BACKGROUND & AIMS: :Rhodopseudomonas palustris is a purple, facultatively phototrophic bacterium that uses hydrogen gas as an electron donor for carbon dioxide fixation during photoautotrophic growth or for ammonia synthesis during nitrogen fixation. It also uses hydrogen as an electron supplement to enable the complete assimilation of oxidized carbon compounds, such as malate, into cell material during photoheterotrophic growth. The R. palustris genome predicts a membrane-bound nickel-iron uptake hydrogenase and several regulatory proteins to control hydrogenase synthesis. There is also a novel sensor kinase gene (RPA0981) directly adjacent to the hydrogenase gene cluster. Here we show that the R. palustris regulatory sensor hydrogenase HupUV acts in conjunction with the sensor kinase-response regulator protein pair HoxJ-HoxA to activate hydrogenase expression in response to hydrogen gas. Transcriptome analysis indicated that the HupUV-HoxJA regulatory system also controls the expression of genes encoding a predicted dicarboxylic acid transport system, a putative formate transporter, and a glutamine synthetase. RPA0981 had a small effect in repressing hydrogenase synthesis. We also determined that the two-component system RegS-RegR repressed expression of the uptake hydrogenase, probably in response to changes in intracellular redox status. Transcriptome analysis indicated that about 30 genes were differentially expressed in R. palustris cells that utilized hydrogen when growing photoheterotrophically on malate under nitrogen-fixing conditions compared to a mutant strain that lacked uptake hydrogenase. From this it appears that the recycling of reductant in the form of hydrogen does not have extensive nonspecific effects on gene expression in R. palustris.

背景与目标： : 红假单胞菌 (Rhodopseudomonas palustris) 是一种紫色的兼性光养细菌，在光自养生长过程中使用氢气作为电子供体进行二氧化碳固定或在固氮过程中进行氨合成。它还使用氢作为电子补充剂，以使氧化的碳化合物 (例如苹果酸盐) 在光异养生长过程中完全同化为细胞材料。R. palustris基因组预测了膜结合的镍铁吸收氢化酶和几种控制氢化酶合成的调节蛋白。还有一个新的传感器激酶基因 (RPA0981) 直接与氢化酶基因簇相邻。在这里，我们显示了R. palustris调节传感器氢化酶HupUV与传感器激酶响应调节蛋白对HoxJ-HoxA共同作用，以响应氢气激活氢化酶表达。转录组分析表明，HupUV-HoxJA调节系统还控制编码预测的二羧酸转运系统，推定的甲酸转运蛋白和谷氨酰胺合成酶的基因的表达。RPA0981在抑制氢化酶合成方面的作用很小。我们还确定，两组分系统RegS-RegR抑制了摄取氢化酶的表达，可能是对细胞内氧化还原状态变化的响应。转录组分析表明，与缺乏摄取氢化酶的突变菌株相比，在固氮条件下在苹果酸上光异养生长时利用氢的R. palustris细胞中约30个基因差异表达。由此看来，以氢形式回收还原剂对R. palustris的基因表达没有广泛的非特异性影响。

BACKGROUND & AIMS: :A novel procaryotic transcriptional regulatory element, AlgP, with a histone H1-like carboxy-terminal domain was identified in Pseudomonas aeruginosa. AlgP is required for transcription of the key biosynthetic gene algD, which is necessary for production of the exopolysaccharide alginate causing mucoidy in P. aeruginosa. Mucoidy is a critical virulence determinant of P. aeruginosa invariably associated with the respiratory infections causing high mortality in cystic fibrosis. Here we show that AlgP and histones H1 both have repeated units of the Lys-Pro-Ala-Ala motif (KPAA) and its variations within their long (over 100 amino acids) carboxy-terminal domains. This region of histone H1 tails has been shown to bind to the linker DNA in eucaryotic chromatin fibers. A synthetic 50-mer peptide consisting of repeats from the AlgP carboxy-terminal domain was found to bind DNA in a mobility shift DNA-binding assay. AlgP is encoded by a gene that contains multiple direct repeats organized as tandem, head-to-tail, 12-base-pair (bp) units overlapping with six highly conserved 75-bp units. The repetitive structure of the algP gene appears to participate in the processes underlying the metastable character of mucoidy in P. aeruginosa. Relatively large DNA rearrangements spanning the region with tandem direct repeats encoding the carboxy-terminal histone H1-like structure of AlgP were detected in several strains upon conversion from the mucoid to the nonmucoid phenotype. The frequency of the detectable algP rearrangements associated with the transition into the nonmucoid state varied from strain to strain and ranged from 0 to 50%. The nonmucoid derivatives with the clearly rearranged chromosomal copy of algP were complemented to mucoidy with plasmids containing algP from P. aeruginosa PAO. When a random collection of mucoid strains, isolated from different cystic fibrosis patients, was analyzed by using polymerase chain reaction, an additional level of strain-dependent sequence variation in algP was observed. Variations in the number of the 12-bp repeats were found; however, they did not appear to influence the mucoid status of the strains examined. Thus, the repeated region of algP appears to be a hot spot for DNA rearrangements and strain-dependent variability.

背景与目标： : 在铜绿假单胞菌中鉴定了一种新型的原核转录调节元件AlgP，其具有组蛋白H1-like羧基末端结构域。AlgP是关键生物合成基因algD转录所必需的，这对于产生引起铜绿假单胞菌粘液的胞外多糖藻酸盐是必需的。粘液症是铜绿假单胞菌的关键毒力决定因素，总是与引起囊性纤维化高死亡率的呼吸道感染相关。在这里，我们显示了AlgP和组蛋白H1都具有Lys-Pro-Ala基序 (KPAA) 的重复单元及其在其长 (超过100个氨基酸) 羧基末端结构域中的变化。已显示组蛋白H1尾巴的该区域与真核染色质纤维中的接头DNA结合。在迁移率转移DNA结合试验中，发现由来自AlgP羧基末端结构域的重复序列组成的合成50聚体肽结合DNA。AlgP由一个基因编码，该基因包含多个直接重复序列，组织为串联，头对尾，12碱基对 (bp) 单元，与六个高度保守的75 bp单元重叠。algP基因的重复结构似乎参与了铜绿假单胞菌黏液的亚稳态特征的潜在过程。从粘液样转化为非粘液样表型后，在几个菌株中检测到跨越编码AlgP羧基末端组蛋白H1-like结构的串联直接重复序列的区域的相对较大的DNA重排。与过渡到非粘液状态相关的可检测的algP重排的频率因菌株而异，范围为0至50%。具有明显重排的algP染色体拷贝的非粘液衍生物与含有铜绿假单胞菌PAO的algP的质粒互补为粘液。当使用聚合酶链反应分析从不同的囊性纤维化患者中分离出的粘液样菌株的随机集合时，观察到algP中菌株依赖性序列变异的额外水平。发现12 bp重复序列的数量有所变化; 但是，它们似乎并未影响所检查菌株的粘液状态。因此，algP的重复区域似乎是DNA重排和应变依赖性变异性的热点。

BACKGROUND & AIMS: :Iron is an essential trace-element for most organisms. However, because high concentration of free intracellular iron is cytotoxic, cells have developed complex regulatory networks that keep free intracellular iron concentration at optimal range, allowing the incorporation of the metal into iron-using enzymes and minimizing damage to the cell. We built a mathematical model of the network that controls iron uptake and usage in the bacterium Escherichia coli to explore the dynamics of iron flow. We simulate the effect of sudden decrease or increase in the extracellular iron level on intracellular iron distribution. Based on the results of simulations we discuss the possible roles of the small RNA RyhB and the Fe-S cluster assembly systems in the optimal redistribution of iron flows. We suggest that Fe-S cluster assembly is crucial to prevent the accumulation of toxic levels of free intracellular iron when the environment suddenly becomes iron rich.

背景与目标： 铁是大多数生物必需的微量元素。但是，由于高浓度的游离细胞内铁具有细胞毒性，因此细胞已经开发出复杂的调节网络，可将游离细胞内铁的浓度保持在最佳范围，从而允许将金属掺入使用铁的酶中，并最大程度地减少对细胞的损害。我们建立了控制大肠杆菌中铁吸收和使用的网络数学模型，以探索铁流动的动力学。我们模拟了细胞外铁水平突然降低或升高对细胞内铁分布的影响。根据模拟结果，我们讨论了小RNA RyhB和Fe-S簇组装系统在铁流最佳重新分布中的可能作用。我们建议，当环境突然变得富含铁时，Fe-S簇组装对于防止有毒水平的游离细胞内铁的积累至关重要。

BACKGROUND & AIMS: :Apoptosis is an important regulatory event in testicular homeostasis and optimization of sperm production. Sertoli cells (SCs) form the blood-testis barrier creating a special microenvironment where germ cells develop and are under strict hormonal control. Estrogens and androgens are known to play critical roles in SCs functioning, improving their in vitro survival by preventing apoptotic progression. Herein, we studied the influence of 17β-estradiol (E2) and 5α-dihydrotestosterone (DHT) on the apoptotic signaling pathways of immature rat cultured SCs. For that we chose key points of the apoptotic pathway that interact with the mitochondria and evaluated the mRNA expression and/or protein levels of several apoptotic markers such as p53, the anti-apoptotic protein Bcl2, the pro-apoptotic Bcl2 family member Bax, the apoptosis-inducing factor (AIF) and caspase-3 and 9. Caspase-3 activity and DNA fragmentation were also evaluated as endpoint markers of apoptosis. E2 and DHT down-regulated the mRNA transcript levels of p53, Bax, caspase-9 and caspase-3. The protein levels of AIF were reduced after DHT treatment while E2-treated cells presented decreased levels of cleaved caspase-9 protein. Moreover, Bax/Bcl2 ratio was significantly decreased in E2-treated cells. The apoptotic endpoints caspase-3 activity and DNA fragmentation presented significant decreased levels after hormonal treatment. Taken together, these results show that E2 and DHT act as apoptotic signaling modulators in in vitro immature rat SCs suggesting that androgens and estrogens may be capable of modulating independent pathways of the apoptotic event by regulating different pro-apoptotic factors.

背景与目标： : 细胞凋亡是睾丸稳态和精子生成优化的重要调节事件。支持细胞 (SCs) 形成血液-睾丸屏障，创造了一个特殊的微环境，生殖细胞发育并受到严格的激素控制。已知雌激素和雄激素在SCs功能中起关键作用，通过防止凋亡进程来改善其体外存活。本文研究了17β-雌二醇 (E2) 和5α-二氢睾酮 (DHT) 对未成熟大鼠SCs凋亡信号通路的影响。为此，我们选择了与线粒体相互作用的凋亡途径的关键点，并评估了几种凋亡标志物的mRNA表达和/或蛋白水平，例如p53，抗凋亡蛋白Bcl2，促凋亡Bcl2家族成员Bax，凋亡诱导因子 (AIF) 与caspase-3和9。Caspase-3活性和DNA片段也被评估为凋亡的终点标记。E2和DHT下调了p53，Bax，caspase-9和caspase-3的mRNA转录水平。DHT处理后AIF的蛋白质水平降低，而E2-treated细胞的裂解caspase-9蛋白水平降低。此外，E2-treated细胞中的Bax/Bcl2比率显着降低。激素治疗后，凋亡终点caspase-3活性和DNA片段化水平显着降低。总之，这些结果表明E2和DHT在体外未成熟大鼠SCs中充当凋亡信号调节剂，这表明雄激素和雌激素可能能够通过调节不同的促凋亡因子来调节凋亡事件的独立途径。

BACKGROUND & AIMS: AIM:To identify the changes of mitochondrial protein expression in diabetic renal parenchyma and to characterize their molecular functions and biological processes in diabetes. METHODS:Mitochondrial proteins extracted from renal parenchyma mitochondria of streptozotocin-induced diabetic rats and normal rats were separated by two-dimensional polyacrylamide gel electrophoresis and identified by matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry. RESULTS:Eleven proteins from 533 visualized protein spots displayed significant different expressions in mitochondria of diabetic kidneys compared with those in normal ones. Among these altered proteins, two proteins with the most obvious changes in protein expression were identified as alpha-2u globulin (mature protein, named A2) and its proteolytically modified form (named A2-fragment) respectively. These proteins were found in mitochondria of male rat renal parenchyma and were proved to be down-regulated in diabetic rats simultaneously. CONCLUSION:Our results suggest that down-regulation of alpha-2u globulin may be associated with an abnormal β-oxidation of long-chain fatty acids during diabetes. The decreased expression of A2-fragment in renal mitochondria of diabetic nephropathy may reduce fatty acid β-oxidation, which leads to a diminished energy supply from mitochondria to kidney tissue and the deposition of a large number of fatty acids in the kidney, ultimately causing and aggravating kidney damage. In conclusion, these findings may be helpful for understanding the molecular mechanism of diabetic nephropathy.

背景与目标：

BACKGROUND & AIMS: :Although Alpinia officinarum has been used in traditional medicine for the treatment of several conditions, such as abdominal pain, emesis, diarrhea, impaired renal function, and dysentery, little is known about its function in obesity. In this study, we investigated the antiobesity effect of A. officinarum ethanol extract (AOE) on lipid accumulation in 3T3-L1 cells and obesity in mice fed a high-fat diet (HFD). AOE dose-dependently suppressed lipid accumulation during differentiation of 3T3-L1 preadipocytes by downregulating CCAAT enhancer binding protein α (C/EBPα), sterol regulatory element binding protein-1 (SREBP-1), and peroxisome proliferator-activated receptor-γ (PPAR-γ) genes. Galangin, a major component of A. officinarum, had antiadipogenic effects in 3T3-L1 cells. AOE supplementation in mice fed a HFD revealed that AOE significantly decreased HFD-induced increases in body, liver, and white adipose tissue weights and decreased serum insulin and leptin levels. To elucidate the inhibitory mechanism of AOE in obesity, lipid metabolism-related genes were identified. AOE efficiently suppressed protein expressions of C/EBPα, fatty acid synthase, SREBP-1, and PPAR-γ in the liver and adipose tissue. The protein expression patterns, observed by immunoblot, were confirmed by quantitative real-time polymerase chain reaction. Collectively, these results suggest that AOE prevents obesity by suppressing adipogenic and lipogenic genes. AOE has potential for use as an antiobesity therapeutic agent that can function by regulating lipid metabolism.

背景与目标： : 尽管高山姜已在传统医学中用于治疗多种疾病，例如腹痛，呕吐，腹泻，肾功能受损和痢疾，但对其在肥胖症中的功能知之甚少。在这项研究中，我们研究了A. officinarum乙醇提取物 (AOE) 对高脂饮食 (HFD) 小鼠3T3-L1细胞脂质积累和肥胖的抗肥胖作用。AOE通过下调CCAAT增强子结合蛋白 α (C/ebp α)，固醇调节元件结合蛋白1 (SREBP-1) 和过氧化物酶体增殖物激活受体-γ (PPAR-γ) 基因，剂量依赖性地抑制3T3-L1前脂肪细胞分化过程中的脂质积累。高良姜是a.officinarum的主要成分，在3T3-L1细胞中具有抗脂肪作用。在喂食HFD的小鼠中补充AOE表明，AOE显着降低了HFD诱导的身体，肝脏和白色脂肪组织重量的增加，并降低了血清胰岛素和瘦素水平。为了阐明AOE对肥胖的抑制机制，确定了脂质代谢相关基因。AOE可有效抑制肝脏和脂肪组织中C/ebp α，脂肪酸合酶，SREBP-1和PPAR-γ 的蛋白表达。通过定量实时聚合酶链反应证实了通过免疫印迹观察到的蛋白质表达模式。总的来说，这些结果表明AOE通过抑制成脂和生脂基因来预防肥胖。AOE具有用作抗肥胖治疗剂的潜力，可以通过调节脂质代谢来发挥作用。

BACKGROUND & AIMS: :Understanding the regulation of human food intake in response to an acute exercise session is of importance for interventions with athletes and soldiers, as well as overweight individuals. However, the influence of hot and cold environments on this crucial function for the regulation of body mass and motor performance has not been summarized. The purpose of this review was to exhaustively search the literature on the effect of ambient temperature during an exercise session on the subsequent subjective feeling of appetite, energy intake (EI) and its regulation. In the absence of stress due to environmental temperature, exercise-induced energy expenditure is not compensated by EI during an ad libitum meal following the session, probably due to decreased acylated ghrelin and increased peptide tyrosine tyrosine (PYY), glucagon-like peptide 1 (GLP-1), and pancreatic polypeptide (PP) levels. No systematic analysis has been yet made for major alterations of relative EI in cold and hot environments. However, observed eating behaviors are altered (proportion of solid/liquid food, carbohydrate/fat) and physiological regulation appears also to be altered. Anorexigenic signals, particularly PYY, appear to further increase in hot environments than in those that are thermoneutral. Ghrelin and leptin may be involved in the observed increase in EI after exercise in the cold, in parallel with increased energy expenditure. The potential influence of ambient thermal environment on eating behaviors after an exercise session should not be neglected.

背景与目标： : 了解对急性运动过程中人类食物摄入量的调节对于对运动员和士兵以及超重个体的干预至关重要。但是，尚未总结冷热环境对调节体重和运动性能的关键功能的影响。这篇综述的目的是详尽地检索有关运动过程中环境温度对随后的主观食欲，能量摄入 (EI) 及其调节的影响的文献。在没有由于环境温度引起的压力的情况下，运动引起的能量消耗在饮食后的饮食过程中未被EI补偿，这可能是由于酰化ghrelin降低和肽酪氨酸 (PYY)，胰高血糖素样肽1 (GLP-1)，和胰多肽 (PP) 水平。尚未对冷热环境中相对EI的主要变化进行系统分析。但是，观察到的饮食行为发生了变化 (固体/液体食物，碳水化合物/脂肪的比例)，生理调节似乎也发生了变化。在炎热的环境中，厌食信号 (尤其是PYY) 似乎比在热中性环境中进一步增加。Ghrelin和leptin可能与寒冷运动后观察到的EI增加有关，同时增加了能量消耗。不应忽略运动后周围热环境对饮食行为的潜在影响。

BACKGROUND & AIMS: :Our knowledge on the physiological function of the insect Neuropeptide F (NPF) mostly comes from studies in the fruit fly, Drosophila melanogaster, where NPF was shown to regulate diverse processes, such as feeding, learning and responding to stress. In the desert locust, Schistocerca gregaria, only a truncated form of the "full-length" NPF (the biologically active "trNPF") has been isolated. In this study, we investigated whether this peptide is involved in the regulation of feeding in this orthopteran species. In the S. gregaria EST-database, an NPF-precursor encoding transcript was found. Alignment with other insect NPF-precursors showed relatively highest sequence conservation within the trNPF region (and the flanking dibasic cleavage site), as compared to other regions of the NPF-precursor. Quantitative real-time RT-PCR revealed that the Schgr-NPF-precursor encoding transcript occurs throughout the central nervous system with relatively high transcript levels in the brain, optic lobes and suboesophageal ganglion. It was also detected at relatively high levels in the midgut, which suggests that the encoded peptide also functions in the digestive system. Moreover, Schgr-NPF-transcript levels were notably higher in starved animals than in animals fed ad libitum, while transcript levels were also shown to be regulated after the consumption of a meal. Injection of locust trNPF in adults stimulated food intake, while RNAi knockdown reduced food intake. Furthermore, injection of trNPF in adults stimulated weight increase, while RNAi knockdown reduced weight gain. This effect of trNPF on body weight gain may result from its stimulatory effect on food intake. Taken together, we provide clear evidence for an important role of trNPF in the regulation of feeding in the desert locust, S. gregaria.

背景与目标： : 我们对昆虫神经肽F (NPF) 的生理功能的了解主要来自果蝇果蝇的研究，其中NPF被证明可以调节多种过程，例如进食，学习和应对压力。在沙漠蝗虫中，仅分离出 “全长” NPF (具有生物活性的 “trNPF”) 的截短形式。在这项研究中，我们调查了该肽是否参与了该直翅目物种的进食调节。在S. gregaria EST数据库中，发现了NPF前体编码转录本。与NPF前体的其他区域相比，与其他昆虫NPF前体的比对在trNPF区域 (和侧翼的二元切割位点) 内显示出相对最高的序列保守性。实时定量rt-pcr显示，Schgr-NPF前体编码转录本发生在整个中枢神经系统中，在大脑，视神经叶和食管下神经节中具有相对较高的转录本水平。在中肠中也检测到相对较高的水平，这表明编码的肽也在消化系统中起作用。此外，饥饿动物的Schgr-NPF转录水平明显高于随意喂养的动物，而食用餐后转录水平也受到调节。成人注射刺槐trNPF刺激了食物摄入，而RNAi敲低则减少了食物摄入。此外，在成年人中注射trNPF可刺激体重增加，而RNAi敲低可减少体重增加。trNPF对体重增加的这种影响可能是由于其对食物摄入的刺激作用所致。总而言之，我们为trNPF在沙漠蝗虫 (S. gregaria) 的摄食调节中的重要作用提供了明确的证据。

BACKGROUND & AIMS: Hormonal fluctuations associated with the menstrual cycle influence appetite control and eating behaviour. Energy intake varies during the reproductive cycle in humans and animals, with a periovulatory nadir and a luteal phase peak. Patterns of macronutrient selection show less consistency but a number of studies report carbohydrate cravings in the premenstrual phase, particularly in women with premenstrual syndrome. The cyclical nature of food cravings are frequently, but not invariably, associated with depression. Fluctuations in appetite, cravings and energy intake during the menstrual cycle may occur in parallel with cyclical rhythms in serotonin, which can be accompanied by affective symptoms. The premenstrual phase can be considered as a time when women are especially vulnerable to overconsumption, food craving and depression; this is often associated with low serotonin activity.

背景与目标： 与月经周期相关的荷尔蒙波动会影响食欲控制和饮食行为。在人类和动物的生殖周期中，能量摄入有所不同，具有排卵周期的最低点和黄体相峰。大量营养素选择的模式显示出较少的一致性，但许多研究报告称在经前期阶段对碳水化合物的渴望，尤其是在患有经前期综合征的女性中。食物渴望的周期性经常但并非总是与抑郁症有关。月经周期中食欲，渴望和能量摄入的波动可能与血清素的周期性节律同时发生，这可能伴有情感症状。经前期可以被认为是女性特别容易过度消费，食物渴望和抑郁的时期; 这通常与血清素活性低有关。

BACKGROUND & AIMS: OBJECTIVE:The intracellular signals that contribute to granulocyte colony-stimulating factor (G-CSF) receptor induced stem cell mobilization are poorly characterized. METHODS:We show enhanced G-CSF induced mobilization of stem cells in mice deficient in expression of Src family kinases (SFK-/-), which is associated with hypersensitivity of SFK-/- bone marrow cells to G-CSF as well as sustained activation of signal transducer and activator of transcription-3. RESULTS:A proteome map of the bone marrow fluid derived from wild-type and SFK-/- mice revealed a significant global reduction in the number of proteins in SFK-/- mice compared to controls, which was associated with elevated matrix metalloproteinase-9 levels, reduced stromal-derived factor-1 expression, and enhanced breakdown of vascular cell adhesion molecule-1. Transplantation of wild-type or SFK-/- stem cells into wild-type mice and treatment with G-CSF recapitulated the G-CSF-induced increase in stem cell mobilization noted in SFK-/- nontransplanted mice; however, the increase was significantly less. G-CSF treatment of SFK-/- mice engrafted with wild-type stem cells also demonstrated a modest increase in stem cell mobilization compared to controls, however, the observed increase was greatest in mice completely devoid of SFKs. CONCLUSIONS:These data suggest an involvement of both hematopoietic intrinsic and microenvironmental factors in Src kinase-mediated mobilization of stem cells and identify Src kinases as potential targets for modulating stem cell mobilization.

背景与目标：

BACKGROUND & AIMS: :Class-switch recombination (CSR) is essential for humoral immunity. However, the regulation of CSR is not completely understood. Here we demonstrate that phosphatidylinositol 3-kinase (PI3K) actively suppressed the onset and frequency of CSR in primary B cells. Consistently, mice lacking the lipid phosphatase, PTEN, in B cells exhibited a hyper-IgM condition due to impaired CSR, which could be restored in vitro by specific inhibition of PI3Kdelta. Inhibition of CSR by PI3K was partially dependent on the transcription factor, BLIMP1, linking plasma cell commitment and cessation of CSR. PI3K-dependent activation of the serine-threonine kinase, Akt, suppressed CSR, in part, through the inactivation of the Forkhead Box family (Foxo) of transcription factors. Reduced PI3K signaling enhanced the expression of AID (activation-induced cytidine deaminase) and accelerated CSR. However, ectopic expression of AID could not fully overcome inhibition of CSR by PI3K, suggesting that PI3K regulates both the expression and function of AID.

背景与目标： : 类别转换重组 (CSR) 对于体液免疫至关重要。然而，对企业社会责任的监管还没有完全理解。在这里，我们证明了磷脂酰肌醇3-激酶 (PI3K) 可以有效抑制原代b细胞中CSR的发作和频率。一致地，由于CSR受损，b细胞中缺乏脂质磷酸酶PTEN的小鼠表现出高IgM状态，可以通过特异性抑制PI3Kdelta在体外恢复。PI3K对CSR的抑制部分取决于转录因子BLIMP1，该转录因子将浆细胞的承诺与CSR的停止联系起来。丝氨酸-苏氨酸激酶Akt的PI3K-dependent激活部分通过转录因子的叉头盒家族 (Foxo) 的失活来抑制CSR。减少的PI3K信号增强了AID (激活诱导的胞苷脱氨酶) 的表达并加速了CSR。但是，AID的异位表达不能完全克服PI3K对CSR的抑制，这表明PI3K调节了AID的表达和功能。

BACKGROUND & AIMS: A variety of experimental models indicate that programmed cell death, or apoptosis, of lymphocytes is a key mechanism in the homeostatic regulation of immunity. Apoptosis is important in early B- and T-cell development to delete cells with nonfunctional antigen receptors, and is also critical for censoring self-reactive cells at the immature lymphocyte stage and at various stages after lymphocytes reach maturity. In this article we focus on the role of the apoptosis regulatory gene bcl-x in controlling survival during lymphocyte development and following B- and T-cell activation. Interesting parallels are observed for bcl-x expression between the B- and T-lineages. The available data also indicate that bcl-x and bcl-2 are expressed in reciprocal patterns during the lifespan of a lymphocyte, suggesting unique regulatory roles for these two survival proteins.

背景与目标： 多种实验模型表明，淋巴细胞的程序性细胞死亡或凋亡是免疫稳态调节的关键机制。凋亡在早期b细胞和T细胞发育中很重要，可以删除具有无功能抗原受体的细胞，并且对于在未成熟淋巴细胞阶段和淋巴细胞成熟后的各个阶段审查自我反应细胞也至关重要。在本文中，我们专注于凋亡调节基因bcl-x在控制淋巴细胞发育期间以及b细胞和T细胞活化后的存活中的作用。在B谱系和T谱系之间观察到bcl-x表达的有趣的相似之处。现有数据还表明，bcl-x和bcl-2在淋巴细胞的寿命期间以相互模式表达，这表明这两种存活蛋白具有独特的调节作用。

BACKGROUND & AIMS: :In rat frontal cortex, extracellular levels of glutamate are raised by the anti-psychotic drug clozapine. We have recently shown that a significant reduction in the levels of the glutamate transporter GLT-1 may be one of the mechanisms responsible for this elevation. Here we studied whether GLT-1 down-regulation induced by chronic clozapine treatment is associated with changes in the expression of synaptophysin, synaptosome-associated protein of 25 kDa (SNAP-25) and vesicular glutamate transporter 1 (VGLUT1), three major presynaptic proteins involved in neurotransmitter release. Quantitative high-resolution confocal microscopy studies in vivo showed that GLT-1 down-regulation is closely associated with a significant increase in synaptophysin, but not SNAP-25 and VGLUT1, expression. This was confirmed in vitro studies, and in western blotting studies of synaptophysin, SNAP-25 and VGLUT1. In addition, our results show that, following clozapine treatment, synaptophysin expression increases in the very cortical regions in which GLT-1 expression is down-regulated. These findings suggest that part of the effects of clozapine may be exerted via an action on the presynaptic machinery involved in neurotransmitter release.

背景与目标： : 在大鼠额叶皮层中，抗精神病药物氯氮平可提高谷氨酸的细胞外水平。我们最近表明，谷氨酸转运蛋白GLT-1水平的显着降低可能是导致这种升高的机制之一。在这里，我们研究了由慢性氯氮平治疗引起的GLT-1下调是否与突触素，突触体相关蛋白25 kDa (SNAP-25) 和囊泡谷氨酸转运蛋白1 (VGLUT1) 的表达变化有关神经递质释放的三种主要突触前蛋白。体内定量高分辨率共聚焦显微镜研究表明，GLT-1下调与突触素的显着增加密切相关，但与SNAP-25和VGLUT1的表达无关。这在体外研究以及突触素，SNAP-25和vglut1的蛋白质印迹研究中得到了证实。此外，我们的结果表明，氯氮平治疗后，突触素表达在GLT-1表达下调的皮质区域增加。这些发现表明，氯氮平的部分作用可能是通过对参与神经递质释放的突触前机制的作用来发挥的。

BACKGROUND & AIMS: The transcription factor E2F-1 interacts stably with cyclin A via a small domain near its amino terminus and is negatively regulated by the cyclin A-dependent kinases. Thus, the activities of E2F, a family of transcription factors involved in cell proliferation, are regulated by at least two types of cell growth regulatorsthe retinoblastoma protein family and the cyclin-dependent kinase family. To investigate further the regulation of E2F by cyclin-dependent kinases, we have extended our studies to include additional cyclins and E2F family members. Using purified components in an in vitro system, we show that the E2F-1-DP-1 heterodimer, the functionally active form of the E2F activity, is not a substrate for the active cyclin D-dependent kinases but is efficiently phosphorylated by the cyclin B-dependent kinases, which do not form stable complexes with the E2F-1-DP-1 heterodimer. Phosphorylation of the E2F-1-DP-1 heterodimer by cyclin B-dependent kinases, however, did not result in down-regulation of its DNA-binding activity, as is readily seen after phosphorylation by cyclin A-dependent kinases, suggesting that phosphorylation per se is not sufficient to regulate E2F DNA-binding activity. Furthermore, heterodimers containing E2F-4, a family member lacking the cyclin A binding domain found in E2F-1, are not efficiently phosphorylated or functionally down-regulated by cyclin A-dependent kinases. However, addition of the E2F-1 cyclin A binding domain to E2F-4 conferred cyclin A-dependent kinase-mediated down-regulation of the E2F-4-DP-1 heterodimer. Thus, both enzymatic phosphorylation and stable physical interaction are necessary for the specific regulation of E2F family members by cyclin-dependent kinases.

背景与目标： 转录因子E2F-1通过其氨基末端附近的小结构域与细胞周期蛋白A稳定相互作用，并被细胞周期蛋白a依赖性激酶负调控。因此，E2F (参与细胞增殖的转录因子家族) 的活性受至少两种类型的细胞生长调节剂 (视网膜母细胞瘤蛋白家族和细胞周期蛋白依赖性激酶家族) 调节。为了进一步研究细胞周期蛋白依赖性激酶对E2F的调节，我们已将研究扩展到包括其他细胞周期蛋白和E2F家族成员。在体外系统中使用纯化的组分，我们表明E2F-1-DP-1异二聚体，即E2F活性的功能活性形式，不是活性细胞周期蛋白D依赖性激酶的底物，而是被细胞周期蛋白B依赖性激酶有效磷酸化，其不与E2F-1-DP-1异二聚体形成稳定的复合物。然而，细胞周期蛋白B依赖性激酶对E2F-1-DP-1异二聚体的磷酸化并未导致其DNA结合活性的下调，正如在细胞周期蛋白A依赖性激酶磷酸化后容易看到的那样，这表明磷酸化本身不足以调节e2fdna结合活性。此外，含有E2F-4的异二聚体 (缺乏E2F-1中发现的细胞周期蛋白a结合结构域的家族成员) 不能被细胞周期蛋白A依赖性激酶有效地磷酸化或功能下调。然而，将E2F-1细胞周期蛋白A结合结构域添加到E2F-4赋予细胞周期蛋白A依赖性激酶介导的E2F-4-DP-1异二聚体的下调。因此，酶促磷酸化和稳定的物理相互作用对于细胞周期蛋白依赖性激酶对E2F家族成员的特异性调节都是必需的。

BACKGROUND & AIMS: :Auto-anti-idiotypic mechanisms can regulate the protective immune response against Schistosoma mansoni. Anti-idiotypic responses were stimulated by immunization of mice either with nonspecifically induced lymphoblasts, produced with Con A, or with Ag-induced lymphoblasts bearing specific idiotypic receptors. The effect of the induced anti-idiotypic response upon clonotypic cellular reactivity was assessed in vitro through the suppression of antigen-mediated blast transformation by cloned T cells and in vivo by suppression of resistance to S. mansoni and delayed-type hypersensitivity responses against specific Ag. Differential regulation of humoral immune responses was studied at the levels of specific epitopic recognition, the expression of specific Id, and the production of anti-idiotypic responses directed against mAb bearing specific Id. Anti-idiotypic sensitization resulted in variable (10 to 90%) suppression of the immune response to discrete antigenic epitopes, the expression of specific idiotypic phenotypes, and anti-idiotypic, antiparatopic responses against T cell clonotypes and antibody idiotypic phenotypes. In vitro admixture and in vivo challenge studies resulted in consonant differential suppression. Thus idiotypic regulation can mold the fine specificities of the protective immune response to S. mansoni at the clonal level and may provide an approach to optimize the expression and assessment of resistance.

背景与目标： : 自身抗独特型机制可以调节曼氏血吸虫的保护性免疫反应。通过用Con A产生的非特异性诱导的淋巴母细胞或带有特定独特型受体的Ag诱导的淋巴母细胞免疫小鼠来刺激抗独特型反应。诱导的抗独特型反应对克隆型细胞反应性的影响在体外通过克隆的T细胞抑制抗原介导的胚转化进行评估，并在体内通过抑制对曼氏杆菌的抗性和对特异性Ag的延迟型超敏反应进行评估。在特定的表位识别，特定Id的表达以及针对带有特定Id的mAb的抗独特型反应的产生的水平上研究了体液免疫反应的差异调节。抗独特型致敏作用导致对离散抗原表位的免疫应答、特定独特型表型的表达以及针对T细胞克隆型和抗体独特型表型的抗独特型、抗独特型应答的可变 (10至90%) 抑制。体外混合和体内激发研究导致辅音差异抑制。因此，独特型调节可以在克隆水平上塑造对曼氏杆菌的保护性免疫反应的精细特异性，并可能提供一种优化表达和评估抗性的方法。