Evolution of neoplastic cell lineages in Barrett oesophagus.

It has been hypothesized that neoplastic progression develops as a consequence of an acquired genetic instability and the subsequent evolution of clonal populations with accumulated genetic errors. Accordingly, human cancers and some premalignant lesions contain multiple genetic abnormalities not present in the normal tissues from which the neoplasms arose. Barrett oesophagus (BE) is a premalignant condition which predisposes to oesophageal adenocarcinoma (EA) that can be biopsied prospectively over time because endoscopic surveillance is recommended for early detection of cancer. In addition, oesophagectomy specimens frequently contain the premalignant epithelium from which the cancer arose. Neoplastic progression in BE is associated with alterations in TP53 (also known as p53) and CDKN2A (also known as p16) and non-random losses of heterozygosity (LOH). Aneuploid or increased 4N populations occur in more than 90-95% of EAs, arise in premalignant epithelium and predict progression. We have previously shown in small numbers of patients that disruption of TP53 and CDKN2A typically occurs before aneuploidy and cancer. Here, we determine the evolutionary relationships of non-random LOH, TP53 and CDKN2A mutations, CDKN2A CpG-island methylation and ploidy during neoplastic progression. Diploid cell progenitors with somatic genetic or epigenetic abnormalities in TP53 and CDKN2A were capable of clonal expansion, spreading to large regions of oesophageal mucosa. The subsequent evolution of neoplastic progeny frequently involved bifurcations and LOH at 5q, 13q and 18q that occurred in no obligate order relative to each other, DNA-content aneuploidy or cancer. Our results indicate that clonal evolution is more complex than predicted by linear models.     

Integrin cytoplasmic tyrosine motif is required for outside-in alphaIIbbeta3 signalling and platelet function.

Integrins not only bind adhesive ligands, they also act as signalling receptors. Both functions allow the integrin alphaIIbbeta3 to mediate platelet aggregation. Platelet agonists activate alphaIIbbeta3 (inside-out signalling) to allow the binding of soluble fibrinogen. Subsequent platelet aggregation leads to outside-in alphaIIbbeta3 signalling, which results in calcium mobilization, tyrosine phosphorylation of numerous proteins including beta3 itself, increased cytoskeletal reorganisation and further activation of alphaIIbbeta3. Thus, outside-in signals enhance aggregation, although the mechanisms and functional consequences of specific signalling events remain unclear. Here we describe a mouse that expresses an alphaIIbbeta3 in which the tyrosines in the integrin cytoplasmic tyrosine motif have been mutated to phenylalanines. These mice are selectively impaired in outside-in alphaIIbbeta3 signalling, with defective aggregation and clot-retraction responses in vitro, and an in vivo bleeding defect which is characterized by a pronounced tendency to rebleed. These data provide evidence for an important role of outside-in signalling in platelet physiology. Furthermore, they identify the integrin cytoplasmic tyrosine motif as a key mediator of beta-integrin signals and a potential target for new therapeutic agents.     

鱼类饲料配方及制作

在约300种养殖鱼类中,仅50种有营养学数据,不到10 种有完全的营养学数据.在饲料蛋白源中,鱼粉是鲑鳟鱼类饲料的主要蛋白源,蛋白质含量为60%～80 %.肉骨粉一般蛋白质含量为50 %左右,赖氨酸含量较鱼粉低.肉骨粉灰分含量可到30 %,限制了其在鱼类饲料中的应用.一般在鲑鳟鱼类饲料中用量不超过10 %,温水性鱼类饲料中用量不超过15 %.血粉蛋白质含量为80 %～86 %,是很好的赖氨酸来源,但缺乏蛋氨酸.血粉的适口性较差,在鲑鳟饲料中用量不超过10 %,温水性鱼类饲料中不超过5 %.肉骨-血粉混合物的营养成分与鱼粉接近,可完全替代沟鲶饲料中的鱼粉.鸡肉粉蛋白质含量为60 %～70 %,可替代鲑鳟饲料中10 %的鱼粉及温水性鱼类饲料中50 %的蛋白质.水解羽毛粉蛋白质含量约为85 %,但消化率较低.可替代鲑鳟及温水性鱼类饲料中10 %的蛋白质.鸡肉粉-羽毛粉混合物可替代虹鳟饲料中50 %的鱼粉.豆粕可替代虹鳟饲料中50 %的鱼粉蛋白,是温水性鱼类饲料的主要蛋白源.豆粕中存在一些抗营养因子.一般豆油提取过程可以分解大部分抗营养因子.一些报道表明进一步热处理可以提高豆粕的营养价值.经过热处理的全脂豆粉,如果添加蛋氨酸及赖氨酸,可以替代虹鳟及鲤鱼饲料中50 %～75 %的鱼粉.棉粕对鱼的适口性好,但缺少赖氨酸.除非添加赖氨酸,棉粕在温水性鱼类饲料中用量不应超过30 %.花生粕适口性好,但缺少赖氨酸.添加量超过20 %时,需添加赖氨酸.葵花子粕赖氨酸含量较低,可替代虹鳟饲料中40%的鱼粉及温水性鱼类饲料中20 %的鱼粉.低毒菜粕可替代虹鳟饲料中66 %的鱼粉.添加增味剂后,去植酸菜籽蛋白浓缩物可完全替代虹鳟饲料中的鱼粉.玉米面筋含42 %～60 %的蛋白质,添加水平在虹鳟饲料可达20 %,鲤鱼饲料可达10 %.酒精业副产物含27 %蛋白质,适口性好但赖氨酸含量低,添加水平在虹鳟饲料可达10 %,温水性鱼类饲料可达30 %.非营养因子也会影响到饲料制作.如制作膨化饲料需至少25 %的谷类原料.棉粕含量过高会减缓挤压速度.非营养性添加剂包括黏合剂、类胡萝卜素、鱼药、激素、抗微生物及真菌制剂、抗氧化剂、增味剂,但不应在饲料中添加纤维素,其含量应尽量降低.饲料制作工艺包括蒸汽制粒及挤压.挤压可制作浮性、沉性及缓沉性饲料,并能提高消化率,但会分解一些维生素.     

Mutations in the human homologue of mouse dl cause autosomal recessive and dominant hypohidrotic ectodermal dysplasia.

X-linked hypohidrotic ectodermal dysplasia results in abnormal morphogenesis of teeth, hair and eccrine sweat glands. The gene (ED1) responsible for the disorder has been identified, as well as the analogous X-linked gene (Ta) in the mouse. Autosomal recessive disorders, phenotypically indistinguishable from the X-linked forms, exist in humans and at two separate loci (crinkled, cr, and downless, dl) in mice. Dominant disorders, possibly allelic to the recessive loci, are seen in both species (ED3, Dlslk). A candidate gene has recently been identified at the dl locus that is mutated in both dl and Dlslk mutant alleles. We isolated and characterized its human DL homologue, and identified mutations in three families displaying recessive inheritance and two with dominant inheritance. The disorder does not map to the candidate gene locus in all autosomal recessive families, implying the existence of at least one additional human locus. The putative protein is predicted to have a single transmembrane domain, and shows similarity to two separate domains of the tumour necrosis factor receptor (TNFR) family.