Endosomal microautophagy is an integrated part of the autophagic response to amino acid starvation

Starvation is a fundamental type of stress naturally occurring in biological systems. All organisms have therefore evolved different safeguard mechanisms to cope with deficiencies in various types of nutrients. Cells, from yeast to humans, typically respond to amino acid starvation by initiating degradation of cellular components by inducing autophagy. This degradation releases metabolic building blocks to sustain essential core cellular processes. Increasing evidence indicates that starvation-induced autophagy also acts to prepare cells for prolonged starvation by degrading key regulators of different cellular processes. In a recent study, we found that within the first hours of amino acid starvation cells elicit an autophagic response causing rapid degradation of specific proteins. The response is executed independently of both MTOR and canonical macroautophagy. Based on RNAi-mediated knockdown of essential components of the Endosomal Sorting Complex Required for Transport (ESCRT) machinery and electron microscopy we conclude that the response relies on some sort of endosomal microautophagy, hence vesicle budding into endosomes. Substantiated by the different substrates that are selectively degraded by this novel pathway we propose that the response predominantly acts to prepare cells for prolonged starvation. Intriguingly, this includes shutting down selective macroautophagy in preparation for a massive induction of bulk macroautophagy.     

Mathematical Model for Optimal Use of Sulfadoxine-Pyrimethamine as a Temporary Malaria Vaccine

In this paper, we introduce a deterministic malaria model for determining the drug administration protocol that leads to the smallest first malaria episodes during the wet season. To explore the effects of administering the malaria drug on different days during the wet season while minimizing the potential harmful effects of drug overdose, we define 40 drug administration protocols. Our results fit well with the clinical studies of Coulibaly et al. at a site in Mali. In addition, we provide protocols that lead to smaller number of first malaria episodes during the wet season than the protocol of Coulibaly et al.     

新疆伊犁维吾尔族和哈萨克族苯硫脲尝味能力测定

用阈值法对新疆伊犁的维吾尔族１２７４人,哈萨克族２０８０人的苯硫脲尝味能力进行了测定。结果表明,维吾尔族中味盲率为１５．２３％,味盲基因频率为０．３９０２,平均尝味阈值为６．９７±２．８７;哈萨克族中味盲率为１８．１２％,味盲基因频率为０．４２５７,平均尝味阈值为６．４４±２．９４。经显性检验,在维吾尔族和哈萨克族中,味盲率,平均尝味阈值和味盲基因频率在同一民族男女间无明显差异,在维吾尔族和哈萨     

Phenolic content of Terminalia catappa L. leaf and toxicity evaluation on red hybrid tilapia (Oreochromis sp.)

Despite the use of Terminalia catappa (TC) leaf by traditional fish farmers around the world to improve the health status of cultured fish, there is a paucity of information on comprehensive metabolite profile and the maximum safe dose of the plant. This study aims at profiling the methanol leaf extract of T. catappa, quantifying total phenolic content (TPC) as well as the total flavonoid content (TFC) and evaluating its acute toxicity on blood, plasma biochemical parameters and histopathology of some vital organs in red hybrid tilapia (Oreochromis sp.). The experimental fish were acclimatised for 2 weeks and divided into six groups. Group (1) served as a control group and was administered 0.2 ml,g⁻¹ of phosphate buffer saline (PBS). Groups 2–6 were orally administered T. catappa leaf extracts (0.2 ml.50 g⁻¹) in the following sequence; 31.25, 62.5, 125, 250 and 500 mg.kg⁻¹ body weight. The metabolites identified in T. catappa using liquid chromatography-tandem mass electrospray ionisation spectrometry (LC-ESI-MS/MS) revealed the presence of organic acids, hydrolysable tannins, phenolic acids and flavonoids. Phenolic quantification revealed reasonable quantity of phenolic compounds (217.48 μg GAEmg⁻¹ for TPC and 91.90 μg. QCEmg⁻¹ for TFC). Furthermore, there was no significant difference in all the tested doses in terms of blood parameters and plasma biochemical analysis except for the packed cell volume (PCV) at 500 mg.kg⁻¹ when compared to the control. Significant histopathological changes were observed in groups administered with the extract at 125, 250 and 500 mg.kg⁻¹ doses. To a very large extent it is therefore safe to administer the extract at 31.25 and 62.5 mg.kg⁻¹ in tilapia.     

Murine retrovirus escapes from murine APOBEC3 via two distinct novel mechanisms

APOBEC3G (A3G) is an antiretroviral host factor that functions by deaminating dC to dU in retroviral cDNA. HIV-1 Vif protein counteracts A3G via a ubiquitin-proteasome pathway. In the case of a simple retrovirus such as the murine leukemia virus (MLV), it remains unclear why it can replicate in cells expressing APOBEC3 (A3) even though it doesn't possess any accessory proteins such as Vif. In this study, we demonstrate that MLV escapes from murine A3 (mA3) via two distinct novel mechanisms. First, viral RNA (vRNA) blocks the binding of mA3 to Gag, resulting in the exclusion of mA3 from MLV virions. Second, viral protease (vPR) cleaves mA3 after maturation of virions. Here, we suggest that each virus has its own strategy to escape from A3 proteins and that these mechanisms might be used by other viruses that do not possess Vif-like protein. On the other hand, mice possess another form of mA3, delta exon5, that escapes from the cleavage by vPR to show more antiviral activity than the wild type mA3. This also suggests that battles between host intrinsic immunity and viruses have led to the evolution of proteins on both sides.     

The enzymatic activity of CEM15/Apobec-3G is essential for the regulation of the infectivity of HIV-1 virion but not a sole determinant of its antiviral activity

Human immunodeficiency virus, type 1 (HIV-1) Vif protein plays an essential role in the regulation of the infectivity of HIV-1 virion. Vif functions to counteract an anti-HIV-1 cellular factor in non-permissive cells, CEM15/Apobec-3G, which shares a cytidine deaminase motif. CEM15/Apobec-3G deaminates dC to dU in the minus strand DNA of HIV-1, resulting in G to A hypermutation in the plus strand DNA. In this study, we have done the mutagenesis analysis on two cytidine deaminase motifs in CEM15/Apobec-3G and examined their antiviral functions as well as the DNA editing activity. Point mutations in the C-terminal active site such as E259Q and C291A almost completely abrogated the antiviral function, while those in the N-terminal active site such as E67Q and C100A retained this activity to a lesser extent as compared with that of the wild type. The DNA editing activities of E67Q and E259Q mutants were both retained but impaired to the same extent. This indicates that the enzymatic activity of this protein is essential but not a sole determinant of the antiviral activity. Furthermore, all the deletion mutants tested in this study lost the antiviral activity because of the loss of the activity for dimerization, suggesting that the entire protein structure is necessary for the antiviral function.     

Monarch butterfly spatially discrete advection model

We study the population cycles of the Monarch butterfly using one of the simplest systems incorporating both migration and local dynamics. The annual migration of the Monarch involves four generations. Members of Generations 1-3 (occasionally 4) migrate from the over-wintering site in Central Mexico to breeding grounds that extend as far north as the Northern United States and Southern Canada. A portion of the Generation 3 and all members of the Generation 4 butterflies begin their return to the over-wintering grounds in August through October where they enter reproductive diapause for several months. We developed a simple discrete-time island chain model in which different fecundity functions are used to model the reproductive strategies of each generation. The fecundity functions are selected from broad classes of functions that capture the effects of either contest or scramble intraspecific competition in the Monarch population. The objectives of our research are multiple and include the study of the generationally dependent intraspecific competition and its effect on the pool size of migrants as well as the persistence of the overall butterfly populations. The stage structure used in modeling the Monarch butterfly dynamics and their generationally dependent reproductive strategies naturally support fluctuating patterns and multiple attractors. The implications of these fluctuations and attractors on the long-term survival of the Monarch butterfly population are explored.     

Regulation of ET-1 biosynthesis in cerebral microvascular endothelial cells by vasoactive agents and PKC

Endothelin-1(ET-1) is the most potent vasoconstrictor agent known. ET-1 is elevatedin the cerebrospinal fluid following hemorrhage and brain injury andcan compromise cerebral microvascular homeostasis. The modulation ofET-1 production by cerebral microvascular endothelial cells and themechanism by which such changes take place are very important in ourunderstanding of the pathological roles of ET-1. In the present study,we investigated the effects of vasoconstrictor agents that can bereleased from hemolyzed blood, cAMP-dependent dilators, and the role ofprotein kinase C (PKC) in the regulation of ET-1 production by pigletcerebral microvascular endothelial cells in culture. ET-1 was measured by RIA. 1) Cerebral microvascularendothelial cells synthesize and release ET-1 into the media;2) 5-hydroxytryptamine (5-HT), lysophosphatidic acid (LPA), thromboxane analog U-46619, fetal bovineserum (20%), and phorbol 12-myristate 13-acetate significantly increase ET-1 production; 3) basaland vasoconstrictor agent-induced increases in ET-1 production byendothelial cells may be mediated via PKC;4) cAMP-dependent vasodilatorsattenuate the basal production of ET-1 by cerebral microvessels; and5) pretreatment of endothelial cellswith a higher concentration of LPA, U-46619, or 5-HT counterbalances the cAMP-dependent dilator agent-induced reduction in basal ET-1 production. Therefore, by-products of hemolyzed blood can stimulate theproduction of ET-1 by a PKC-mediated mechanism. cAMP-dependent dilatorscan attenuate the vasoconstrictor agent-induced elevation in ET-1production. These results suggest that cerebral microvascular homeostasis could be compromised by effects of interactions among vasoactive agents released during conditions injurious to the brain andthey may further the understanding of potential contributions ofhemolyzed blood clots to subarachnoid hemorrhage-induced vasospasm.