BACKGROUND & AIMS: :The sulfite tolerance of meat yeasts was shown to be determined by pH, sulfite concentration, substrate availability, and the composition of the preincubation medium. Acetaldehyde production by Candida norvegica was sulfite-induced and occurred during the exponential growth phase in sulfited (500 micrograms SO2 ml-1) lab lemco glucose broth cultures buffered at pH 5, 6, or 7. Growth at pH 4, however, was inhibited by sulfite. Acetaldehyde production occurred in sulfited medium containing fructose or ethanol but not lactate nor a range of other assimilable substrates. A non-acetaldehyde-producing yeast, Candida vini, grew in sulfited (500 micrograms SO2 ml-1) lab lemco broth containing glucose or lactate buffered at pH 6 or 7 but not at pH 4 or 5.

背景与目标： : 肉酵母的亚硫酸盐耐受性由pH，亚硫酸盐浓度，底物利用率和预孵育培养基的组成决定。由褐家菜念珠菌产生乙醛是亚硫酸盐诱导的，并且在指数生长期中发生在硫酸化 (500微克SO2 ml-1) 实验室lemco葡萄糖肉汤培养物中，该培养物在pH 5、6或7下缓冲。然而，在pH 4下生长被亚硫酸盐抑制。乙醛的产生发生在含有果糖或乙醇的硫酸化培养基中，但不包含乳酸或一系列其他可同化底物。非产生乙醛的酵母，vini假丝酵母，在含有在ph6或7下缓冲但不在ph4或5下缓冲的葡萄糖或乳酸的硫酸化 (500微克SO2 ml-1) lab lemco肉汤中生长。

BACKGROUND & AIMS: It has been established that oxidized LDL (ox-LDL) modifies cytokine secretion by macrophages, for example, by reducing tumor necrosis factor alpha (TNF-(alpha) m-RNA. However, little is known about the effects of oxidized high density lipoprotein (ox-HDL). This study reports the effects of ox-HDL subfractions 2 and 3 (ox-HDL2, ox-HDL3) compared with that of ox-LDL and some products of oxidation (hydroperoxides and aldehydes) on the secretion of TNF-alpha from THP-1 human monocytes derived macrophages in vitro. HDL2, HDL3 and LDL were oxidized with 10 microM Cu++ for 12 h and/or 24 h. Native and oxidized HDL and LDL were incubated for 24 h with macrophages with or without LPS (10 ng/ml) after which TNF-alpha secretion was measured in the culture medium. Lipid hydroperoxides and apolar aldehydes were also incubated with the cells for 2 h following which the medium was replaced and TNF-alpha secretion measured after a further 22 h of incubation. An inhibition of TNF-alpha by ox-HDL2 (p < .05), ox-HDL3 (p < .05) and ox-LDL (p < .05) from THP-1 macrophages was observed in the presence and absence of LPS. This inhibition remained the same after incubation with ox-HDL 12 h and 24 h. Hydroperoxides of linoleic acid did not modify TNF-alpha secretion by cells while five out of eight aldehydes analyzed (2,4-heptadienal, hexanal, 2-nonenal, 2-octenal, 2,4-decadienal) inhibited TNF-alpha secretion (p < .05). These findings demonstrate that ox-HDL, and some of its lipid peroxidation products, plays a role in the modulation of the inflammatory response by macrophages as previously observed for ox-LDL.

背景与目标： 已经确定氧化的LDL (ox-LDL) 修饰巨噬细胞的细胞因子分泌，例如，通过减少肿瘤坏死因子 α (TNF-(α) m-RNA。然而，对氧化型高密度脂蛋白 (ox-HDL) 的影响知之甚少。这项研究报告了ox-HDL亚组分2和3 (ox-HDL2，ox-HDL3) 与ox-LDL和某些氧化产物 (氢过氧化物和醛) 对体外THP-1人单核细胞来源的巨噬细胞分泌TNF-α 的影响相比。HDL2，HDL3和LDL用10 microM Cu ++ 氧化12小时和/或24小时。将天然和氧化的HDL和LDL与有或没有LPS (10 ng/ml) 的巨噬细胞孵育24小时，然后在培养基中测量TNF-α 分泌。脂质氢过氧化物和极性醛还与细胞一起孵育2小时，然后更换培养基，再孵育22小时后测量TNF-α 分泌。ox-HDL2对TNF-α 的抑制作用 (p <.05)，在存在和不存在LPS的情况下观察到来自THP-1巨噬细胞的ox-HDL3 (p < .05) 和ox-LDL (p <.05)。与ox-HDL孵育12小时和24小时后，这种抑制作用保持不变。亚油酸的氢过氧化物不会改变细胞分泌TNF-α，而五在分析的八种醛中 (2，4-庚二烯醛，己醛，2-壬烯醛，2-辛烯醛，2,4-癸烯醛) 抑制TNF-α 分泌 (p <.05)。这些发现表明ox-HDL及其某些脂质过氧化产物，如先前对ox-LDL所观察到的，在巨噬细胞调节炎症反应中起作用。

BACKGROUND & AIMS: :A biomimetic approach involving the self-assembly of mineral within the pores of three-dimensional porous polymer scaffolds is a promising strategy to integrate advantages of inorganic and organic phases into a single material for hard tissue engineering. Such a material enhances the ability of progenitor cells to differentiate down an osteoblast lineage in vitro and in vivo, compared with polymer scaffolds. The mechanisms regulating mineral formation in this one-step process, however, are poorly understood, especially the effects of ionic activity products (IP) of the mineralizing solution and incubation time. The aims of this study were to define the structure and composition of mineral formed within the pores of biodegradable polymer scaffolds as a function of IP and time. Three-dimensional poly(lactide-co-glycolide) scaffolds were fabricated by solvent casting/particulate leaching and incubated for 4-16 days in six variants of simulated body fluid whose IPs were varied by adjusting ionic concentrations. Scanning electron microscopy, X-ray diffraction, and Fourier transform infrared spectroscopy demonstrated the formation of carbonated apatite with sub-micrometer sized crystals that grew into spherical globules extending out of the scaffold pore surfaces. As IP increased, more mineral grew on the scaffold pore surfaces, but the apatite became less crystalline and the Ca/P molar ratio decreased from 1.63 +/- 0.005 to 1.51 +/- 0.002. Since morphology, composition, and structure of mineral are factors that affect cell function, this study demonstrates that the IP of the mineralizing solution is an important modulator of material properties, potentially leading to enhanced control of cell function.

背景与目标： : 一种仿生方法，涉及矿物在三维多孔聚合物支架的孔中自组装，是一种将无机和有机相的优势整合到用于硬组织工程的单一材料中的有前途的策略。与聚合物支架相比，这种材料增强了祖细胞在体外和体内分化成骨细胞谱系的能力。然而，对这种一步过程中调节矿物形成的机制知之甚少，尤其是矿化溶液的离子活性产物 (IP) 和孵育时间的影响。这项研究的目的是定义在可生物降解的聚合物支架的孔中形成的矿物的结构和组成随IP和时间的变化。通过溶剂浇铸/颗粒浸出制备三维聚 (丙交酯-共-乙交酯) 支架，并在六种模拟体液变体中孵育4-16天，其IPs通过调节离子浓度而变化。扫描电子显微镜，x射线衍射和傅立叶变换红外光谱证明了碳酸磷灰石的形成，其亚微米尺寸的晶体长成球形小球，延伸出支架孔表面。随着IP的增加，更多的矿物在支架孔表面上生长，但是磷灰石变得不那么结晶，并且Ca/P摩尔比从1.63 +/- 0.005降低到1.51 +/- 0.002。由于矿物的形态，组成和结构是影响细胞功能的因素，因此这项研究表明，矿化溶液的IP是材料特性的重要调节剂，有可能导致对细胞功能的增强控制。

BACKGROUND & AIMS: Inflammatory exudates from 10 patients with bullous skin diseases were analysed by immunochemical techniques including crossed immunoelectrophoresis. The results were compared with those obtained in fluid from suction bullae obtained in normal skin in 13 control subjects and synovial fluid from 20 patients with rheumatoid arthritis. Abnormal fibrinogen degradation products identical with those found in synovial fluid from patients with rheumatoid arthritis were detected in exudates from each of the patients with bullous dermatoses, whereas significantly smaller amounts of fibrinogen antigenic material were detected in fluid obtained by suction. The fibrinogen antigenic material demonstrated in exudates from pathological bullae, immunochemically similar to that found in rheumatoid synovial fluid, indicates that the presence of these products reflects the more general features of an inflammatory exudate.

背景与目标： 通过免疫化学技术 (包括交叉免疫电泳) 分析了10例大疱性皮肤病患者的炎性渗出物。将结果与13名对照受试者在正常皮肤中获得的抽吸大疱液和20名类风湿性关节炎患者的滑液中获得的结果进行了比较。在每位大疱性皮肤病患者的渗出物中检测到与类风湿性关节炎患者滑液中发现的异常纤维蛋白原降解产物相同的产物，而在通过抽吸获得的液体中检测到的纤维蛋白原抗原物质明显较少。在病理性大疱的渗出物中显示出的纤维蛋白原抗原物质，与类风湿滑液中的免疫化学相似，表明这些产物的存在反映了炎性渗出液的更一般特征。

BACKGROUND & AIMS: :The advantages of liposomes as delivery systems for peptide, protein and DNA vaccines is well-recognised, unfortunately their application has been stinted by their instability during storage and their limited shelf-life. Further, sterilisation of these systems has been problematic, with degradation of the liposomes being reported after sterilisation using the various techniques available. Work form our laboratory has investigated techniques that can be applied to particulate liposomal vaccines such that they can be prepared in a freeze-dried and sterile format. In this article, we describe techniques for the lyophilisation, cryoprotection and sterilisation of liposomal vaccines. Applying these methods allows for the retention of both the chemical integrity of the lipids and the key physico-chemical characteristics of the liposomes (e.g., particle size, zeta potential, and dynamic viscosity), thus supporting the enhanced transition of liposomal vaccines from the bench to the clinic.

背景与目标： : 脂质体作为肽，蛋白质和DNA疫苗的递送系统的优势已广为人知，不幸的是，它们的应用因其在储存过程中的不稳定性和有限的保质期而受到限制。此外，这些系统的灭菌一直存在问题，在使用各种可用技术灭菌后报道了脂质体的降解。工作形式我们的实验室已经研究了可应用于微粒脂质体疫苗的技术，以便可以冷冻干燥和无菌形式制备。在本文中，我们描述了脂质体疫苗的冻干，冷冻保护和灭菌技术。应用这些方法可以保留脂质的化学完整性和脂质体的关键理化特性 (例如粒径，ζ 电位和动态粘度)，从而支持脂质体疫苗从实验室到临床的增强转变。

BACKGROUND & AIMS: :The 26S proteasome is a multicatalytic threonine protease complex responsible for degradation of the majority of proteins in eukaryotic cells. In the last two decades, the ubiquitin proteasome system (UPS) has been increasingly recognized as an integral component in numerous biologic processes including cell proliferation, adaptation to stress, and cell death. The turnover of intracellular proteins inevitably affects the contributions of these molecules to cellular networks and pathways in any given tissue or organ, including the myocardium. Perturbations in the protein-degradation process have been shown to affect protein turnover and thereby affect the cardiac cell functions that these molecules are designated to carry out, engendering diseased cardiac phenotypes. Recent studies have implicated the role of proteasomes in stressed cardiac phenotypes including postischemia-reperfusion injury and cardiac remodeling (e.g., heart failure). The 26S proteasomes also appear to be susceptible to modulation by stresses (e.g., reactive oxygen species). This review focuses on roles of the 26S proteasome system in protein degradation; it provides an overview of the progress made in cardiac proteasome research as well as a discussion of recent controversies regarding the UPS system in diseased cardiac phenotypes.

背景与目标： : 26s蛋白酶体是一种多催化苏氨酸蛋白酶复合物，负责真核细胞中大多数蛋白质的降解。在过去的二十年中，泛素蛋白酶体系统 (UPS) 已被越来越多地视为许多生物学过程 (包括细胞增殖，对压力的适应和细胞死亡) 中不可或缺的组成部分。细胞内蛋白质的转换不可避免地影响这些分子对任何给定组织或器官 (包括心肌) 中细胞网络和途径的贡献。已显示蛋白质降解过程中的扰动会影响蛋白质的更新，从而影响这些分子被指定执行的心脏细胞功能，从而导致患病的心脏表型。最近的研究表明蛋白酶体在压力心脏表型中的作用，包括缺血后再灌注损伤和心脏重塑 (例如心力衰竭)。26s蛋白酶体似乎也容易受到压力 (例如活性氧) 的调节。这篇综述着重于26s蛋白酶体系统在蛋白质降解中的作用; 它概述了心脏蛋白酶体研究的进展，并讨论了有关UPS系统在患病心脏表型中的最新争议。

BACKGROUND & AIMS: An enzyme-linked immunosorbent assay for measuring type I collagen degradation products in serum (S-ELISA) was developed. The assay uses a high affinity polyclonal antibody which reacts with an isomerized form of an 8 amino acid sequence of the C-telopeptides of type I collagen (EKAHD-beta-GGR). Cross-reactivity to a nonisomerized synthetic peptide form of the 8 amino acid sequence is less than 0.2%. Values obtained in a group of premenopausal women (age, 33.3 +/- 3.11 years) were 69 +/- 24 ng/ml(n = 22). In a group of early postmenopausal women (age, 51.8 +/- 1.88 years) values obtained were 125 +/- 43 ng/ml (n = 46), which represents an increase of 81% (p < 0.001). Values found in untreated patients with Paget's disease were 234 +/- 95 ng/ml (n = 15), and for primary hyperparathyroidism we found 335 +/- 82 ng/ml (n = 10). Intravenous administration of a bisphosphonate (Pamidronate) to Paget's disease patients for 3 days was reflected in the S-ELISA by a decrease in the values of 55% when compared with values before treatment (n = 15). Following treatment with another bisphosphonate (Alendronate) for 6 months, values were decreased to 48 +/- 19 ng/ml (n = 12), which corresponds to a 62% decrease. Clinical results presented in this context support that the assay is a sensitive and specific index of bone resorption. It may, therefore, prove useful in the follow up of treatment of patients with metabolic bone diseases and in the clinical investigation of osteoporosis.

背景与目标： 开发了一种用于测量血清中I型胶原蛋白降解产物的酶联免疫吸附测定法 (S-ELISA)。该测定使用高亲和力多克隆抗体，该抗体与I型胶原蛋白 (EKAHD-β-GGR) 的C-端肽的8个氨基酸序列的异构化形式反应。对8个氨基酸序列的非异构化合成肽形式的交叉反应性小于0.2%。在一组绝经前妇女 (年龄，33.3 +/- 3.11岁) 中获得的值为69 +/- 24 ng/ml(n = 22)。在一组绝经后早期妇女 (年龄，51.8 +/- 1.88岁) 中，获得的值为125 +/- 43 ng/ml (n = 46)，这表示增加了81% (p <0.001)。在未经治疗的Paget病患者中发现的值为234/- 95 ng/ml (n = 15)，对于原发性甲状旁腺功能亢进，我们发现335/- 82 ng/ml (n = 10)。与治疗前的值相比 (n = 15)，在S-ELISA中反映了将双膦酸盐 (帕米膦酸盐) 静脉给药至Paget病患者3天的55% 值降低。用另一种双膦酸盐 (阿仑膦酸盐) 治疗6个月后，值降低至48 +/- 19 ng/ml (n = 12)，这对应于62% 降低。在这种情况下提出的临床结果支持该测定是骨吸收的敏感且特异性的指标。因此，它可能对代谢性骨病患者的治疗随访和骨质疏松症的临床研究有用。

BACKGROUND & AIMS: :Epidemiological investigations suggest a link between exposure to indoor air chemicals and adverse health effects. Consumer products contain reactive chemicals which can form secondary pollutants which may contribute to these effects. The reaction of limonene and ozone is a well characterized example of this type of indoor air chemistry. The studies described here characterize an in vitro model using an epithelial cell line (A549) or differentiated epithelial tissue (MucilAir™). The model is used to investigate adverse effects following exposure to combinations of limonene and ozone. In A549 cells, exposure to both the parent compounds and reaction products resulted in alterations in inflammatory cytokine production. A one hour exposure to limonene+ozone resulted in decreased proliferation when compared to cells exposed to limonene alone. Repeated dose exposures of limonene or limonene+ozone were conducted on MucilAir™ tissue. No change in proliferation was observed but increases in cytokine production were observed for both the parent compounds and reaction products. Factors such as exposure duration, chemical concentration, and sampling time point were identified to influence result outcome. These findings suggest that exposure to reaction products may produce more severe effects compared to the parent compound.

背景与目标： 流行病学调查表明，暴露于室内空气化学品与不良健康影响之间存在联系。消费品中含有可形成二次污染物的反应性化学物质，可能会导致这些影响。柠檬烯和臭氧的反应是这种室内空气化学的一个很好的例子。此处描述的研究表征了使用上皮细胞系 (A549) 或分化的上皮组织 (粘液) 的体外模型。™)。该模型用于研究暴露于柠檬烯和臭氧组合后的不利影响。在A549细胞中，暴露于母体化合物和反应产物会导致炎性细胞因子产生的改变。与单独暴露于柠檬烯的细胞相比，暴露于柠檬烯臭氧一小时导致增殖减少。在粘液上重复剂量暴露柠檬烯或柠檬烯臭氧™组织。未观察到增殖的变化，但观察到母体化合物和反应产物的细胞因子产生增加。确定了诸如暴露时间，化学浓度和采样时间点之类的因素会影响结果。这些发现表明，与母体化合物相比，暴露于反应产物可能会产生更严重的影响。

BACKGROUND & AIMS: :Microtubule-stabilizing and -destabilizing proteins play a crucial role in regulating the dynamic instability of microtubules during neuronal development and synaptic transmission. The microtubule-destabilizing protein SCG10 is a neuron-specific protein implicated in neurite outgrowth. The SCG10 protein is significantly reduced in mature neurons, suggesting that its expression is developmentally regulated. In contrast, the microtubule-stabilizing protein tau is expressed in mature neurons and its function is essential for the maintenance of neuronal polarity and neuronal survival. Thus, the establishment and maintenance of neuronal polarity may down-regulate the protein level/function of SCG10. In this report, we show that treatment of PC12 cells and neuroblastoma cells with the microtubule-stabilizing drug Taxol induced a rapid degradation of the SCG10 protein. Consistently, overexpression of tau protein in neuroblastoma cells also induced a reduction in SCG10 protein levels. Calpain inhibitor MDL-28170, but not caspase inhibitors, blocked a significant decrease in SCG10 protein levels. Collectively, these results indicate that tau overexpression and Taxol treatment induced a calpain-dependent degradation of the microtubule-destabilizing protein SCG10. The results provide evidence for the existence of an intracellular mechanism involved in the regulation of SCG10 upon microtubule stabilization.

背景与目标： : 微管稳定和不稳定的蛋白质在调节神经元发育和突触传递过程中微管的动态不稳定性中起着至关重要的作用。微管不稳定蛋白SCG10是一种神经元特异性蛋白，与神经突生长有关。SCG10蛋白在成熟神经元中明显减少，表明其表达受到发育调节。相反，微管稳定蛋白tau在成熟神经元中表达，其功能对于维持神经元极性和神经元存活至关重要。因此，神经元极性的建立和维持可能会下调scg10的蛋白质水平/功能。在本报告中，我们显示用微管稳定药物紫杉醇处理PC12细胞和神经母细胞瘤细胞可诱导SCG10蛋白的快速降解。一致地，神经母细胞瘤细胞中tau蛋白的过表达也诱导了SCG10蛋白水平的降低。钙蛋白酶抑制剂MDL-28170而非胱天蛋白酶抑制剂阻断了SCG10蛋白水平的显著降低。总的来说，这些结果表明tau过表达和紫杉醇处理诱导了微管不稳定蛋白scg10的钙蛋白酶依赖性降解。结果为微管稳定后SCG10调控的细胞内机制的存在提供了证据。

BACKGROUND & AIMS: BACKGROUND/PURPOSE:Sunscreen products today represent a trend of providing not only simple sun protection factor (SPF)/protection of UVA (PFA) but also other additional benefits. For example, as popularized by seasonless use of sunscreens, the special function of water resistance or sand proof is added to sunscreens as well as for leisure. Because a human in vivo test is time consuming and expensive, a screening process has been tried using an accurate in vitro system. In this study, we suggest the development of an in vitro test that can predict the result of in vivo water resistance of sunscreens. METHODS:Water resistance is presented as a comparison of initial SPF and water-exposed SPF by immersion and washing. In order to be comparable with the in vivo test, water immersion and flow were defined as the basic statements. Also, substrate, revolutions per minute (r.p.m.)--rotative velocity--of propeller inducing water flow, and time of immersion were defined as controlled factors. Considering the strength, separation of test material and adhesive texture, a PMMA plate was selected as suitable among commercial substrates: Transpore tape, VITRO SKIN, and PMMA plate. Also, when the PMMA plate was adhered on the wall of a water bath, the water turbulence of the rotational propeller alone was not strong enough to wash off the test material from the substrate. Therefore, PMMA plates were fixed on the axis. In this experiment, the most important thing is whether this in vitro system can predict correctly. Hence, we tried to match the in vitro water resistance following from our control factors and water resistance value of the in vivo test. RESULTS:We found the immersion time and r.p.m. of controlled factors to obtain the target water resistance using design of experiment, MiniTab statistical package. Response optimization yielded the optimal in vitro conditions of 150 r.p.m./60 min. The repeatability and reproducibility of this in vitro system were also good in validation studies. CONCLUSIONS:This study enables to modify an in vivo water resistance test and predict the result of in vivo water resistance by the manufacture of effective equipment and choosing a suitable substrate. Compared with in vivo results, our in vitro system is more time and cost effective, and provides reliable results.

背景与目标：

BACKGROUND & AIMS: :Cocoa and chocolate contain the tetrahydroisoquinoline alkaloid salsolinol up to a concentration of 25 microg/g. Salsolinol is a dopaminergic active compound which binds to the D(2) receptor family, especially to the D(3) receptor with a K(i) of 0.48+/-0.021 micromol/l. It inhibits the formation of cyclic AMP and the release of beta-endorphin and ACTH in a pituitary cell system. Taking the detected concentration and the pharmacological properties into account, salsolinol seems to be one of the main psychoactive compounds present in cocoa and chocolate and might be included in chocolate addiction.

背景与目标： : 可可和巧克力含有四氢异喹啉生物碱salsolinol，浓度高达25微克/克。Salsolinol是一种多巴胺能活性化合物，与D(2) 受体家族结合，特别是与D(3) 受体结合，K(i) 为0.48 +/-0.021微摩尔/升。它抑制垂体细胞系统中环状AMP的形成以及 β-内啡肽和ACTH的释放。考虑到检测到的浓度和药理特性，salsolinol似乎是可可和巧克力中存在的主要精神活性化合物之一，可能包括在巧克力成瘾中。

BACKGROUND & AIMS: :Strains carrying both the ramA1 and the neaA301 mutations do not exhibit the restriction of informational suppressors normally associated with resistance to neamine. Furthermore, ribosomes from such strains exhibit increased misreading in vitro with respect to particles from the neaA strain. These properties suggest that translational fidelity may be cooperatively controlled by ribosomal proteins S4 and S17, coded by ramA (rpsd) and neaA (rpsq) genes respectively.

背景与目标： : 同时携带ramA1和neaA301突变的菌株不表现出通常与对neamine抗性相关的信息抑制因子的限制。此外，来自此类菌株的核糖体在体外相对于来自neaA菌株的颗粒表现出增加的误读。这些特性表明，翻译保真度可能由分别由ramA (rpsd) 和neaA (rpsq) 基因编码的核糖体蛋白S4和S17共同控制。

BACKGROUND & AIMS: :The investigational drugs E7820, indisulam and tasisulam (aryl-sulfonamides) promote the degradation of the splicing factor RBM39 in a proteasome-dependent mechanism. While the activity critically depends on the cullin RING ligase substrate receptor DCAF15, the molecular details remain elusive. Here we present the cryo-EM structure of the DDB1-DCAF15-DDA1 core ligase complex bound to RBM39 and E7820 at a resolution of 4.4 Å, together with crystal structures of engineered subcomplexes. We show that DCAF15 adopts a new fold stabilized by DDA1, and that extensive protein-protein contacts between the ligase and substrate mitigate low affinity interactions between aryl-sulfonamides and DCAF15. Our data demonstrate how aryl-sulfonamides neo-functionalize a shallow, non-conserved pocket on DCAF15 to selectively bind and degrade RBM39 and the closely related splicing factor RBM23 without the requirement for a high-affinity ligand, which has broad implications for the de novo discovery of molecular glue degraders.

背景与目标： : 研究药物E7820，地苏拉姆和tassullam (芳基磺酰胺) 以蛋白酶体依赖性机制促进剪接因子RBM39的降解。尽管活性主要取决于cullin环连接酶底物受体DCAF15，但分子细节仍然难以捉摸。在这里，我们介绍了以4.4 å å 的分辨率与RBM39和E7820结合的DDB1-DCAF15-DDA1核心连接酶复合物的cryo-EM结构，以及工程亚复合物的晶体结构。我们证明DCAF15采用了由DDA1稳定的新折叠，并且连接酶和底物之间广泛的蛋白质-蛋白质接触减轻了芳基磺酰胺和DCAF15之间的低亲和力相互作用。我们的数据证明了芳基磺酰胺如何使DCAF15上的浅，非保守的口袋官能化，以选择性地结合和降解RBM39和密切相关的剪接因子RBM23，而不需要高亲和力配体，这对从头发现分子胶降解剂具有广泛的意义。

BACKGROUND & AIMS: :Degradation of endothelial glycocalyx (EG) is associated with inflammation and endothelial dysfunction, which may contribute to the development of acute kidney injury (AKI). We investigated the association between a marker of EG degradation and AKI after valvular heart surgery. Serum syndecan-1 concentrations were measured at induction of anesthesia and discontinuation of cardiopulmonary bypass in 250 patients. Severe AKI was defined as Kidney Disease: Improving Global Outcomes Criteria Stage 2 or 3. Severe AKI occurred in 13 patients (5%). Receiver operating characteristic analysis of preoperative syndecan-1 to predict severe AKI showed area under curve of 0.714 (95% confidence interval (CI), 0.575-0.853; p = 0.009). The optimal cut-off value was 90 ng/mL, with a sensitivity of 61.5% and specificity of 78.5%. In multivariable analysis, both preoperative syndecan-1 ≥ 90 ng/mL and Cleveland Clinic Foundation score independently predicted severe AKI. Severe tricuspid regurgitation was more frequent (42.4% vs. 17.8%, p < 0.001), and baseline right ventricular systolic pressure (41 (33-51) mmHg vs. 33 (27-43) mmHg, p = 0.001) and TNF-α (1.85 (1.37-2.43) pg/mL vs. 1.45 (1.14-1.92) pg/mL, p <0.001) were higher in patients with high preoperative syndecan-1. Patients with high preoperative syndecan-1 had longer hospital stay (16 (12-24) days vs. 13 (11-17) days, p = 0.001). In conclusion, a high preoperative syndecan-1 concentration greater than 90 ng/mL was able to predict severe AKI after valvular heart surgery and was associated with prolonged hospitalization.

背景与目标： : 内皮糖萼 (EG) 的降解与炎症和内皮功能障碍有关，这可能有助于急性肾损伤 (AKI) 的发展。我们调查了心脏瓣膜手术后EG降解标志物与AKI之间的关系。在250例患者的麻醉诱导和体外循环停止时测量血清syndecan-1浓度。严重AKI被定义为肾脏疾病: 改善全球结局标准第2或第3阶段。13例患者 (5%) 发生严重AKI。术前syndecan-1预测严重AKI的受试者操作特征分析显示0.714曲线下面积 (95% 置信区间，0.575-0.853; p = 0.009)。最佳临界值为90 ng/mL，灵敏度为61.5%，特异性为78.5%。在多变量分析中，术前syndecan-1 ≥ 90 ng/mL和Cleveland Clinic Foundation评分均独立预测严重AKI。严重的三尖瓣反流更频繁 (42.4% vs. 17.8%，p <0.001)，基线右心室收缩压 (41 (33-51) mmHg vs. 33 (27-43) mmHg，p = 0.001) 和TNF-α (1.85 (1.37-2.43) pg/mL vs 1.45 (1.14-1.92) pg/mL，p <0.001) 在术前syndecan-1较高。术前syndecan-1高的患者住院时间较长 (16 (12-24) 天vs. 13 (11-17) 天，p = 0.001)。总之，术前syndecan-1浓度大于90 ng/mL能够预测瓣膜手术后的严重AKI，并且与住院时间延长有关。

BACKGROUND & AIMS: Lp(a) is an important contributing factor to the development of atherosclerosis, and in structure is similar to LDL. Given the central role of the LDL receptor (LDL-R) in the metabolism of LDL, we felt that a study of the binding and degradation of Lp(a) facilitated by the LDL-R of human monocyte derived macrophages (HMDM) would be of value in understanding its pathological nature. In this study we compared equimolar amounts of Lp(a) and LDL and found that nearly equal amounts of Lp(a) and LDL bound to the LDL-R of HMDM at 4 degrees C, however the affinity of both lipoproteins was much lower than has been observed for the LDL-R of fibroblasts, being 0.80 muM for Lp(a) and 0.23 muM for LDL. The binding of Lp(a) to HMDM could be competed by 63% with a 50-fold excess of LDL. Degradation of Lp(a) at 37 degree C, unlike 4 degrees C binding, was mainly nonspecific (75% of total Lp(a) degradation) and when compared on an equimolar basis, nearly 6 times more LDL than Lp(a) was processed by the LDL-R pathway in 5 hr. Lower degradation of Lp(a) appears to be the result of lower binding at 37 degree C and a lower degradation rate when compared to LDL. It was not caused by increased intracellular accumulation or retroendocytosis. Degradation of both lipoproteins was only modestly affected by up and down regulation of the LDL-R. Because the binding of LDL at 4 degrees C and degradation at 37 degree C is mainly LDL-R specific, whereas only the 4 degree C binding of Lp(a) is so, suggests that the poor LDL-R dependent degradation of Lp(a) at 37 degree C is caused by a conformational change that is inducted in Lp(a) upon lowering the temperature to 4 degree C which allows better recognition of Lp(a) by the HMDM LDL-R.

背景与目标： Lp(a) 是动脉粥样硬化发展的重要促成因素，并且在结构上与LDL相似。鉴于LDL受体 (ldl-r) 在LDL代谢中的核心作用，我们认为对人类单核细胞衍生的巨噬细胞 (HMDM) 的ldl-r促进Lp(a) 的结合和降解的研究对于了解其病理性质具有价值。在这项研究中，我们比较了等摩尔量的Lp(a) 和LDL，发现几乎相等量的Lp(a) 和LDL在4摄氏度下与HMDM的ldl-r结合，然而，两种脂蛋白的亲和力远低于已观察到的成纤维细胞的ldl-r，0.80 Lp(a) 的muM和LDL的0.23 muM。Lp(a) 与HMDM的结合可通过63% 50倍过量的LDL来竞争。与4 ℃ 结合不同，Lp(a) 在37 ℃ 下的降解主要是非特异性的 (占总Lp(a) 降解的75%)，并且当以等摩尔为基础进行比较时，在5小时内通过ldl-r途径处理的LDL比Lp(a) 多近6倍。与LDL相比，Lp(a) 的较低降解似乎是在37 ℃ 下较低结合和较低降解率的结果。它不是由细胞内积累或胞吞作用增加引起的。Ldl-r的上下调节仅对两种脂蛋白的降解产生适度的影响。因为LDL在4 ℃ 的结合和37 ℃ 的降解主要是ldl-r特异性的，而只有4 ℃ 的Lp(a) 的结合是如此，表明Lp(a) 在37摄氏度时的低ldl-r依赖性降解差是由将温度降低到4摄氏度时在Lp(a) 中诱导的构象变化引起的，这允许HMDM ldl-r更好地识别Lp(a)。
<