BACKGROUND & AIMS: :Given the paucity of data on the distribution of serotonin (5-HT) receptors of type 6 (5-HT(6)) in the human brain, the aim of this study was to investigate their distribution in postmortem human prefrontal cortex, striatum and hippocampus by either immunohistochemical or immunofluorescence techniques. The brain samples were obtained from 6 subjects who had died for causes not involving primarily or secondarily the CNS. The 5-HT(6) receptor distribution was explored by the [(125)I]SB-258585 binding to brain membranes followed by immunohistochemical and immunofluorescence evaluations. A specific [(125)I]SB-258585 binding was detected in all the regions under investigation, whilst the content in the hippocampus and cortex being about 10-30 times lower than in the striatum. Immunohistochemistry and double-label immunofluorescence microscopy experiments, carried out in the prefrontal cortex and hippocampus only, since data in the striatum were already published, showed the presence of 5-HT(6) receptors in both pyramidal and glial cells of prefrontal cortex, while positive cells were mainly pyramidal neurons in the hippocampus. The heterogeneous distribution of 5-HT(6) receptors provides a preliminary explanation of how they might regulate different functions in different brain areas, such as, perhaps, brain trophism in the cortex and neuronal firing in the hippocampus. This study, taking into account all the limitations due to the postmortem model used, represents the starting point to explore the 5-HT(6) receptor functionality and its sub-cellular distribution.

背景与目标： ：鉴于缺乏6型血清素（5-HT）受体（5-HT（6））在人脑中的分布的数据，本研究的目的是研究它们在死后人类前额叶皮层，纹状体中的分布免疫组织化学或免疫荧光技术检测海马和海马。脑样本是从6名因主要或次要不涉及CNS的原因死亡的受试者中获得的。通过[（125）I] SB-258585与脑膜的结合，然后进行免疫组织化学和免疫荧光评估，探索了5-HT（6）受体的分布。在所有研究区域中均检测到特定的[（125）I] SB-258585结合，而海马和皮质中的含量比纹状体低约10-30倍。仅在前额叶皮层和海马体中进行的免疫组织化学和双标记免疫荧光显微镜实验，因为纹状体中的数据已经发表，显示在前额叶皮层的锥体细胞和神经胶质细胞中都存在5-HT（6）受体，而阳性细胞主要是海马中的锥体神经元。 5-HT（6）受体的异质分布为它们如何在不同的大脑区域调节不同的功能提供了初步的解释，例如，大脑皮层的营养和海马神经元的放电。这项研究，考虑到由于使用死后模型的所有限制，代表了探索5-HT（6）受体功能及其亚细胞分布的起点。

BACKGROUND & AIMS: :Accumulating evidence indicates that Toll-like receptor (TLR) signaling adapter protein interactions with Toll/Interleukin-1 Receptor (TIR) domains present in sensory neurons may modulate neuropathic pain states. Following ligand interaction with TLRs, TIR serves to both initiate intracellular signaling and facilitate recruitment of signaling adapter proteins to the intracytoplasmic domain. Although TLR TIR is central to a number of TLR signaling cascades, its role in sensory neurons is poorly understood. In this study we investigated the degree to which TLR TIR decoy peptide modified to include a TAT sequence (Trans-Activator of Transcription gene in HIV; TAT-4BB) affected LPS-induced intracellular calcium flux and excitation in sensory neurons, and behavioral changes due to TLR4 active metabolite, morphine-3-glucuronide (M3G) exposure in vivo. TAT-4BB inhibited LPS-induced calcium changes in a majority of sensory neurons and decreased LPS-dependent neuronal excitability in small diameter neurons. Acute systemic administration of the TAT-4BB reversed M3G-induced tactile allodynia in a dose-dependent manner but did not affect motor activity, anxiety or responses to noxious thermal stimulus. These data suggest that targeting TLR TIR domains may provide novel pharmacological targets to reduce or reverse TLR4-dependent pain behavior in the rodent.

背景与目标： ：越来越多的证据表明，Toll样受体（TLR）信号转接头蛋白与感觉神经元中存在的Toll / Interleukin-1受体（TIR）域相互作用可能会调节神经性疼痛状态。配体与TLR相互作用后，TIR既可以启动细胞内信号传导，也可以促进信号传导衔接子蛋白募集到胞质内域。尽管TLR TIR是许多TLR信号级联的核心，但对其在感觉神经元中的作用知之甚少。在这项研究中，我们调查了TLR TIR诱饵肽修饰为包含TAT序列（HIV转录基因的反式激活因子； TAT-4BB）在多大程度上影响LPS诱导的细胞内钙通量和感觉神经元的兴奋，以及行为改变对TLR4活性代谢产物吗啡-3-葡糖醛酸（M3G）的体内暴露。 TAT-4BB抑制了LPS诱导的大多数感觉神经元中钙的变化，并降低了小直径神经元中LPS依赖性神经元的兴奋性。 TAT-4BB的急性全身给药以剂量依赖的方式逆转了M3G诱导的触觉异常性疼痛，但并未影响运动活动，焦虑或对有害热刺激的反应。这些数据表明，靶向TLR TIR结构域可提供新的药理学靶标，以减少或逆转啮齿动物中TLR4依赖性的疼痛行为。

BACKGROUND & AIMS: BACKGROUND:Interleukin-17 (IL-17), which is secreted by Th17 cells, is a proinflammatory cytokine that is implicated in the pathogenesis of multiple sclerosis (MS) and plays a role in nonresponse of MS patients to interferon-β (IFN-β) therapy. OBJECTIVES:The purpose of this study was to establish a correlation between nonresponders (NR) and IL-17A serum titers and binding antibodies (BAbs) to IFN-β, as well as to find a correlation between IL-17A serum levels and other features of MS patients. METHODS:Our prospective study included 72 inactive relapsing-remitting multiple sclerosis (RRMS) patients that had been treated for at least 18 months with IFN-β and 15 healthy subjects. We determined the serum levels of IL-17A and of BAbs. IL-17A levels were considered elevated (IL-17A+) if the recorded value was greater than 1.6 pg/ml. RESULTS:Twenty-seven patients (37.5%) were NR and had a significantly higher serum IL-17A level compared to the responders group. Nineteen patients (26.4%) were IL-17A+ and had had a significantly higher number of relapses in the previous year and a higher Expanded Disability Status Score. The majority of IL-17A+ patients were NR and had a shorter MS duration. CONCLUSIONS:RRMS patients with high serum IL-17A levels do not respond well to IFN-β therapy and have shorter MS duration compared to patients with low IL-17A levels. This response is not influenced by the presence of BAbs.

背景与目标： 背景：Th17细胞分泌的白细胞介素17（IL-17）是一种促炎细胞因子，与多发性硬化症（MS）的发病机制有关，并且在MS患者对干扰素-β（IFN- β）疗法。
目的：本研究的目的是建立无应答者（NR）与IL-17A血清滴度和针对IFN-β的结合抗体（BAbs）之间的相关性，以及找出IL-17A血清水平与其他特征之间的相关性MS患者。
方法：我们的前瞻性研究包括72例接受IFN-β治疗至少18个月的非活动性复发缓解型多发性硬化症（RRMS）患者和15名健康受试者。我们确定了IL-17A和BAbs的血清水平。如果记录值大于1.6 pg / ml，则认为IL-17A水平升高（IL-17A）。
结果：27名患者（37.5％）为NR，与应答者组相比，血清IL-17A水平显着更高。 19名患者（26.4％）为IL-17A，在前一年中复发率明显更高，而“扩展残疾状态评分”更高。大多数IL-17A患者为NR，MS病程较短。
结论：与低IL-17A水平的患者相比，血清IL-17A水平高的RRMS患者对IFN-β治疗的反应不佳，MS病程较短。该反应不受BAbs的存在的影响。

BACKGROUND & AIMS: :IL-23 and IL-17 are pro-inflammatory cytokines. IL-23 is secreted by activated macrophages and dendritic cells, while IL-17 by Th17 cells. Serum IL-23 and IL-17 are known to be elevated in numerous inflammatory diseases including neurodegenerative diseases. The role of serum IL-23 and IL-17 in aneurysmal subarachnoid hemorrhage (aSAH) has still not been investigated. The present work investigates the serum IL-23 and IL-17 levels and their association with post hemorrhagic complications and clinical outcome in patients with aSAH. METHODS:In this study, 80 patients with aSAH (Hunt and Hess grade I-V) were prospectively recruited. We enrolled 24 control patients with lumbar spinal stenosis. Peripheral venous blood was withdrawn from controls and from aSAH patients at day 1 and day 7, allowed to clot and centrifuged to obtain serum. Enzyme linked immunoassay kits were employed to quantify the serum levels of IL-23 and IL-17 by applying 50µL of serum samples. Post hemorrhagic complications and clinical outcome were documented prospectively from patient's hospital record. RESULTS:Serum IL-23 and IL-17 levels were significantly elevated in aSAH patients at day 1 and day 7 (n=80) as compared to control patients (n=24). Further analysis after dichotomy of patients who suffered from post hemorrhagic complications including cerebral vasospasm, chronic hydrocephalus, seizures, cerebral ischemia, delayed neurological deficits showed differential correlations with different post hemorrhagic complications (Table 1). Serum IL-23 and IL-17 levels did not correlate with clinical outcome. CONCLUSION:Serum IL-23 and IL-17 levels were elevated in patients with aSAH showing upregulation of IL-23/IL-17 inflammatory axis after aSAH. Serum IL-23 and IL-17 showed differential correlations with post hemorrhagic complications and no correlation with clinical outcome.

背景与目标： ：IL-23和IL-17是促炎性细胞因子。 IL-23由活化的巨噬细胞和树突状细胞分泌，而IL-17由Th17细胞分泌。已知血清IL-23和IL-17在包括神经退行性疾病在内的许多炎性疾病中均升高。血清IL-23和IL-17在动脉瘤性蛛网膜下腔出血（aSAH）中的作用尚未进行研究。本工作调查了aSAH患者的血清IL-23和IL-17水平及其与出血后并发症和临床结局的关系。
方法：在这项研究中，前瞻性招募了80例aSAH患者（Hunt和Hess I-V级）。我们招募了24名腰椎管狭窄的对照患者。在第1天和第7天从对照和aSAH患者中抽取外周静脉血，使其凝结并离心以获得血清。采用酶联免疫分析试剂盒，通过施加50µL血清样品定量IL-23和IL-17的血清水平。从患者的住院记录中前瞻性地记录了出血后并发症和临床结局。
结果：与对照组患者（n = 24）相比，aSAH患者在第1天和第7天的血清IL-23和IL-17水平显着升高（n = 80）。二分法对患有出血后并发症（包括脑血管痉挛，慢性脑积水，癫痫发作，脑缺血，迟发性神经功能缺损）的患者进行二分法手术后的进一步分析显示，不同出血后并发症的相关性不同（表1）。血清IL-23和IL-17水平与临床结果无关。
结论：aSAH患者血清IL-23和IL-17水平升高，显示aSAH后IL-23 / IL-17炎症轴上调。血清IL-23和IL-17与出血后并发症呈差异相关，与临床结局无相关性。

BACKGROUND & AIMS: :Pneumocystis pneumonia (PCP) incidence was decreased in renal transplant thanks to prophylaxis, recommended during the first months after transplantation. However, many late PCP cases are observed after the first 6 months and recommendations to maintain or reintroduce prophylaxis are lacking. The objective of the study was to identify risk factors to guide the individual prescription of prophylaxis, 6 months after transplantation. Thirty-three late PCP cases were identified between 1995 and 2012 in Lille Hospital, France, and were compared to 72 randomized controls transplant recipients. In univariate analysis, age of donor (>48 years), retransplantation, a decrease glomerular filtration rate (≤45 mL/min), induction therapy mediated by anti-thymocyte globulin (ATG), steroid maintenance, high calcineurin inhibitors (CNI) doses (tacrolimus ≥0.5 mg/kg/day and cyclosporine ≥2.1 mg/kg/day), and cytomegalovirus (CMV) infection were significantly associated with PCP. In multivariate analysis, ATG (hazard ratio [HR]: 2.4 [1.1-5.4]), steroid therapy (HR: 3.1 [1.20-7.84], CNI (HR: 2.9 [1.28-6.38], and CMV (HR: 6.1 [2.74-16.33] remained associated with late PCP. In conclusion, we confirm that intensive immunosuppressive regimen and CMV infection are critical risk factors for late PCP and should be taken into account to decide on maintenance or reintroduction of a prophylactic treatment.

背景与目标： ：由于预防，建议在移植后的头几个月内，减少肾脏移植中肺囊虫性肺炎（PCP）的发生率。但是，在头6个月后观察到许多晚期PCP病例，缺乏维持或重新引入预防措施的建议。该研究的目的是确定危险因素，以指导移植后6个月进行预防的个体处方。在1995年至2012年之间，法国里尔医院确定了33例晚期PCP病例，并将其与72名随机对照移植受者进行了比较。在单因素分析中，供体年龄（> 48岁），再移植，肾小球滤过率降低（≤45mL / min），抗胸腺细胞球蛋白（ATG）介导的诱导治疗，类固醇维持，钙调神经磷酸酶抑制剂（CNI）剂量高他克莫司≥0.5mg / kg /天，环孢菌素≥2.1mg / kg /天）和巨细胞病毒（CMV）感染与PCP显着相关。在多变量分析中，ATG（危险比[HR]：2.4 [1.1-5.4]），类固醇治疗（HR：3.1 [1.20-7.84]，CNI（HR：2.9 [1.28-6.38]）和CMV（HR：6.1 [ [2.74-16.33]仍与晚期PCP相关，总的来说，我们确认强化免疫抑制方案和CMV感染是晚期PCP的关键危险因素，应考虑维持或重新引入预防性治疗。

BACKGROUND & AIMS: :An effective immune response to antigen requires professional antigen-presenting cell (APC), which not only present antigen, but also provide costimulation and cytokines (eg, IL-12) that drive T cell differentiation down the appropriate effector pathway (Tc1/TH1). For T cell-based immunotherapy protocols, the availability of large numbers of autologous professional APC is a major limitation because professional APC do not proliferate in vitro. T cells themselves can proliferate exponentially in vitro and have the ability to present antigen. They can also express costimulatory molecules after activation. Therefore, we hypothesized that if activated T cells were genetically modified to express proinflammatory cytokines required to polarize T cells toward a Tc1 response, they could fulfill the requirements for an abundant, autologous APC. To test this potential, T cells were activated by CD3/CD28 antibodies and pulsed with model HLA-A2+ peptides derived from CMVpp65, MAGE-3, and MART-1. Activated T-APC readily reactivated CD8 pp65 memory T cells from healthy CMV seropositive donors; however, the activation of MAGE-3 and MART-1-specific CD8 T cells required both IL-7 and IL-12, which could be provided either exogenously or by genetic modification of the T-APC. Responder T cells could be expanded to large numbers with subsequent stimulations using activated, peptide-pulsed T-APC and IL-2. Tumor antigen-specific T cell lines killed both peptide-pulsed target cells and tumor cell lines. Thus, T cells provide a platform for the generation of autologous APC that can be customized to express both antigens and therapeutic molecules for the induction of antigen-specific T cell immunity.

背景与目标： ：对抗原的有效免疫反应需要专业的抗原呈递细胞（APC），它不仅呈递抗原，而且还提供共刺激和细胞因子（例如IL-12），以驱动T细胞向适当的效应子途径（Tc1 / TH1）分化）。对于基于T细胞的免疫疗法方案，大量的自体专业APC的可用性是一个主要限制，因为专业APC不会在体外增殖。 T细胞本身可以在体外成倍增殖，并具有呈递抗原的能力。它们还可以在激活后表达共刺激分子。因此，我们假设，如果对活化的T细胞进行基因修饰以表达使T细胞朝Tc1反应极化所需的促炎细胞因子，那么它们就可以满足丰富的自体APC的要求。为了测试这种潜力，T细胞被CD3 / CD28抗体激活，并用衍生自CMVpp65，MAGE-3和MART-1的模型HLA-A2肽脉冲。激活的T-APC可以很容易地激活来自健康CMV血清反应阳性供体的CD8 pp65记忆T细胞。然而，MAGE-3和MART-1特异性CD8 T细胞的激活需要IL-7和IL-12，这可以通过外源或通过T-APC的遗传修饰来提供。可以使用激活的，肽脉冲的T-APC和IL-2在随后的刺激下将应答剂T细胞扩增为大量。肿瘤抗原特异性T细胞系杀死了肽脉冲的靶细胞和肿瘤细胞系。因此，T细胞提供了用于产生自体APC的平台，该平台可以被定制以表达抗原和治疗性分子以诱导抗原特异性T细胞免疫。

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: 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: :Germinal centers (GCs) support high-affinity, long-lived humoral immunity. How memory B cells develop in GCs is not clear. Through the use of a cell-cycle-reporting system, we identified GC-derived memory precursor cells (GC-MP cells) that had quit cycling and reached G0 phase while in the GC, exhibited memory-associated phenotypes with signs of affinity maturation and localized toward the GC border. After being transferred into adoptive hosts, GC-MP cells reconstituted a secondary response like genuine memory B cells. GC-MP cells expressed the interleukin 9 (IL-9) receptor and responded to IL-9. Acute treatment with IL-9 or antibody to IL-9 accelerated or retarded the positioning of GC-MP cells toward the GC edge and exit from the GC, and enhanced or inhibited the development of memory B cells, which required B cell-intrinsic responsiveness to IL-9. Follicular helper T cells (TFH cells) produced IL-9, and deletion of IL-9 from T cells or, more specifically, from GC TFH cells led to impaired memory formation of B cells. Therefore, the GC development of memory B cells is promoted by TFH cell-derived IL-9.

背景与目标： ：生殖器中心（GC）支持高亲和力，长寿命的体液免疫。尚不清楚GC中记忆B细胞如何发育。通过使用细胞周期报告系统，我们确定了GC衍生的记忆前体细胞（GC-MP细胞）已经退出循环并达到G0期，而在GC中则表现出与记忆相关的表型，并伴有亲和力成熟和定位于GC边界。在被转移到过继宿主中之后，GC-MP细胞像真正的记忆B细胞一样重新构成了次级反应。 GC-MP细胞表达白介素9（IL-9）受体并对IL-9作出反应。用IL-9或IL-9抗体进行的急性治疗可加速或延迟GC-MP细胞向GC边缘定位并从GC退出，并增强或抑制记忆B细胞的发育，这需要B细胞内在的响应能力IL-9。卵泡辅助性T细胞（TFH细胞）产生IL-9，T细胞或更具体地从GC TFH细胞中删除IL-9导致B细胞记忆形成受损。因此，源自TFH细胞的IL-9促进了记忆B细胞的GC发育。

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。

BACKGROUND & AIMS: :A symmetric triazinone (toltrazuril) was tested in vivo against Glugea anomala parasitizing the connective tissue of sticklebacks (Gasterosteus aculeatus). Naturally infected sticklebacks were incubated in water containing 0, 5, 10 or 20 μg toltrazuril/ml or in pure solvent (4 ml/1000 ml water). In addition, treatment was done by intermittent therapy (6 × 5 or 20 μg/ml for 4 or 1 h, respectively, in two days intervals). After single treatment the drug caused significant damages on uni- or multinucleate meronts, sporogonial plasmodia, sporoblasts and immature spores. The damages mainly consisted in a decrease of the number of ribosomes, a reduction of the multinucleate meronts, a disturbance in the formation of the sporophorous vesicles, in general a lysis of the karyoplasm and malformations of the polaroplast. The extent of damages was correlated with the dose of the drug administered. After intermittent therapy the damages described above were intensified; the multinucleate meronts and the sporogonial plasmodia then disappeared. However, even by intermittent treatment the mature spores were not affected. It is suggested that chemotherapy of Glugea - infected fishes may be accomplished by bathing the fishes in separate, aerated containers by means of interval treatment (six times with 5 or 20 μg toltrazuril/ml for 4 h, respectively 1 h in two days intervals). The treatment will decrease considerably the output of spores. However, since the mature spores are not affected, a repetition of the interval treatment within several months is recommended. Fish with extended skin lesions, caused by net catching, or infections by fungi should be carefully observed during the treatment, because these factors decrease their drug tolerance.

背景与目标： ：在体内测试了一种对称的三嗪酮（托曲唑），可防止寄生于stick背结缔组织（Gasterosteus aculeatus）的异食性谷胱甘肽（Glugea anomala）。将自然感染的棘背s在含有0、5、10或20μg托曲唑/ ml的水中或在纯溶剂（4 ml / 1000 ml水）中孵育。另外，通过间歇治疗进行治疗（间隔2天，分别为6×5或20μg/ ml，持续4或1 h）。单次治疗后，该药物对单核或多核鱼肉，孢子虫，疟原虫，孢子母细胞和未成熟孢子造成了严重损害。损害主要包括核糖体数量的减少，多核鱼的减少，孢子囊的形成受到干扰，通常是核质的溶解和原生质体的畸形。损害程度与所用药物的剂量有关。间歇治疗后，上述损害加剧。然后，多核鱼肉和孢子虫病消失了。但是，即使通过间歇性处理，成熟孢子也不会受到影响。建议对格鲁吉亚（Glugea）感染的鱼进行化学疗法，方法是通过间隔治疗将鱼分别浸在充气的容器中来进行（6次，分别以5或20μg托曲唑/ ml连续4 h，每两天间​​隔1 h） 。这种处理将大大降低孢子的产量。但是，由于成熟孢子不受影响，建议在几个月内重复间隔治疗。在治疗过程中应仔细观察因网捕或真菌感染而导致皮肤病变扩展的鱼类，因为这些因素会降低其药物耐受性。

BACKGROUND & AIMS: :hCAP-18/LL-37 is an antimicrobial peptide that is mainly expressed in epithelial cells. Gingival epithelial cells play pivotal roles in antimicrobial defense by expressing hCAP-18/LL-37. Porphyromonas gingivalis is a primary pathogen for chronic periodontitis and produces cysteine proteinase gingipains, which induce proinflammatory cytokines production, leading to enhance inflammatory responses. In contrast, gingipains attenuate immune responses, leading to induce anti-inflammatory responses. In this study, we investigated the ability of gingipains to attenuate P. gingivalis-induced hCAP-18/LL-37 production by human gingival epithelial Ca9-22 cells. The expression of LL-37 mRNA was increased by the infection of Ca9-22 cells with a P. gingivalis gingipains-null mutant KDP136 compared with P. gingivalis wild-type strain ATCC 33277. Interleukin (IL)-33 is involved in the development of chronic inflammatory diseases, and P. gingivalis infection increases IL-33 production by human gingival epithelial cells. P. gingivalis-induced LL-37 mRNA expression was augmented in IL-33 small interfering RNA-transfected Ca9-22 cells. Maxacalcitol (22-oxacalcitriol: OCT) is a biologically active metabolite of vitamin D3 analog, and OCT increases hCAP-18/LL-37 production by human gingival epithelial cells. The increasing expression of LL-37 mRNA by OCT was down-regulated by infection of the cells with P. gingivalis ATCC 33277 in Ca9-22 cells. Furthermore, P. gingivalis infection induced IL-33 mRNA expression in Ca9-22 cells; therefore, P. gingivalis-induced endogenous IL-33 down-regulated hCAP-18/LL-37 production by the bacterium. These findings suggested that endogenous IL-33 down-regulates the induction of hCAP-18/LL-37 production in human gingival epithelial cells.

背景与目标： ：hCAP-18 / LL-37是一种抗菌肽，主要在上皮细胞中表达。牙龈上皮细胞通过表达hCAP-18 / LL-37在抗菌防御中起关键作用。牙龈卟啉单胞菌是慢性牙周炎的主要病原体，并产生半胱氨酸蛋白酶齿龈蛋白酶，从而诱导促炎细胞因子的产生，从而增强炎症反应。相反，姜黄素减弱免疫反应，导致诱导抗炎反应。在这项研究中，我们调查了牙龈蛋白酶减弱人牙龈上皮Ca9-22细胞对牙龈卟啉单胞菌诱导的hCAP-18 / LL-37产生的能力。与齿龈假单胞菌野生型菌株ATCC 33277相比，齿龈假单胞菌齿龈蛋白酶空突变体KDP136感染Ca9-22细胞可增加LL-37 mRNA的表达。白介素（IL）-33参与了发育慢性炎症性疾病和牙龈卟啉单胞菌感染会增加人牙龈上皮细胞产生IL-33的数量。在IL-33小干扰RNA转染的Ca9-22细胞中，牙龈卟啉单胞菌诱导的LL-37 mRNA表达增加。 Maxacalcitol（22-oxacalcitriol：OCT）是维生素D3类似物的生物活性代谢产物，OCT可增加人牙龈上皮细胞产生的hCAP-18 / LL-37。通过OCT LL-37 mRNA的表达增加被Ca9-22细胞中牙龈卟啉单胞菌ATCC 33277感染的细胞下调。此外，牙龈卟啉单胞菌感染诱导Ca9-22细胞中IL-33 mRNA表达。因此，牙龈卟啉单胞菌诱导的内源性IL-33下调了细菌的hCAP-18 / LL-37产生。这些发现表明内源性IL-33下调人牙龈上皮细胞中hCAP-18 / LL-37产生的诱导。