RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis

RANK ligand (RANKL), a TNF-related molecule, is essential for osteoclast formation, function and survival through interaction with its receptor RANK. Mammary glands of RANK- and RANKL-deficient mice develop normally during sexual maturation, but fail to form lobuloalveolar structures during pregnancy because of defective proliferation and increased apoptosis of mammary epithelium. It has been shown that RANKL is responsible for the major proliferative response of mouse mammary epithelium to progesterone during mammary lactational morphogenesis, and in mouse models, manipulated to induce activation of the RANK/RANKL pathway in the absence of strict hormonal control, inappropriate mammary proliferation is observed. However, there is no evidence so far of a functional contribution of RANKL to tumorigenesis. Here we show that RANK and RANKL are expressed within normal, pre-malignant and neoplastic mammary epithelium, and using complementary gain-of-function (mouse mammary tumour virus (MMTV)-RANK transgenic mice) and loss-of function (pharmacological inhibition of RANKL) approaches, define a direct contribution of this pathway in mammary tumorigenesis. Accelerated pre-neoplasias and increased mammary tumour formation were observed in MMTV-RANK transgenic mice after multiparity or treatment with carcinogen and hormone (progesterone). Reciprocally, selective pharmacological inhibition of RANKL attenuated mammary tumour development not only in hormone- and carcinogen-treated MMTV-RANK and wild-type mice, but also in the MMTV-neu transgenic spontaneous tumour model. The reduction in tumorigenesis upon RANKL inhibition was preceded by a reduction in pre-neoplasias as well as rapid and sustained reductions in hormone- and carcinogen-induced mammary epithelial proliferation and cyclin D1 levels. Collectively, our results indicate that RANKL inhibition is acting directly on hormone-induced mammary epithelium at early stages in tumorigenesis, and the permissive contribution of progesterone to increased mammary cancer incidence is due to RANKL-dependent proliferative changes in the mammary epithelium. The current study highlights a potential role for RANKL inhibition in the management of proliferative breast disease.     

Prenatal and early life home environment exposure in relation to preschool children’s asthma, allergic rhinitis and eczema in Taiyuan, China

Prenatal and early life home environment might be related to children’s asthma or allergic diseases later in life.A cross-sectional epidemiological study was designed and a questionnaire survey was performed in 3700 preschool children in urban areas in Taiyuan,Shanxi Province,China.Questions on children’s asthma and allergic diseases from the International Study on Asthma and Allergies in Childhood(ISAAC)were integrated with questions on home environment from the Swedish Dampness in Buildings and Health(DBH)study,appropriately modified for Chinese life habits.By multivariate regression analyses controlling for age,gender,heredity,location in urban/suburban or rural areas,environmental tobacco smoke(ETS)and breastfeeding,we found that home new furniture(HNF)before birth(referring to 1 year before pregnancy and during pregnancy)was positively associated with wheezing ever(odds ratio(OR)1.23 with 95%CI of 1.03–1.48)and wheezing last 12 months(1.24,1.00–1.54),allergic rhinitis(AR)(1.26,1.06–1.51),and eczema(1.42,1.01–1.99).HNF between 0–1 years old was also positively associated with wheezing last 12 months.Home new decoration(HND)during 0–1 years old was positively associated with AR symptoms and eczema symptoms,more in the last 12 months.Stronger positive associations were found for signs of home mold and dampness with almost all children’s asthmatic and allergic symptoms(OR ranging from 1.23–1.85,P<0.05).By mutual adjustment between HNF before children’s birth and home mold or dampness,all the significance remained unchanged.Prenatal HNF and home mold or dampness was independently associated with children’s asthmatic and allergic diseases later in life.     

Nitrogen saturation and net ecosystem production

Magnani et al. found that net carbon (C) sequestration of temperate and boreal forests is clearly driven by nitrogen (N) deposition. From the positive relationship between average net ecosystem production (NEP) and wet N deposition, the authors further conclude that "no signs of N saturation were apparent" in the studied forests and that this is "casting doubts on the risk of widespread ecosystem nitrogen saturation". Nitrogen additions can clearly alter net ecosystem production, but net ecosystem production cannot be used as an indicator of N saturation.     

Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance

Recognition of self-antigen-derived epitopes presented by major histocompatibility complex class II (MHC II) molecules on thymic epithelial cells (TECs) is critical for the generation of a functional and self-tolerant CD4 T-cell repertoire. Whereas haematopoietic antigen-presenting cells generate MHC-II-peptide complexes predominantly through the processing of endocytosed polypeptides, it remains unknown if and how TECs use unconventional pathways of antigen presentation. Here we address the role of macroautophagy, a process that has recently been shown to allow for endogenous MHC II loading, in T-cell repertoire selection in the mouse thymus. In contrast to most other tissues, TECs had a high constitutive level of autophagy. Genetic interference with autophagy specifically in TECs led to altered selection of certain MHC-II-restricted T-cell specificities and resulted in severe colitis and multi-organ inflammation. Our findings indicate that autophagy focuses the MHC-II-peptide repertoire of TECs on their intracellular milieu, which notably comprises a wide array of otherwise strictly 'tissue-specific' self antigens. In doing so, it contributes to T-cell selection and is essential for the generation of a self-tolerant T-cell repertoire.     

Peptidergic transmitters in synaptic boutons of sympathetic ganglia

In sympathetic ganglia of the bullfrog, a slow synaptic potential lasting for minutes--the late slow excitatory postsynaptic potential (e.p.s.p.)--was discovered. This slow response, unlike other previously known synaptic potentials in the autonomic nervous system, is not mediated by acetylcholine or monoamines. Similar non-cholinergic, non-adrenergic slow synaptic potentials have since been found in several other vertebrate autonomic ganglia. We found that the late slow e.p.s.p. is probably mediated by a peptide that is identical to, or closely resembles, mammalian luteinizing hormone releasing hormone (LHRH), because (1) when applied directly to sympathetic neurones, LHRH and its agonists elicit a slow depolarization, associated with similar changes in membrane conductance and excitability as those occurring during the late slow e.p.s.p. Furthermore, both peptide-induced and nerve-evoked responses are blocked by antagonists of LHRH; and (2) radioimmunoassays indicate that a chain of sympathetic ganglia contains 100-800 pg of a LHRH-like peptide. Its distribution among spinal nerves, the great reduction of this substance following denervation, and its release from ganglia following isotonic KCl treatment or nerve stimulation suggest that the LHRH-like material is contained in preganglionic nerve fibres. Here we report that immunohistochemical staining of sympathetic ganglia shows that LHRH-like immunoreactivity is indeed present in synaptic boutons. We also show that the two types of ganglion cells (B cells and C cells) receive strikingly different patterns of peptidergic innervation.     

一种改进的启发式属性约简算法

文章对现有启发式属性约简算法进行分析,通过实例说明一般启发式算法求得的相对约简有冗余属性存在的问题.针对这一不足,在算法中加入消除冗余属性的二次约简过程,得到一种改进的启发式属性约简算法.提供了实例分析,验证了该改进算法具有较好的约简效果.     

Fenton氧化工艺处理石油树脂生产废水研究

试验研究了难生物降解石油树脂生产废水Fenton氧化处理效果,考查了各影响因子最佳工艺条件.结果表明,在pH值为2.5、FeSO4投加量为800 mg·L-1、H2O2投加量为3000 mg·L-1、反应时间为2 h、反应温度为50～55℃的条件下,Fenton氧化工艺COD去除率为73%左右.将Fenton氧化处理水同低浓度含油废水混合后经进一步混凝沉淀处理,处理水COD值可降低至350 mg·L-1左右,达到了污水三级排放标准(COD<500 mg·L-1).     

运筹学线性规划模型求解的计算机应用

结合一特定的线性规划数学模型,在转换为计算机能够识别的格式的基础上,用Excel的solver得出其结果报告及灵敏度分析报告,并简单地对其进行分析,从而为解决线性规划模型手工操作精度低、周期长的问题提供了一条有效途径。     

基于从头算量化参数的BPx网络模型在吡啶类化合物pKa中的应用

用量子化学从头算RHF方法在6-31G水平下对吡啶类分子进行构型全优化,并用优化得到的量化参数作为反向传播人工神经网络的输入向量,并将此模型（人工神经网络）应用到吡啶类化合物pKa值的预测。将预测结果与多元线性回归算法的结果相比较。研究表明,所构造的人工神经网模型在预测吡啶类化合物的pKa值中得到满意的结果．