目标越多,对车辆表观特征提取耗费时间的也越多,推理时间也相应变长。针对这一问题,基于经典的Tracking-By-Detection模式,提出一种改进的YOLO模型：在YOLO网络中添加ReID特征识别模块,使YOLO在输出目标位置信息的同时输出目标特征信息,以提高算法的跟踪速度。针对车辆间彼此覆盖的情况,提出一种基于动态IOU阈值的非极大抑制算法,以提高算法的跟踪精度。最后将YOLO输出的信息进行数据匹配,从而实现多目标跟踪。在UA-DETRAC数据集上验证改进模型的有效性,实验结果表明,将YOLOv5网络进行改进后运用在目标跟踪算法中,相对于经典的YOLO+DeepSORT跟踪模型,在车辆密集的情景下平均推理时间减少了17%;在改进后的网络上添加动态IOU阈值非极大抑制,跟踪精度提高了3.9个百分点。改进后的模型有较好的实时性与跟踪准确率。     

土壤中PVA降解菌的分离与筛选

以含PVA的土壤作为菌种来源,PVA为唯一碳源,在相同培养条件下,采用I2-KI及硼酸染色法进行初筛,再通过测定PV A 降解效率的方法进行复筛。初筛得到PV A 降解菌6株,复筛得到4株单一的PV A降解菌A ,C ,E ,F ,降解效率在48％～61％之间。通过对4株PV A降解单菌进行生理生化实验鉴定出A为假单胞菌属,C为球菌属,E为微球菌属,F为链球菌属。     

陕北油田降解石油微生物的筛选及其降解能力

从陕北油田的渣油、含油污泥和污水中富集、分离，并筛选出以原油为唯一碳源的菌株13株，经初步降解试验，筛选出对原油降解率高的DYT2-2和DYSHX1 2株石油降解菌菌株。通过对其降解能力的测试，结果表明，2个菌株对原油的降解能力在含油浓度ρ=14．29g／L的摇瓶试验中，其降解率高迭98．2％～99．5％。此结果表明，这两种降解菌对原油的降解效果高于目前已有的报道，具有很好的应用前景。     

Base pairing between U2 and U6 snRNAs is necessary for splicing of a mammalian pre-mRNA.

Splicing of pre-messenger RNA in eukaryotic cells occurs in a multicomponent complex termed the spliceosome, which contains small nuclear ribonucleoprotein particles (snRNPs), protein factors and substrate pre-mRNA. Assembly of the spliceosome involves the stepwise binding of snRNPs and protein factors to the pre-mRNA through a poorly understood mechanism which probably involves specific RNA-RNA, RNA-protein and protein-protein interactions. Of particular interest are the interactions between snRNPs, which are likely to be important not only for assembly of the spliceosome but also for catalysis. U1 snRNP interacts with the 5' splice site and U2 snRNP with the branch site of the pre-mRNA; both of these interactions involve Watson-Crick base pairing. But very little is known about how other factors such as the U4/U6 and U5 snRNPs reach the spliceosome and function in splicing. Here we report evidence that U6 snRNA interacts directly with U2 snRNA by a mechanism involving base-pairing, and that this interaction can be necessary for splicing of a mammalian pre-mRNA in vivo.     

Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas

Overexpression of the polycomb group gene Bmi1 promotes cell proliferation and induces leukaemia through repression of Cdkn2a (also known as ink4a/Arf) tumour suppressors. Conversely, loss of Bmi1 leads to haematological defects and severe progressive neurological abnormalities in which de-repression of the ink4a/Arf locus is critically implicated. Here, we show that Bmi1 is strongly expressed in proliferating cerebellar precursor cells in mice and humans. Using Bmi1-null mice we demonstrate a crucial role for Bmi1 in clonal expansion of granule cell precursors both in vivo and in vitro. Deregulated proliferation of these progenitor cells, by activation of the sonic hedgehog (Shh) pathway, leads to medulloblastoma development. We also demonstrate linked overexpression of BMI1 and patched (PTCH), suggestive of SHH pathway activation, in a substantial fraction of primary human medulloblastomas. Together with the rapid induction of Bmi1 expression on addition of Shh or on overexpression of the Shh target Gli1 in cerebellar granule cell cultures, these findings implicate BMI1 overexpression as an alternative or additive mechanism in the pathogenesis of medulloblastomas, and highlight a role for Bmi1-containing polycomb complexes in proliferation of cerebellar precursor cells.     

安徽省干线公路路面大中修工程设计浅议

结合安徽省路面大中修工程实际,从公路路面大中修工程设计内容、设计原则和设计步骤等方面进行阐述,对全省公路养护大中修工程的设计提出一些建议.