Cyclophosphamide-impaired regulation of hepatic heme metabolism

Summary Im male rats hepatic cytochromes b₅ and P-450 were reduced at different times after treatment with cyclophosphamide (CP) (200 mg/kg i.p. for 3 days). In contrast, microsomal heme did not change until 48 h after the last dose of CP, leading to accumulation of heme in a non-cytochromal form. Parallel to the above changes the heme metabolism showed derangement: -aminolaevulinate synthase, the rate-limiting enzyme in heme synthesis, was depressed and heme oxygenase, the enzyme which catalyzes the oxidative degradation of heme, was increased.     

不适定逆成像问题的多准则正则化求解方法

不适定性（ｉｌｌ－ｐｏｓｅｄｎｅｓｓ）是图像重建（Ｘ射线ＣＴ的投影重建、心电ＥＣＧ及电ＥＥＧ信号的逆成像重建）逆问题求解中非常普遍的情况,由于对观测数据及正问题数字离散化过程中所产生的误差极为敏感,它在银行大程度上将影响到重建图像的质量、稳定性和求解精度。通过对由投影重建图像逆问题求解过程中的不适宜性分析,给出了求解不适定逆成像问题的多准则正则化方法及其理论基础,实验结果表明该方法比传统的单准则正     

Ebola virus entry requires the cholesterol transporter Niemann-Pick C1

Infections by the Ebola and Marburg filoviruses cause a rapidly fatal haemorrhagic fever in humans for which no approved antivirals are available. Filovirus entry is mediated by the viral spike glycoprotein (GP), which attaches viral particles to the cell surface, delivers them to endosomes and catalyses fusion between viral and endosomal membranes. Additional host factors in the endosomal compartment are probably required for viral membrane fusion; however, despite considerable efforts, these critical host factors have defied molecular identification. Here we describe a genome-wide haploid genetic screen in human cells to identify host factors required for Ebola virus entry. Our screen uncovered 67 mutations disrupting all six members of the homotypic fusion and vacuole protein-sorting (HOPS) multisubunit tethering complex, which is involved in the fusion of endosomes to lysosomes, and 39 independent mutations that disrupt the endo/lysosomal cholesterol transporter protein Niemann-Pick C1 (NPC1). Cells defective for the HOPS complex or NPC1 function, including primary fibroblasts derived from human Niemann-Pick type C1 disease patients, are resistant to infection by Ebola virus and Marburg virus, but remain fully susceptible to a suite of unrelated viruses. We show that membrane fusion mediated by filovirus glycoproteins and viral escape from the vesicular compartment require the NPC1 protein, independent of its known function in cholesterol transport. Our findings uncover unique features of the entry pathway used by filoviruses and indicate potential antiviral strategies to combat these deadly agents.     

Epigenetic asymmetry of imprinted genes in plant gametes

Plant imprinted genes show parent-of-origin expression in seed endosperm, but little is known about the nature of parental imprints in gametes before fertilization. We show here that single differentially methylated regions (DMRs) correlate with allele-specific expression of two maternally expressed genes in the seed and that one DMR is differentially methylated between gametes. Thus, plants seem to have developed similar strategies as mammals to epigenetically mark imprinted genes.     

Multiplicative computation in a visual neuron sensitive to looming

Multiplicative operations are important in sensory processing, but their biophysical implementation remains largely unknown. We investigated an identified neuron (the lobula giant movement detector, LGMD, of locusts) whose output firing rate in response to looming visual stimuli has been described by two models, one of which involves a multiplication. In this model, the LGMD multiplies postsynaptically two inputs (one excitatory, one inhibitory) that converge onto its dendritic tree; in the other model, inhibition is presynaptic to the LGMD. By using selective activation and inactivation of pre- and postsynaptic inhibition, we show that postsynaptic inhibition has a predominant role, suggesting that multiplication is implemented within the neuron itself. Our pharmacological experiments and measurements of firing rate versus membrane potential also reveal that sodium channels act both to advance the response of the LGMD in time and to map membrane potential to firing rate in a nearly exponential manner. These results are consistent with an implementation of multiplication based on dendritic subtraction of two converging inputs encoded logarithmically, followed by exponentiation through active membrane conductances.     

非嵌插类DNA结合药物的碱基序列特异性

本文讨论了非嵌插类DNA结合药物的碱基序列特异性,这对于探讨药物与DNA相互作用的分子机制是很有意义的。通过这些探索,得到了一些有意义的结果。     

Site-specific DICER and DROSHA RNA products control the DNA-damage response

Non-coding RNAs (ncRNAs) are involved in an increasingly recognized number of cellular events. Some ncRNAs are processed by DICER and DROSHA RNases to give rise to small double-stranded RNAs involved in RNA interference (RNAi). The DNA-damage response (DDR) is a signalling pathway that originates from a DNA lesion and arrests cell proliferation3. So far, DICER and DROSHA RNA products have not been reported to control DDR activation. Here we show, in human, mouse and zebrafish, that DICER and DROSHA, but not downstream elements of the RNAi pathway, are necessary to activate the DDR upon exogenous DNA damage and oncogene-induced genotoxic stress, as studied by DDR foci formation and by checkpoint assays. DDR foci are sensitive to RNase A treatment, and DICER- and DROSHA-dependent RNA products are required to restore DDR foci in RNase-A-treated cells. Through RNA deep sequencing and the study of DDR activation at a single inducible DNA double-strand break, we demonstrate that DDR foci formation requires site-specific DICER- and DROSHA-dependent small RNAs, named DDRNAs, which act in a MRE11–RAD50–NBS1-complex-dependent manner (MRE11 also known as MRE11A; NBS1 also known as NBN). DDRNAs, either chemically synthesized or in vitro generated by DICER cleavage, are sufficient to restore the DDR in RNase-A-treated cells, also in the absence of other cellular RNAs. Our results describe an unanticipated direct role of a novel class of ncRNAs in the control of DDR activation at sites of DNA damage.