BACKGROUND & AIMS: :Peptidylarginine deiminase 6 (PAD6) is an enzyme that is uniquely expressed in male and female germ cells. To study the function of this enzyme in vivo we generated mice deficient for PAD6. Here we show that inactivation of the PAD6 gene in mice leads to female infertility whereas male fertility is not affected. The absence of the PAD6 protein and consequently absence of citrullination activity in oocytes results in dispersal of the cytoskeletal sheets in oocytes, indicating an essential role of these germ cell-specific structures in zygote/embryo development. PAD6 deficient mice do not show any other overt phenotype. Thus, we identify citrullination as a new regulator of fertility.

背景与目标： ：肽基精氨酸脱亚氨酶6（PAD6）是一种在雄性和雌性生殖细胞中独特表达的酶。为了研究该酶在体内的功能，我们产生了PAD6缺陷的小鼠。在这里，我们显示，小鼠中PAD6基因的失活导致女性不育，而男性不育不受影响。卵母细胞中缺乏PAD6蛋白，因此缺乏瓜氨酸化活性，导致卵母细胞中细胞骨架片的分散，表明这些生殖细胞特异性结构在合子/胚胎发育中起着至关重要的作用。 PAD6缺陷的小鼠没有显示任何其他明显的表型。因此，我们确定瓜氨酸化是生育的新调节剂。

BACKGROUND & AIMS: :The identification of germ-line mutations in 2 genes (BRCA1 and BRCA2) responsible for the majority of hereditary ovarian cancers has led an increasing number of women carriers of these mutations to undergo prophylactic oophorectomy (PO) to reduce their risk of subsequent ovarian carcinoma. A large number of unexpected, clinically occult neoplasms are thus being discovered. Up to December 2004, the Medical Genetics Service of the National Cancer Institute in Milan, Italy, has tested 756 probands from breast and/or ovarian cancer families for BRCA1 and BRCA2 germ-line mutations. Molecular screening of family members led to the identification of 344 female carriers of BRCA1 (239) or BRCA2 (105) germ-line mutations. Of the 186 potentially eligible women (37 of whom had tested positive for BRCA1 and 13 for BRCA2 mutation), 50 (26.8%) chose to undergo PO. Six clinically occult primary gynecologic malignancies (2 stage IIIC serous carcinomas of the ovary, 3 in situ serous carcinomas of the fallopian tube, and 1 stage IIB invasive serous carcinoma of the fallopian tube) and 1 occult ovarian metastasis from breast carcinoma were identified in the PO specimens of 7 women (all BRCA1 mutated). Four of the patients with occult primary gynecologic cancers are alive without disease 129, 87, 38, and 7 months after PO, respectively. One of the 2 patients with primary ovarian cancer and the single patient with tubal invasive carcinoma are alive with recurrent disease 83 and 20 months after PO, respectively. In addition, one of the patients whose PO specimen did not show any malignancy presented with stage IIIC tubal carcinoma 77 months after PO. The relatively high number of tubal neoplasms found at PO in this group of patients underlines the linkage between mutation and the risk of developing tubal cancer, and stresses the need to include removal of the entire tubes at the time of PO and of thoroughly evaluating the specimens at the microscopic level. The upstaging of all 3 invasive carcinomas after staging surgery, and the late recurrence and persistence of 2 of them despite treatment indicate that small size of the tumors should not preclude therapy.

背景与目标： ：对负责大多数遗传性卵巢癌的2个基因（BRCA1和BRCA2）的种系突变的鉴定，导致越来越多的女性携带这些突变的人进行了预防性卵巢切除术（PO），以降低其患上卵巢癌的风险。因此，发现了大量意想不到的临床隐匿性肿瘤。截至2004年12月，意大利米兰国家癌症研究所的医学遗传学服务已对756个来自乳腺癌和/或卵巢癌家族的先证者进行了BRCA1和BRCA2种系突变测试。家庭成员的分子筛查导致识别出BRCA1（239）或BRCA2（105）种系突变的344个雌性携带者。在186名可能符合条件的妇女中（其中37人的BRCA1测试呈阳性，13人的BRCA2突变检测为阳性），其中50人（26.8％）选择接受PO。在临床中确定了6例临床隐匿的原发性妇科恶性肿瘤（2例卵巢IIIC浆液性癌，3例输卵管原位浆液性癌和1例IIB输卵管浸润性浆液性癌）和1例隐匿性卵巢癌卵巢转移。 7名妇女的PO标本（所有BRCA1突变）。分别在PO后129、87、38和7个月，有四名患有隐匿性原发性妇科癌症的患者还活着而没有疾病。 2例原发性卵巢癌患者中的1例和输卵管浸润性癌的1例患者在PO后分别存活83个月和20个月。此外，其中一名PO标本未显示任何恶性肿瘤的患者在PO后77个月出现IIIC期输卵管癌。该组患者在PO中发现的相对较多的输卵管肿瘤强调了突变与发生输卵管癌的风险之间的联系，并强调需要在PO时切除整个管并彻底评估标本在微观层面上。分期手术后所有3种浸润性癌的分期升级，并且尽管有治疗，但其中2种仍较晚复发和持续存在，这表明较小的肿瘤不应排除治疗的可能性。

BACKGROUND & AIMS: :A transmembrane extracellular matrix receptor of the integrin family, alpha 6 beta 4, is a component of the hemidesmosome, an adhesion complex of importance in epithelial cell-connective tissue attachment (Stepp, M. A., S. Spurr-Michaud, A. Tisdale, J. Elwell, and I. K. Gipson. 1990. Proc. Natl. Acad. Sci. USA. 87:8970-8974; Jones, J. C. R., M. A. Kurpakus, H. M. Cooper, and V. Quaranta. 1991. Cell Regulation. 2:427-438). Cytosolic components of hemidesmosomes include bullous pemphigoid (BP) antigens while extracellular components include a 125-kD component of anchoring filaments (CAF) and collagen type VII-containing anchoring fibrils. We have monitored the incorporation of the alpha 6 beta 4 integrins into forming hemidesmosomes in an in vitro wound-healing explant model. In epithelial cells recently migrated from the edges of unwounded sites over bare connective tissue, alpha 6 beta 4 first appears along the entire cell surface. At this stage, these cells contain little or no cytosolic hemidesmosomal components, at least as detectable by immunofluorescence using BP autoantibodies, whereas they are already positive for laminin and CAF. At a later stage, as cells become positive for cytosolic hemidesmosome components such as BP antigens as well as collagen type VII, alpha 6 beta 4 becomes concentrated along the basal pole of the epithelial cell where it abuts the connective tissue of the explant. Polyclonal antibodies to beta 4 do not interfere with the migration of epithelial cells in the explant. However, they prevent assembly of hemidesmosomal complexes and inhibit expression of collagen type VII in cells that have migrated over wound areas. In addition, they induce disruption of established hemidesmosomes in nonmigrating cells of the unwounded area of the explant. Monoclonal antibodies to alpha 6 have a more dramatic effect, since they completely detach epithelial cells in the unwounded area of the explant. Antibodies to CAF also detach epithelial cells in unwounded areas, apparently by inducing separation between epithelium and connective tissue at the lamina lucida of the basement membrane zone. These results suggest a model whereby polarization of alpha 6 beta 4 to the basal surface of the cells, perhaps induced by a putative anchoring filament-associated ligand, triggers assembly of hemidesmosome plaques.

背景与目标： ：整联蛋白家族的跨膜细胞外基质受体，α6 beta 4，是半桥粒的成分，半桥粒是在上皮细胞结缔组织附着中重要的粘附复合物（Stepp，MA，S。Spurr-Michaud，A。Tisdale， J. Elwell和IK Gipson。1990.美国国家科学院院刊87：8970-8974； Jones，JCR，MA Kurpakus，HM Cooper和V.Quaranta。1991.《细胞调节》 2：427- 438）。血小体的胞质成分包括大疱性类天疱疮（BP）抗原，而细胞外成分包括锚定丝（CAF）和含VII型胶原的锚定纤丝的125 kD成分。我们已经监测了在体外伤口愈合的外植体模型中将α6β4整合素整合到形成hemidemosomes中。在最近从裸结缔组织上方未受伤部位边缘迁移的上皮细胞中，α6 beta 4首先沿整个细胞表面出现。在这一阶段，这些细胞几乎不含有或不含胞质半桥粒成分，至少可以通过使用BP自身抗体的免疫荧光检测到，而对于层粘连蛋白和CAF则已经呈阳性。在稍后的阶段，随着细胞对胞质半桥体成分（例如BP抗原）和VII型胶原呈阳性，α6β4沿着上皮细胞的基极集中，并与外植体的结缔组织邻接。针对β4的多克隆抗体不会干扰外植体中上皮细胞的迁移。然而，它们阻止了半桥粒复合物的组装并抑制了在伤口区域上迁移的细胞中VII型胶原的表达。另外，它们在外植体未受伤区域的非迁移细胞中诱导已建立的半染色体的破坏。针对α6的单克隆抗体具有更引人注目的效果，因为它们可以完全脱离外植体未受伤区域中的上皮细胞。 CAF抗体还可以在未受伤的区域分离上皮细胞，这显然是通过诱导基底膜区域的透明层上皮与结缔组织之间的分离来实现的。这些结果表明了一个模型，其中α6β4极化到细胞的基底表面（可能是由假定的锚定细丝相关配体诱导的）触发了半血球斑块的组装。

BACKGROUND & AIMS: :Mesenchymal stem cells (MSCs) have been exploited as cellular vectors to treat a wide array of diseases but the mechanisms responsible for their therapeutic effect remain indeterminate. Previously, we reported that MSCs inhibit bleomycin (BLM)-induced inflammation and fibrosis within the lungs of mice. Interrogation of the MSC transcriptome identified interleukin 1 receptor antagonist (IL1RN) as a potential mediator of this effect. Fractionation studies indicated that MSCs are the principal source of IL1RN in murine bone marrow and that its expression is restricted to a unique subpopulation of cells. Moreover, MSC-conditioned media was shown to block proliferation of an IL-1alpha-dependent T cell line and inhibit production of TNF-alpha by activated macrophages in vitro. Studies conducted in mice revealed that MSC administration was more effective than recombinant IL1RN delivered via adenoviral infection or osmotic pumps in inhibiting BLM-induced increases in TNF-alpha, IL-1alpha, and IL1RN mRNA in lung, IL1RN protein in bronchoalveolar lavage (BAL) fluid, and trafficking of lymphocytes and neutrophils into the lung. Therefore, MSCs protect lung tissue from BLM-induced injury by blocking TNF-alpha and IL-1, two fundamental proinflammatory cytokines in lung. Identification of IL1RN-expressing human MSC subpopulations may provide a novel cellular vector for treating chronic inflammatory diseases in humans.

背景与目标： 间充质干细胞（MSCs）已被用作治疗多种疾病的细胞载体，但其治疗效果的机制仍不确定。以前，我们报道了MSC抑制博来霉素（BLM）诱导的小鼠肺内炎症和纤维化。对MSC转录组的询问确定白介素1受体拮抗剂（IL1RN）是这种作用的潜在介体。分级研究表明，MSC是鼠骨髓中IL1RN的主要来源，其表达仅限于细胞的独特亚群。此外，MSC条件培养基显示在体外可阻断IL-1alpha依赖性T细胞系的增殖并抑制巨噬细胞活化TNF-α的产生。在小鼠中进行的研究表明，与通过腺病毒感染或渗透泵输送的重组IL1RN相比，MSC抑制BLM诱导的肺中TNF-α，IL-1alpha和IL1RN mRNA的增加，支气管肺泡灌洗（BAL）中的IL1RN蛋白的抑制作用更有效。液体，以及淋巴细胞和中性粒细胞向肺的运输。因此，MSC通过阻断TNF-α和IL-1（肺中两种基本的促炎细胞因子）来保护肺组织免受BLM诱导的损伤。鉴定表达IL1RN的人MSC亚群可以提供用于治疗人的慢性炎性疾病的新型细胞载体。

BACKGROUND & AIMS: BACKGROUND:Malnutrition remains one of the most common causes of morbidity and mortality among children throughout the world. This study aimed to assess prevalence of malnutrition and associated factors among children aged 6-59 months in Damot Gale, South Ethiopia. METHODS:A community based cross sectional study was conducted on 398 children aged 6-59 months in the Damot Gale district. A two-stage cluster sample design was used to select kebele and households. Anthropometric measurements and structured questionnaires were used to collect data. Bivariate and multivariate logistic regression was done by using SPSS version 20. RESULTS:The results of this study indicated that 27.6% of children were under-weight and 9% were wasted. Being male (AOR: 1.90; 95% CI: (1.10-3.32), children with shorter birth interval (AOR:2.89;95% CI: (1.23-6.80), children who had sickness some times for past 2 weeks (AOR:0.42; 95% CI:(0.10-0.93) and children whose mothers attended ANC (AOR:0.29; 95% CI: (0.16-0.52) were associated with underweight. Children whose mother's main occupation was non-farm (AOR: 7.06;95% CI: (1.31-38.21), presence of diarrhea (AOR:39.5, 95% CI: (13.68-114.30), and children whose mothers attended ANC (AOR:0.18,95% CI: (0 .18 (0.07-0.45) were associated with wasting. CONCLUSION:The prevalence of malnutrition in the study area was high. Health extension workers and stakeholders should give due concern on promotion of proper nutrition in the community.

背景与目标： 背景：营养不良仍然是全世界儿童发病和死亡的最常见原因之一。这项研究旨在评估南埃塞俄比亚达莫特盖勒（Damot Gale）6至59个月大儿童的营养不良患病率及其相关因素。
方法：在Damot Gale地区对398名6-59个月的儿童进行了基于社区的横断面研究。使用两阶段集群样本设计来选择kebele和家庭。人体测量和结构化问卷用于收集数据。使用SPSS版本20进行双变量和多变量logistic回归。
结果：这项研究的结果表明，有27.6％的儿童体重不足，有9％的儿童体重不足。男性（AOR：1.90; 95％CI：（1.10-3.32），生育间隔较短的孩子（AOR：2.89; 95％CI：（1.23-6.80）），过去两周内有过一段时间生病的孩子（AOR： 0.42； 95％CI：（0.10-0.93）和母亲参加ANC的孩子（AOR：0.29； 95％CI：（0.16-0.52））与体重过轻相关。母亲主要从事非农业工作的孩子（AOR：7.06； 95％CI（1.31-38.21），腹泻（AOR：39.5、95％CI：（13.68-114.30）和母亲参加ANC的孩子（AOR：0.18,95％CI：（0 .18（0.07- 0.45）与浪费相关。
结论：研究区营养不良发生率很高。卫生保健工作者和利益相关者应在促进社区适当营养方面给予应有的关注。

BACKGROUND & AIMS: :Monounsaturated fatty acids (MUFA)-rich and n-6 polyunsaturated fatty acid (n-6 PUFA)-rich vegetable oils are increasingly used as fish oil replacers for aquafeed formulation. The present study investigated the fatty acid metabolism in juvenile European sea bass (Dicentrarchus labrax, 38.4 g) fed diets containing fish oil (FO, as the control treatment) or two different vegetable oils (the MUFA-rich canola/rapeseed oil, CO; and the n-6 PUFA-rich cottonseed oil, CSO) tested individually or as a 50/50 blend (CO/CSO). The whole-body fatty acid balance method was used to deduce the apparent in vivo fatty acid metabolism. No effect on growth performance and feed utilization was recorded. However, it should be noted that the fish meal content of the experimental diets was relatively high, and thus the requirement for n-3 long-chain polyunsaturated fatty acid (n-3 LC-PUFA) may have likely been fulfilled even if dietary fish oil was fully replaced by vegetable oils. Overall, relatively little apparent in vivo fatty acid bioconversion was recorded, whilst the apparent in vivo β-oxidation of dietary fatty acid was largely affected by the dietary lipid source, with higher rate of β-oxidation for those fatty acids which were provided in dietary surplus. The deposition of 20:5n-3 and 22:6n-3, as % of the dietary intake, was greatest for the fish fed on the CSO diet. It has been shown that European sea bass seems to be able to efficiently use n-6 PUFA for energy substrate, and this may help in minimizing the β-oxidation of the health benefiting n-3 LC-PUFA and thus increase their deposition into fish tissues.

背景与目标： ：富含不饱和脂肪酸（MUFA）和富含n-6多不饱和脂肪酸（n-6 PUFA）的植物油越来越多地用作水产饲料配方的鱼油替代品。本研究调查了以鱼油（FO作为对照）或两种不同的植物油（富含MUFA的低芥酸菜籽/菜籽油，CO；食用鱼油）作为饮食的欧洲鲈鱼（Dicentrarchus labrax，38.4 g）日粮中的脂肪酸代谢。以及分别或以50/50的混合物（CO / CSO）进行测试的n-6富含PUFA的棉籽油（CSO）。全身脂肪酸平衡法用于推导体内明显的脂肪酸代谢。没有记录到对生长性能和饲料利用率的影响。但是，应注意的是，实验饮食中鱼粉含量较高，因此即使食用鱼，也可能满足n-3长链多不饱和脂肪酸（n-3 LC-PUFA）的要求。油被植物油完全替代。总的来说，记录的体内脂肪酸的明显表观生物转化相对较少，而膳食脂肪酸的表观体内β-氧化作用很大程度上受膳食脂质来源的影响，膳食中提供的那些脂肪酸的β-氧化率较高。剩余。以日粮摄入量的百分比计，20：5n-3和22：6n-3的沉积量对以CSO日粮喂养的鱼类最大。研究表明，欧洲鲈鱼似乎能够有效地将n-6 PUFA用作能量底物，这可能有助于将有益于健康的n-3 LC-PUFA的β-氧化作用降至最低，从而增加其在鱼类中的沉积组织。

BACKGROUND & AIMS: :6-sulfate modified N-acetylglucosamine (6-sulfo-GlcNAc) is often found as part of many biologically important carbohydrate epitopes such as 6-sulfo-Le(X). In these epitopes, the 6-sulfo-GlcNAc moiety is extended by a galactose sugar in a β1-4 linkage. The β4GalT1 enzyme transfers galactose (Gal) from UDP-Gal to N-acetylglucosamine (GlcNAc) in the presence of manganese. Here we report that the β4GalT1 enzyme transfers Gal to the 6-sulfo-GlcNAc and 4-methylumbelliferyl-6-sulfo-N-acetyl-β-D-glucosaminide (6-sulfo-βGlcNAc-MU) acceptor substrates, although with very low efficiency. To understand the effect that the 6-sulfate group on the GlcNAc acceptor has on the catalytic activity of the β4GalT1 molecule, we have determined the crystal structure of the catalytic domain of bovine β4GalT1 mutant enzyme M344H-β4GalT1 complex with the 6-sulfo-GlcNAc molecule. In the crystal structure, the 6-sulfo-GlcNAc is bound to the protein in a way that is similar to the GlcNAc molecule. However, the 6-sulfate group engages in additional interactions with the hydrophobic region, residues 276-285, of the protein molecule, and this group is found wedged between the aromatic side chains of Phe-280 and Trp314 residues. Since the side chain of the Trp314 residue undergoes conformational changes during the catalytic cycle of the enzyme, molecular interaction between Trp314 and the 6-sulfate group might hinder this conformational change. Therefore, the lack of a favorable binding environment, together with hindrance to the conformational changes, might be responsible for the poor catalytic activity.

背景与目标： ：6-硫酸盐修饰的N-乙酰氨基葡萄糖（6-sulfo-GlcNAc）通常作为许多生物学上重要的碳水化合物表位（如6-sulfo-Le（X））的一部分被发现。在这些表位中，6-磺基-GlcNAc部分被β1-4键中的半乳糖延伸。在锰的存在下，β4GalT1酶将半乳糖（Gal）从UDP-Gal转移到N-乙酰氨基葡萄糖（GlcNAc）。在这里我们报告说，β4GalT1酶将Gal转移到6-磺基-GlcNAc和4-甲基伞形基-6-磺基-N-乙酰基-β-D-氨基葡萄糖（6-磺基-βGlcNAc-MU）受体底物上，尽管其受体底物非常低效率。为了了解GlcNAc受体上的6硫酸盐基团对β4GalT1分子的催化活性的影响，我们确定了牛β4GalT1突变酶M344H-β4GalT1与6-Sulfo-GlcNAc的催化结构域的晶体结构。分子。在晶体结构中，6-磺基-GlcNAc以与GlcNAc分子相似的方式与蛋白质结合。然而，6-硫酸基团与蛋白质分子的疏水区，残基276-285进行额外的相互作用，并且发现该基团夹在Phe-280和Trp314残基的芳族侧链之间。由于Trp314残基的侧链在酶的催化循环过程中发生构象变化，因此Trp314与6-硫酸酯基团之间的分子相互作用可能会阻碍这种构象变化。因此，缺乏有利的结合环境以及对构象变化的阻碍可能是不良的催化活性的原因。