BACKGROUND & AIMS: BACKGROUND:Meta-analyses enable summarization and interpretation of data across clinical trials. When applied to safety data they allow for detection of rare events. Recently, a 13-valent pneumococcal conjugate vaccine (PCV13) was approved in multiple countries worldwide for routine immunization of infants and young children. This meta-analysis was conducted to identify potentially clinically important rare safety events associated with PCV13. OBJECTIVE:To summarize the safety of PCV13 compared with 7-valent pneumococcal conjugate vaccine (PCV7) administered to infants and toddlers. METHODS:A meta-analysis was performed of integrated safety data from 13 infant studies (PCV13 n=4729 and PCV7 n=2760) conducted in 9 North American, European, and Asian countries. Local reactions at the vaccine injection site and systemic events were collected for 4-7 days after each dose into electronic diaries. Adverse events (AEs) were collected after each vaccination. RESULTS:Overall, rates of local reactions after any dose of the infant series were similar between PCV13 and PCV7 groups: tenderness (46.7% vs 44.8%, respectively); swelling (28.5% vs 26.9%); and redness (36.4% vs 33.9%). After the toddler dose, tenderness was significantly higher among PCV7 subjects than PCV13 subjects (54.4% vs 48.8%; P=0.005). Frequencies of fever (≥38°C) were similar in both groups and mostly mild (≤39°C); incidence of moderate fever (>39°C to ≤40°C) with PCV13 was ≤2.8% after any infant dose and 5.0% after the toddler dose, compared with ≤2.6% and 7.3%, respectively, with PCV7. Fever >40°C was uncommon in both groups. Frequencies of decreased appetite, irritability, and sleep disturbances were similar in both groups. AEs were the types of conditions and symptoms expected in infants and children, and clinically significant differences between vaccine groups were not observed. CONCLUSION:PCV13 has a favorable safety profile similar to that of PCV7, a vaccine for which there is >10 years clinical experience.

背景与目标： 背景：元分析可以汇总和解释整个临床试验中的数据。当应用于安全数据时，它们允许检测罕见事件。最近，一种13价肺炎球菌结合疫苗（PCV13）已在全球多个国家/地区批准用于婴儿和幼儿的常规免疫。进行了这项荟萃分析，以鉴定与PCV13相关的潜在的临床重要罕见安全事件。
目的：总结与婴幼儿使用的7价肺炎球菌结合疫苗（PCV7）相比，PCV13的安全性。
方法：对9个北美，欧洲和亚洲国家进行的13项婴儿研究（PCV13 n = 4729和PCV7 n = 2760）的综合安全性数据进行了荟萃分析。每次注射疫苗后4-7天，将疫苗注射部位的局部反应和全身性事件收集到电子日记中。每次疫苗接种后收集不良事件（AE）。
结果：总的来说，在PCV13和PCV7组中，任何剂量的婴儿系列后的局部反应率相似：压痛（分别为46.7％和44.8％）；肿胀（28.5％对26.9％）;和发红（36.4％比33.9％）。幼儿服药后，PCV7受试者的压痛明显高于PCV13受试者（54.4％比48.8％； P = 0.005）。两组的发烧频率（≥38°C）相似，且多数为轻度（≤39°C）。在任何婴儿剂量下，PCV13发生中度发烧（> 39°C到≤40°C）的发生率≤2.8％，在幼儿剂量后为5.0％，而PCV7分别为≤2.6％和7.3％。两组中发烧> 40°C的情况很少见。两组食欲减退，烦躁不安和睡眠障碍的频率相似。不良事件是婴儿和儿童中预期的疾病和症状类型，未观察到疫苗组之间的临床显着差异。
结论：PCV13具有与PCV7类似的良好安全性，后者具有10年以上的临床经验。

BACKGROUND & AIMS: :Cellular-FLICE inhibitory protein (c-FLIP) is an inhibitor of apoptosis downstream of the death receptors Fas, DR4, and DR5, and is expressed as long (c-FLIP(L)) and short (c-FLIP(S)) splice forms. We found that the knockdown of c-FLIP using small interfering RNA (siRNA) triggered ligand-independent caspase-8- and -9-dependent spontaneous apoptosis and decreased the proliferation of MCF-7 breast cancer cells. Further analysis revealed that an apoptotic inhibitory complex (AIC) comprised of DR5, FADD, caspase-8, and c-FLIP(L) exists in MCF-7 cells, and the absence of c-FLIP(L) from this complex induces DR5- and FADD-mediated caspase-8 activation in the death inducing signaling complex (DISC). c-FLIP(S) was not detected in the AIC, and using splice form-specific siRNAs we showed that c-FLIP(L) but not c-FLIP(S) is required to prevent spontaneous death signaling in MCF-7 cells. These results clearly show that c-FLIP(L) prevents ligand-independent death signaling and provides direct support for studying c-FLIP as a relevant therapeutic target for breast cancers.

背景与目标： ：细胞FLICE抑制蛋白（c-FLIP）是死亡受体Fas，DR4和DR5下游的凋亡抑制剂，表达为长（c-FLIP（L））和短（c-FLIP（S） ）拼接形式。我们发现使用小干扰RNA（siRNA）敲低c-FLIP会触发不依赖配体的caspase-8和-9依赖性自发凋亡，并降低MCF-7乳腺癌细胞的增殖。进一步的分析表明，MCF-7细胞中存在由DR5，FADD，caspase-8和c-FLIP（L）组成的凋亡抑制复合物（AIC），并且该复合物中不存在c-FLIP（L）会诱导DR5。 -和FADD介导的caspase-8激活在死亡诱导信号复合物（DISC）中。在AIC中未检测到c-FLIP（S），使用剪接形式特异性siRNA，我们发现c-FLIP（L）而非c-FLIP（S）是防止MCF-7细胞自发死亡信号所必需的。这些结果清楚地表明，c-FLIP（L）可以防止配体依赖性死亡信号传导，并为研究c-FLIP作为乳腺癌的相关治疗靶标提供了直接支持。

BACKGROUND & AIMS: :The mammalian matrix metalloproteinase-9 (MMP-9), which might play a role in ovulation, uterus remodeling, embryo development, and implantation in mammals, is one of the potential functional candidate genes for porcine reproductive traits. In this study, the entire genomic sequence of porcine MMP-9 (pMMP-9) gene was established; it contains 13 exons and 12 introns. Real-time PCR analysis revealed that pMMP-9 is highly expressed in the Minzhu uterus before puberty and decreases significantly after sexual maturity (p < 0.05). Two single-nucleotide polymorphisms (A3011G and T5079C) that can be detected by PCR restriction fragment length polymorphism (PCR-RFLP) were discovered and tested for statistical associations with litter size traits in a crossbred population (Line DIV) derived from Landrace, Large White, Chinese Tongcheng and/or Chinese Meishan pigs. For A3011G, the GG genotype was associated with a significantly higher (p < 0.05) number of live births than those recorded for AA sows and the additive effect was significant (p < 0.05). The T5079C marker is not associated with litter size in this population. Further studies are needed to confirm the results of this study.

背景与目标： ：哺乳动物基质金属蛋白酶9（MMP-9），可能在排卵，子宫重塑，胚胎发育和哺乳动物的植入中起作用，是猪繁殖性状的潜在功能候选基因之一。在这项研究中，建立了猪MMP-9（pMMP-9）基因的完整基因组序列。它包含13个外显子和12个内含子。实时PCR分析显示，pMMP-9在青春期前的zhu竹子宫中高表达，在性成熟后明显降低（p <0.05）。发现了两个可以通过PCR限制性片段长度多态性（PCR-RFLP）检测到的单核苷酸多态性（A3011G和T5079C）并测试了来自长白大白杂交种（Line DIV）与杂种大小性状的统计关联，中国桐城猪和/或中国眉山猪。对于A3011G，GG基因型的活产数显着高于（AA）母猪记录的活产数（p <0.05），累加效应显着（p <0.05）。 T5079C标记与该种群中的产仔数无关。需要进一步的研究以确认这项研究的结果。

BACKGROUND & AIMS: :The structural and functional analyses of heterochromatin are essential to understanding how heterochromatic genes are regulated and how centromeric chromatin is formed. Because the repetitive nature of heterochromatin hampers its genome analysis, new approaches need to be developed. Here, we describe how, in double mutants for Su(var)3-9 and SuUR genes encoding two structural proteins of heterochromatin, new banded heterochromatic segments appear in all polytene chromosomes due to the strong suppression of under-replication in pericentric regions. FISH on salivary gland polytene chromosomes from these double mutant larvae allows high resolution of heterochromatin mapping. In addition, immunostaining experiments with a set of antibodies against euchromatic and heterochromatic proteins reveal their unusual combinations in the newly appeared segments: binding patterns for HP1 and HP2 are coincident, but both are distinct from H3diMetK9 and H4triMetK20. In several regions, partial overlapping staining is observed for the proteins characteristic of active chromatin RNA Pol II, H3triMetK4, Z4, and JIL1, the boundary protein BEAF, and the heterochromatin-enriched proteins HP1, HP2, and SU(VAR)3-7. The exact cytological position of the centromere of chromosome 3 was visualized on salivary gland polytene chromosomes by using the centromeric dodeca satellite and the centromeric protein CID. This region is enriched in H3diMetK9 and H4triMetK20 but is devoid of other proteins analyzed.

背景与目标： ：异染色质的结构和功能分析对于了解异色基因如何调控以及着丝粒染色质如何形成至关重要。由于异染色质的重复性质妨碍了其基因组分析，因此需要开发新的方法。在这里，我们描述了如何在Su（var）3-9和SuUR基因的双突变体中编码异染色质的两个结构蛋白，新条带化的异色片段由于强烈抑制外周中心区域的复制不足而在所有多烯染色体中出现。这些双突变幼虫在唾液腺多态染色体上的FISH可以实现高分辨率的异染色质定位。此外，使用针对常染色体和异源蛋白质的抗体的免疫染色实验在新出现的片段中揭示了它们的不寻常组合：HP1和HP2的结合模式是重合的，但两者均不同于H3diMetK9和H4triMetK20。在几个区域中，观察到活性染色质RNA Pol II，H3triMetK4，Z4和JIL1，边界蛋白BEAF和富含异染色质的蛋白HP1，HP2和SU（VAR）3-7的蛋白具有部分重叠染色。 。通过使用着丝粒十二指肠卫星和着丝粒蛋白CID，在唾液腺多烯染色体上可以看到3号染色体着丝粒的确切细胞学位置。该区域富含H3diMetK9和H4triMetK20，但没有其他被分析的蛋白质。

BACKGROUND & AIMS: Background:Childhood non-vaccination can have different short-and long-term negative outcomes on their health. In Ethiopia, in addition to low coverage of full vaccination, street children were among the neglected part of the community who were missed during planning and reporting vaccination coverage. Moreover, there is no related research conducted on this title specifically. Objective:The objective of the study was to assess the vaccination status and its associated factors among street children 9-24 months old in Sidama zone. Methods:Community-based cross-sectional study design was conducted in four selected towns of Sidama region, southern Ethiopia. The convenience sampling method was applied to involve mothers of street children younger than two years during the study period. Data entry was done with EpiData version 3.1 and exported to SPSS22 for analysis. Bivariate and multivariable logistic regression analysis were performed to identify factors associated with immunization status of street children. Results:A significant number (26 [24.3%]) of the street children younger than two years were not vaccinated. Those mothers who are ≤20 years old (P = 0.014, AOR = 0.216, 95% CI: 0.064-0.732) and who gave birth at home (P = 0.029, AOR = 0.292, 95% CI: 0.097-0.879) had less odds of vaccinating their child than those older than 20 and who gave birth at health facility respectively. Conclusion:A significant number of the street children in this study are not fully vaccinated. Mothers aged <20 years and home births were significantly associated with non-vaccination status.

背景与目标： 背景：儿童未接种疫苗可能会对他们的健康产生不同的短期和长期负面影响。在埃塞俄比亚，除了全面接种疫苗的覆盖率低外，流浪儿童是社区中被忽略的一部分，在计划和报告接种疫苗覆盖率时被遗漏了。而且，还没有对此标题进行专门的相关研究。
目的：本研究的目的是评估西达玛州9-24个月大的街头儿童的疫苗接种状况及其相关因素。
方法：在埃塞俄比亚南部锡达玛地区的四个选定城镇中进行了基于社区的横断面研究设计。在研究期间，便利抽样方法被用于涉及不到两岁的流浪儿童的母亲。数据输入使用EpiData 3.1版完成，并导出到SPSS22进行分析。进行了双变量和多变量logistic回归分析，以确定与流浪儿童免疫状况相关的因素。
结果：相当多（26 [24.3％]）岁以下的街头儿童未接种疫苗。 ≤20岁（P = 0.014，AOR = 0.216，95％CI：0.064-0.732）且在家分娩（P = 0.029，AOR = 0.292，95％CI：0.097-0.879）的母亲较少给他们的孩子接种疫苗的几率分别高于20岁和在卫生机构分娩的孩子。
结论：本研究中有相当数量的流浪儿童没有完全接种疫苗。年龄小于20岁的母亲和家庭生育与非疫苗接种状态显着相关。

BACKGROUND & AIMS: BACKGROUND:The balance between proteinases and antiproteinases plays an important role in tissue destruction and remodelling. In chronic obstructive pulmonary disease (COPD) and emphysema, an imbalance between matrix metalloproteinases (MMPs) and inhibitors of tissue metalloproteinase (TIMPs) has been reported. Alveolar macrophages are considered to be the main source of MMPs. We therefore have analyzed the effects of free and liposomal all trans-retinoic acid (ATRA) on the expression of MMP-9 and TIMP-1 in bronchoalveolar lavage (BAL) cells from patients with COPD and patients with other lung diseases. MATERIAL AND METHODS:BAL cells were incubated 1-3 day with either liposomal or free ATRA. Supernatants were tested for MMP-9 and TIMP-1 protein in specific ELISA systems; mRNA analysis was performed by semi-quantitative RT-PCR and by quantitative LightCycler PCR. RESULTS:We demonstrate that either liposomal or free ATRA selectively down-regulates MMP-9 and up-regulates TIMP-1. At the protein level, MMP-9 is decreased 3-fold and TIMP-1 is increased 3.5-fold compared to the base line with empty liposomes or untreated cells. The ratio of MMP-9 and its inhibitor TIMP-1, which may be crucial to the overall proteolytic potential decreased by factor 8. That this countercurrent effect of ATRA is not due to an altered protein stability but to transcriptional regulation could be demonstrated by RT-PCR. Quantitative LightCycler analysis revealed a 2.5-fold decrease of MMP-9 mRNA and a 4.5 fold increase of TIMP- 1 mRNA. CONCLUSIONS:These data suggest that ATRA treatment via its impact on the proteinase/antiproteinase ratio may become a new therapeutic strategy for patients with inflammatory destructive lung diseases.

背景与目标： 背景：蛋白酶和抗蛋白酶之间的平衡在组织破坏和重塑中起着重要作用。在慢性阻塞性肺疾病（COPD）和肺气肿中，基质金属蛋白酶（MMPs）和组织金属蛋白酶抑制剂（TIMPs）之间存在失衡的报道。肺泡巨噬细胞被认为是MMP的主要来源。因此，我们分析了游离和脂质体全反式维甲酸对COPD患者和其他肺部疾病患者支气管肺泡灌洗（BAL）细胞中MMP-9和TIMP-1表达的影响。
材料与方法：将BAL细胞与脂质体或游离ATRA孵育1-3天。在特定的ELISA系统中检测上清液中的MMP-9和TIMP-1蛋白。通过半定量RT-PCR和定量LightCycler PCR进行mRNA分析。
结果：我们证明脂质体或游离ATRA选择性下调MMP-9和上调TIMP-1。与空脂质体或未经处理的细胞相比，在蛋白质水平上，MMP-9降低了3倍，TIMP-1升高了3.5倍。 MMP-9及其抑制剂TIMP-1的比例可能对总蛋白水解潜力至关重要，降低了8倍。ATRA的这种逆流作用不是由于蛋白质稳定性的改变，而是转录调控，可以通过RT证实。 -PCR。定量LightCycler分析显示MMP-9 mRNA下降了2.5倍，TIMP-1 mRNA上升了4.5倍。
结论：这些数据表明，通过对蛋白酶/抗蛋白酶比率的影响，ATRA治疗可能成为炎性破坏性肺疾病患者的一种新的治疗策略。

BACKGROUND & AIMS: :The multidrug resistant cell line DC-3F/ADII was obtained by stepwise selection for growth in actinomycin D (ActD). Compared with parental cells, it displays high resistance to ActD and vincristine and low resistance to colchicine and daunorubicin. These cells overexpress a form of P-glycoprotein (Pgp1) containing a double mutation, I837L and N839I, in transmembrane domain (TM) 9; when transfected into DC-3F, this mutation confers the DC-3F/ADII phenotype. We have shown previously that another cell line, DC-3F/ADX, also displays this phenotype and overexpresses a mutant form of Pgp1 containing a double mutation in TM6 (G338A, A339P). Hence, mutations in TM9 and TM6 are independently capable of conferring the same cross-resistance phenotype. The TM6 mutations inhibit the ability of cyclosporin A to reverse cross-resistance and to block labeling of the protein by [125I]iodoarylazidoprazosin (IAAP), whereas the TM9 mutations do not show similar effects. A chimeric protein containing both pairs of mutations confers twice the level of resistance to ActD than expected from the sum of the individual mutations, but it cannot be labeled to detectable levels with [125I]IAAP. Thus, TM9 represents a novel site that cooperates with TM6 to mediate drug resistance and [125I]IAAP labeling.

背景与目标： ：通过逐步选择放线菌素D（ActD）中的生长获得多药耐药细胞系DC-3F / ADII。与亲代细胞相比，它对ActD和长春新碱具有较高的抵抗力，而对秋水仙碱和柔红霉素的抵抗力则较低。这些细胞过表达一种P-糖蛋白（Pgp1），该蛋白在跨膜结构域（TM）9中包含一个双突变，即I837L和N839I。当转染至DC-3F时，此突变赋予DC-3F / ADII表型。先前我们已经证明，另一种细胞系DC-3F / ADX也显示此表型，并过表达Pgp1的突变形式，该突变形式包含TM6中的双重突变（G338A，A339P）。因此，TM9和TM6中的突变能够独立赋予相同的交叉抗性表型。 TM6突变抑制环孢菌素A反向交叉耐药性并阻止[125I]碘代芳基叠氮吡唑嗪（IAAP）标记蛋白质的能力，而TM9突变没有显示出相似的作用。包含两对突变的嵌合蛋白对ActD的抗性水平要比单个突变的总和预期的抗性水平高一倍，但无法用[125I] IAAP标记为可检测水平。因此，TM9代表一个与TM6协同介导耐药性和[125I] IAAP标记的新位点。

BACKGROUND & AIMS: BACKGROUND:IL-9 is an important cytokine in allergic diseases such as asthma, atopic dermatitis, etc. T helper (Th) cells seem to be the main source of IL-9. Cellular and molecular mechanisms of IL-9 production by human Th cells have been poorly understood. METHODS:Dermatophagoides farinae(Der f)-specific Th clones were established from peripheral blood lymphocytes of atopic asthmatics, and cytokine synthesis in response to various stimuli was determined by specific ELISAs. RESULTS:IL-9 was produced by 14 of 27 human Th clones upon T cell receptor (TCR) stimulation, immobilized anti-CD3 antibody (Ab). IL-9 production was significantly enhanced by the addition of anti-CD28 Ab into the culture, indicating the role of costimulatory signal on IL-9 synthesis. Pharmacologically, IL-9 production was induced by ionomycin (IOM) alone, and enhanced by phorbol 12-myristate 13-acetate (PMA). rIL-2 induced IL-9 production by 8 out of 19 Th clones. IL-9 production by Th clones stimulated with immobilized anti-CD3 Ab was significantly suppressed by the addition of anti-IL-2 neutralizing Ab into the culture. CONCLUSION:Approximately half of the Der f-specific Th clones derived from atopic asthmatics produced IL-9 upon TCR stimulation. Ca(2+) signal, CD28 signal, and IL-2 receptor signal seem to play important roles in IL-9 production by human Th cells. Moreover, synthesis of IL-9, a Th2 cytokine, is dependent on IL-2, a Th1 cytokine, which is produced by Th cells themselves.

背景与目标： 背景：IL-9在过敏性疾病（例如哮喘，特应性皮炎等）中是重要的细胞因子。T辅助（Th）细胞似乎是IL-9的主要来源。人们对人Th细胞产生IL-9的细胞和分子机制了解甚少。
方法：从特应性哮喘患者外周血淋巴细胞中建立特异的Dermatophagoides farinae（Der f）Th克隆，并通过特异性ELISA法测定响应各种刺激的细胞因子合成。
结果：IL-9由27个人类Th克隆中的14个在T细胞受体（TCR）刺激下产生，并固定了抗CD3抗体（Ab）。向培养物中添加抗CD28 Ab可显着增强IL-9的产生，表明共刺激信号对IL-9合成的作用。在药理上，IL-9的产生仅由离子霉素（IOM）诱导，并由佛波12-肉豆蔻酸酯13-乙酸酯（PMA）增强。 rIL-2诱导19个克隆中的8个产生IL-9。通过向培养物中添加抗IL-2中和抗体，显着抑制了由固定化抗CD3 Ab刺激的Th克隆产生的IL-9。
结论：来自特应性哮喘的Der f-特异性Th克隆约有一半在TCR刺激下产生IL-9。 Ca（2）信号，CD28信号和IL-2受体信号似乎在人类Th细胞产生IL-9中起重要作用。此外，IL-9（Th2细胞因子）的合成依赖于Th-2细胞本身产生的IL-2（Th1细胞因子）。

BACKGROUND & AIMS: :Early detection of polyps or colorectal carcinoma can reduce colorectal carcinoma-associated deaths. Previous studies have demonstrated raised serum levels of matrix metalloproteinase 9 (sMMP-9) in a range of cancers. The aim of this study was to investigate the role of sMMP-9 levels in identifying colorectal neoplasia. Consenting patients donated a blood sample and were assessed by proforma-led history and physical examination. Samples were analysed for sMMP-9 concentration (enzyme-linked immuno-sorbant assay) and compared to final diagnoses. Logistic regression modelling determined independent factors associated with neoplasia. A total of 365 patients were recruited of whom 300 were analysed, including 46 normal controls. A total of 27 significant adenomas and 63 malignancies were identified. The median sMMP-9 concentration was 443 ng ml(-1) (IQR: 219-782; mean: 546). Patients with neoplasia had significantly elevated sMMP-9 levels (P<0.001). Logistic regression modelling identified elevated log(sMMP-9) as the most significant predictor of neoplasia (chi(2)=38.33, P<0.001). Other significant factors were age, sex, smoking history, abdominal pain and weight loss. The model accurately predicted neoplasia in 77.3% of cases. Sensitivity and specificity were 77.9 and 77.1%. sMMP-9 estimation can accurately stratify patient to low- or high-risk cohorts. Serum sampling is a potential means of avoiding unnecessary colonoscopy and reducing patient anxiety, iatrogenic morbidity and mortality, and cost.

背景与目标： ：及早发现息肉或大肠癌可以减少与大肠癌相关的死亡。先前的研究表明，在多种癌症中血清基质金属蛋白酶9（sMMP-9）的血清水平升高。这项研究的目的是调查sMMP-9水平在鉴定结直肠肿瘤中的作用。同意的患者捐赠了血液样本，并通过形式记录的病史和体格检查进行了评估。分析样品的sMMP-9浓度（酶联免疫吸附测定），并与最终诊断结果进行比较。 Logistic回归模型确定了与瘤形成相关的独立因素。总共招募了365位患者，其中300位被分析，包括46位正常对照。总共鉴定出27个重要的腺瘤和63个恶性肿瘤。 sMMP-9的中位数浓度为443 ng ml（-1）（IQR：219-782;平均值：546）。瘤形成患者的sMMP-9水平显着升高（P <0.001）。 Logistic回归模型确定升高的log（sMMP-9）是瘤形成的最重要预测因子（chi（2）= 38.33，P <0.001）。其他重要因素是年龄，性别，吸烟史，腹痛和体重减轻。该模型在77.3％的病例中可以准确预测肿瘤。敏感性和特异性分别为77.9％和77.1％。 sMMP-9评估可以将患者分为低危或高危人群。血清采样是避免不必要的结肠镜检查并减少患者焦虑，医源性发病率和死亡率以及成本的潜在手段。

BACKGROUND & AIMS: :Congo red (CR) is a commonly used histological amyloid dye and a weak amyloid inhibitor. There is currently no experimentally available structure of CR bound to an amyloid fibril and the binding modes, and the mechanisms governing its inhibitory and optical properties are poorly understood. In this work, we present the first, to our knowledge, atomistically detailed picture of CR binding to protofibrils of the Alzheimer Aβ(9-40) peptide. We identify three major binding modes, with the primary mode residing in the grooves formed by the β-sheets, and observe a restriction of the torsional rotation of the CR molecule upon binding. Our simulations reveal a novel, to our knowledge, electrostatic steering mechanism that plays an important role in the initial recognition and binding of CR to the positively charged surface residues of the fibril. Our simulations provide new, to our knowledge, insights into the striking spectrophotometric and inhibitory properties of CR. In particular, we show that birefringence upon CR binding is due to the anisotropic orientation of the CR dipoles resulting from the spatial ordering of these molecules in the grooves along the fibril axis. The fluorescent enhancement of the bound CR, in turn, is associated with the torsional restriction of this molecule upon binding.

背景与目标： 刚果红（CR）是常用的组织学淀粉样蛋白染料和弱淀粉样蛋白抑制剂。目前尚没有实验上可得到的与淀粉样蛋白原纤维结合的CR结构和结合方式，而对其抑制和光学性质的控制机理知之甚少。在这项工作中，据我们所知，我们首次呈现了与阿尔茨海默病Aβ（9-40）肽原纤维结合的CR的原子学详细图片。我们确定了三种主要的结合模式，主要模式驻留在由β-折叠形成的凹槽中，并观察到结合后CR分子扭转旋转的限制。我们的模拟揭示了一种据我们所知的新型静电操纵机制，该机制在CR的初次识别和与原纤维表面带正电荷的残基的结合中起着重要作用。据我们所知，模拟为CR的惊人的分光光度法和抑制性质提供了新的见解。特别地，我们表明，CR结合的双折射归因于CR偶极子的各向异性取向，这是由于这些分子在沿原纤维轴的凹槽中的空间顺序所致。结合的CR的荧光增强又与该分子在结合时的扭转限制有关。

BACKGROUND & AIMS: :Wet deposition of nitrogen (N) occurs in oxidized (nitrate) and reduced (ammonium) forms. Whether one form drives vegetation change more than the other is widely debated, as field evidence has been lacking. We are manipulating N form in wet deposition to an ombrotrophic bog, Whim (Scottish Borders), and here report nine years of results. Ammonium and nitrate were provided in rainwater spray as NH4 Cl or NaNO3 at 8, 24 or 56 kg N ha(-1)  yr(-1) , plus a rainwater only control, via an automated system coupled to site meteorology. Detrimental N effects were observed in sensitive nonvascular plant species, with higher cumulative N loads leading to more damage at lower annual doses. Cover responses to N addition, both in relation to form and dose, were species specific and mostly dependent on N dose. Some species were generally indifferent to N form and dose, while others were dose sensitive. Calluna vulgaris showed a preference for higher N doses as ammonium N and Hypnum jutlandicum for nitrate N. However, after 9 years, the magnitude of change from wet deposited N on overall species cover is small, indicating only a slow decline in key species. Nitrogen treatment effects on soil N availability were likewise small and rarely correlated with species cover. Ammonium caused most N accumulation and damage to sensitive species at lower N loads, but toxic effects also occurred with nitrate. However, because different species respond differently to N form, setting of ecosystem level critical loads by N form is challenging. We recommend implementing the lowest value of the critical load range where communities include sensitive nonvascular plants and where ammonium dominates wet deposition chemistry. In the context of parallel assessment at the same site, N treatments for wet deposition showed overall much smaller effects than corresponding inputs of dry deposition as ammonia.

背景与目标： ：氮（N）的湿沉积以氧化（硝酸盐）和还原（铵）形式发生。由于缺乏实地证据，一种形式是否比其他形式更能驱动植被变化。我们正在将N形态以湿沉降的形式运用于营养养生的沼泽Whim（苏格兰边界），这里报告了9年的研究结果。通过耦合到现场气象的自动化系统，在雨水喷雾中以8、24或56 kg N·ha（-1）yr（-1）的铵盐和硝酸盐的形式提供NH4 Cl或NaNO3，加上仅雨水的控制。在敏感的非维管植物物种中观察到有害的氮素影响，较高的累积氮素负荷在较低的年剂量下导致更多的伤害。对氮添加的覆盖响应，无论是形式还是剂量，都是物种特异性的，并且主要取决于氮的剂量。一些物种通常对氮的形式和剂量无动于衷，而另一些则对剂量敏感。寻常的愈伤组织表现出较高的N剂量的偏好，如铵态氮和金丝桃属植物对硝酸盐N的偏好。然而，在9年后，湿法沉积氮在整个物种覆盖率上的变化幅度很小，表明关键物种仅缓慢下降。氮处理对土壤氮素利用率的影响同样很小，很少与物种覆盖率相关。在较低的氮负荷下，铵会引起大部分氮的积累和对敏感物种的破坏，但是硝酸盐也会产生毒性作用。但是，由于不同物种对N形态的反应不同，因此以N形态设定生态系统水平的临界负荷具有挑战性。我们建议在社区包括敏感的非维管植物以及铵在湿法沉积化学中占主导地位的情况下，将临界负荷范围的最小值设为最低值。在同一地点进行并行评估的情况下，与湿法沉积相应的氨投入相比，湿法沉积的N处理总体效果要小得多。

BACKGROUND & AIMS: :The Drosophila suppressor of position-effect variegation Su(var)3-9 encodes a heterochromatin-associated protein that is evolutionarily conserved. In contrast to its yeast and mammalian orthologs, the Drosophila Su(var)3-9 gene is fused with the locus encoding the gamma subunit of translation initiation factor eIF2. Synthesis of the two unrelated proteins is resolved by alternative splicing. A similar dicistronic Su(var)3-9/eIF-2gamma transcription unit was found in Clytus arietis, Leptinotarsa decemlineata, and Scoliopterix libatrix, representing two different orders of holometabolic insects (Coleoptera and Lepidoptera). In all these species the N terminus of the eIF-2gamma, which is encoded by the first two exons, is fused to SU(VAR)3-9. In contrast to Drosophila melanogaster, RT-PCR analysis in the two coleopteran and the lepidopteran species demonstrated the usage of a nonconserved splice donor site located within the 3' end of the SU(VAR)3-9 ORF, resulting in removal of the Su(var)3-9-specific stop codon from the mRNA and complete in-frame fusion of the SU(VAR)3-9 and eIF-2gamma ORFs. In the centipede Lithobius forficatus eIF-2gamma and Su(var)3-9 are unconnected. Conservation of the dicistronic Su(var)3-9/eIF-2gamma transcription unit in the studied insects indicates its origin before radiation of holometabolic insects and represents a useful tool for molecular phylogenetic analysis in arthropods.

背景与目标： ：果蝇位置效应杂色抑制素Su（var）3-9编码的一种异染色质相关蛋白在进化上是保守的。与它的酵母和哺乳动物直系同源物相反，果蝇Su（var）3-9基因与编码翻译起始因子eIF2的γ亚基的基因座融合。两种不相关的蛋白质的合成可通过选择性剪接来解决。一个类似的双顺反子Su（var）3-9 / eIF-2gamma转录单位被发现在Clytus arietis，Leptinotarsa decemlineata和Scoliopterix libatrix中，代表了两个不同阶的全新陈代谢昆虫（鞘翅目和鳞翅目）。在所有这些物种中，由前两个外显子编码的eIF-2gamma的N末端与SU（VAR）3-9融合。与果蝇相比，两种鞘翅目和鳞翅目物种的RT-PCR分析表明，使用了位于SU（VAR）3-9 ORF 3'末端的非保守剪接供体位点，从而去除了Su来自mRNA的（var）3-9特异性终止密码子和SU（VAR）3-9和eIF-2gamma ORF的完整读框融合。在forLithobius forficatus中，eIF-2gamma和Su（var）3-9是不相连的。研究昆虫中双顺反子Su（var）3-9 / eIF-2gamma转录单位的保守性表明其起源于新陈代谢昆虫的辐射之前，并且代表了节肢动物分子系统发育分析的有用工具。

BACKGROUND & AIMS: OBJECTIVE:Two depression screening tools, Patient Health Questionnaire (PHQ)-9 and PHQ-2, have not had their validity examined in general internal medicine settings in Japan. We examined the validity of these screening tools. METHODS:A total of 598 outpatients of an internal medicine clinic in a rural general hospital were enrolled consecutively and stratified by PHQ-9 score. Seventy-five patients randomly selected and 29 patients whose results from the PHQ-9 were considered to be positive for depressive disorder were then interviewed with a semistructured interview, the Mini International Neuropsychiatric Interview. We calculated diagnostic accuracy of the PHQ-9 and PHQ-2 to detect major depression and that of the suicidality item of the PHQ-9 to detect suicidality using sampling weights with multiple imputations. RESULTS:Sensitivity and specificity for depression were 0.86 and 0.85, respectively, for the PHQ-9 with cutoff points of 4/5, and 0.77 and 0.95, respectively, for the PHQ-2 with cutoff points of 2/3. Sensitivity and specificity of the suicidality item of the PHQ-9 were 0.70 and 0.97, respectively. CONCLUSION:In internal medicine clinics in Japanese rural hospitals, the PHQ-2 with an optimal cutoff point for each setting plus the suicidality item of the PHQ-9 can be recommended to detect depression without missing suicidality.

背景与目标： 目的：在日本的一般内科医学中，尚未对两种抑郁症筛查工具患者健康问卷（PHQ）-9和PHQ-2进行过有效性检验。我们检查了这些筛查工具的有效性。
方法：连续纳入农村综合医院内科门诊的598名门诊患者，并按PHQ-9评分进行分层。随机选择的75例患者和29例PHQ-9结果被认为对抑郁症呈阳性的患者随后接受了半结构式访谈（Mini International Neuropsychiatric Interview）。我们计算了PHQ-9和PHQ-2的诊断准确性，以检测重度抑郁症，并使用多重插补权重计算了PHQ-9的自杀性项目以检测自杀性。
结果：对于PHQ-9（截止点为4/5），抑郁的敏感性和特异性分别为0.86和0.85；对于PHQ-2（截止点为2/3），抑郁的敏感性和特异性分别为0.77和0.95。 PHQ-9自杀性项目的敏感性和特异性分别为0.70和0.97。
结论：在日本乡村医院的内科诊所中，建议使用每种设置的最佳截止点的PHQ-2加上PHQ-9的自杀性项目来检测抑郁症而不会丧失自杀性。

BACKGROUND & AIMS: :The aim of this study was to investigate whether tumor cells as well as tumor-associated macrophages (TAMs) contribute to the generation of protease activities essential to tumor cell invasiveness, such as matrix metalloproteinase 2 and 9 (MMP-2 and MMP-9), and the urokinase-type plasminogen activator (uPA) and uPA receptor (uPAR). We found that the enhanced invasiveness through Matrigel-coated filters of B16 murine melanoma cells stimulated with IFNgamma was associated with an higher expression of uPAR and MMP-9 in these cells. Moreover, treatment with anti-MMP-9 or anti-uPAR monoclonal antibodies abrogated the increase of invasiveness in IFNgamma-stimulated melanoma cells, suggesting a cooperation of uPA system and MMP-9 in cytokine-stimulated invasiveness. Invasiveness through Matrigel was also enhanced in B16 melanoma cells exposed to a medium conditioned by TAMs, represented in our experimental model by thioglycollate-elicited macrophages co-cultivated with melanoma cells. Macrophages isolated from these co-cultures were found to express higher levels of uPAR and MMP-9 compared to macrophage cultures alone, and the pro-invasive activity of the co-culture-conditioned medium was abrogated by anti-MMP-9 monoclonal antibodies, but not anti-uPAR monoclonal antibodies. Furthermore, the enhanced uPAR and MMP-9 expression in macrophages co-cultivated with tumor cells seems a rather specific phenomenon, generated through a cell-to-cell contact mechanism. On the whole, our data point to a cooperation between tumor cells and macrophages elicited by tumor cells themselves in generating key enzymes essential in the promotion of tumor invasiveness, such as uPAR and MMP-9.

背景与目标： ：这项研究的目的是研究肿瘤细胞以及与肿瘤相关的巨噬细胞（TAM）是否有助于产生对肿瘤细胞侵袭至关重要的蛋白酶活性，例如基质金属蛋白酶2和9（MMP-2和MMP-9 ），尿激酶型纤溶酶原激活剂（uPA）和uPA受体（uPAR）。我们发现，通过IFN-γ刺激的B16鼠黑色素瘤细胞通过基质胶包被的滤器的侵袭性增强与这些细胞中uPAR和MMP-9的更高表达有关。此外，用抗MMP-9或抗uPAR单克隆抗体治疗消除了IFNγ刺激的黑色素瘤细胞的侵袭性增加，表明uPA系统和MMP-9在细胞因子刺激的侵袭性中具有协同作用。在暴露于TAMs的培养基中的B16黑色素瘤细胞中，通过Matrigel的侵袭也得到了增强，在我们的实验模型中，巯基乙酸诱导的与黑色素瘤细胞共培养的巨噬细胞代表了这种情况。发现与单独的巨噬细胞培养相比，从这些共培养物中分离的巨噬细胞表达更高水平的uPAR和MMP-9，并且抗MMP-9单克隆抗体消除了共培养条件培养基的促侵袭活性，但不是抗uPAR单克隆抗体。此外，在与肿瘤细胞共培养的巨噬细胞中增强的uPAR和MMP-9表达似乎是一种相当特殊的现象，是通过细胞与细胞之间的接触机制产生的。总体而言，我们的数据表明肿瘤细胞与由肿瘤细胞自身引发的巨噬细胞之间的合作，产生了促进肿瘤侵袭性必不可少的关键酶，如uPAR和MMP-9。

BACKGROUND & AIMS: OBJECTIVE:We examined the independent relationships between objectively measured physical activity and insulin resistance in Portuguese children. RESEARCH DESIGN AND METHODS:This is a school-based, cross-sectional study in 147 randomly selected girls (aged 9.8 +/- 0.3 years; 27.8 +/- 9.3% body fat) and 161 boys (aged 9.8 +/- 0.3 years; 22.0 +/- 9.2% body fat). Physical activity was assessed by the Actigraph accelerometer for 4 days and summarized as time spent sedentary (accelerometer counts <500/min), in light-intensity (accelerometer counts 500-2,000/min), and in moderate- and vigorous-intensity activity (accelerometer counts >2,001/min). We measured total and central fat mass by dual-energy X-ray absorptiometry. Insulin resistance was expressed as the homeostasis model assessment score. RESULTS:Time (min/day) spent sedentary was significantly and positively associated with insulin resistance (beta-coefficient = 0.001 [95% CI 0.0002-0.002]; P = 0.013). Time spent in moderate- and vigorous-intensity physical activity (-0.002 [-0.003 to -0.001]; P = 0.0009) and overall physical activity (-0.001 [-0.008 to 0.003]; P < 0.0001) were significantly and inversely associated with insulin resistance. All associations remained statistically significant, although they were attenuated after further adjustments for sex, birth weight, sexual maturity, and total or central fat mass (P < 0.03). CONCLUSIONS:Physical activity is associated with insulin resistance independent of total and central fat mass in children. Our results emphasize the importance of decreasing sedentary behavior and increasing time spent in moderate- and vigorous-intensity activity in children, which may have beneficial effects on metabolic risk factors regardless of the degree of adiposity.

背景与目标： 目的：我们研究了客观测量的体育锻炼与葡萄牙儿童胰岛素抵抗之间的独立关系。
研究设计和方法：这是一项基于学校的横断面研究，研究对象是147个随机选择的女孩（9.8 /-0.3岁； 27.8 /-9.3％体脂）和161个男孩（9.8 /-0.3岁； 22.0 / -9.2％的体内脂肪）。通过Actigraph加速度计评估了4天的身体活动，并总结为久坐的时间（加速度计计数<500 / min），光强度（加速度计计数500-2,000 / min）以及中度和剧烈强度的运动（加速度计计数> 2,001 / min）。我们通过双能X射线吸收法测量了总脂肪和中央脂肪量。胰岛素抵抗表示为稳态模型评估得分。
结果：久坐的时间（分钟/天）与胰岛素抵抗显着正相关（β系数= 0.001 [95％CI 0.0002-0.002]； P = 0.013）。中度和剧烈运动所花费的时间（-0.002 [-0.003至-0.001]； P = 0.0009）和整体运动（-0.001 [-0.008至0.003]； P <0.0001）与以下各项显着且呈负相关胰岛素抵抗。尽管对性别，出生体重，性成熟度和总或中心脂肪量作进一步调整后，所有相关性均减弱，但所有相关性仍具有统计学意义（P <0.03）。
结论：儿童的体育活动与胰岛素抵抗有关，而与总脂肪和中央脂肪无关。我们的研究结果强调了减少久坐行为和增加儿童中度和剧烈运动时间的重要性，这与肥胖程度无关，可能对代谢危险因素产生有益影响。