A druggable addiction to de novo pyrimidine biosynthesis in diffuse midline glioma

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New advances in Amyotrophic Lateral Sclerosis genetics: Towards gene therapy opportunities for familial and young cases

Due to novel gene therapy opportunities, genetic screening is no longer restricted to familial cases of ALS (FALS) cases but also aplies to the sporadic populations (SALS). Screening of four main genes (C9orf72, SOD1, TARDBP and FUS) identified the causes in 15% of Amyotrophic Lateral Sclerosis (ALS) patients (two third of the familial cases and 8% of the sporadic ones) but their respective contribution to ALS phenotype varies according the age of disease onset. The genetic overlap between ALS and other diseases is expanding and includes frontotemporal dementia, Paget's Disease of Bone, myopathy for adult cases, HSP and CMT for young cases highlighing the importance of retrieving the exhaustive familial history for each indivdual with ALS. Incomplete disease penetrance, diversity of the possible phenotypes, as well as the lack of confidence concerning the pathogenicity of most identified variants and/or possible oligogenic inheritance are burdens of ALS genetic counseling to be delivered to patients and at risk individuals. The multitude of rare ALS genetic causes identifed seems to converge to similar cellular pathways leading to inapropriate response to stress emphacising new potential therapeutic options for the disease.     

新疆生产建设兵团第十三师天然草地资源现状及其利用探讨

新疆生产建设兵团第十三师位于在新疆东部哈密市,辖区有8个团场。十三师草场面积占兵团草场面积的15.7%,是兵团草场面积最大的师。十三师草原生态十分脆弱,主要以荒漠、半荒漠草场为主。除了部分与地方乡镇接壤草场以外,草场承包确权工作基本完成。由于超载放牧、基础设施落后、防灾减灾能力弱等原因,导致天然草场退化、沙化,有毒、有害植物增加,产草量和草质量明显下降,影响牧民收入。超载放牧是草场退化的根本原因,本文围绕这个主题,对草场面临的困难和难题进行分析,并提出了建设性的建议。通过异地搬迁、办理贷款及改善牧民生产生活等措施,减少天然草原载畜量,减轻夏草场放牧强度,逐步达到草畜平衡的目标,为十三师畜牧业可持续健康发展提供理论基础。     

The different roles of selective autophagic protein degradation in mammalian cells

Autophagy is an intracellular pathway for bulk protein degradation and the removal of damaged organelles by lysosomes. Autophagy was previously thought to be unselective; however, studies have increasingly confirmed that autophagy-mediated protein degradation is highly regulated. Abnormal autophagic protein degradation has been associated with multiple human diseases such as cancer, neurological disability and cardiovascular disease; therefore, further elucidation of protein degradation by autophagy may be beneficial for protein-based clinical therapies. Macroautophagy and chaperone-mediated autophagy (CMA) can both participate in selective protein degradation in mammalian cells, but the process is quite different in each case. Here, we summarize the various types of macroautophagy and CMA involved in determining protein degradation. For this summary, we divide the autophagic protein degradation pathways into four categories: the post-translational modification dependent and independent CMA pathways and the ubiquitin dependent and independent macroautophagy pathways, and describe how some non-canonical pathways and modifications such as phosphorylation, acetylation and arginylation can influence protein degradation by the autophagy lysosome system (ALS). Finally, we comment on why autophagy can serve as either diagnostics or therapeutic targets in different human diseases.     

The Cystine Knot Is Responsible for the Exceptional Stability of the Insecticidal Spider Toxin ω-Hexatoxin-Hv1a

The inhibitor cystine knot (ICK) is an unusual three-disulfide architecture in which one of the disulfide bonds bisects a loop formed by the two other disulfide bridges and the intervening sections of the protein backbone. Peptides containing an ICK motif are frequently considered to have high levels of thermal, chemical and enzymatic stability due to cross-bracing provided by the disulfide bonds. Experimental studies supporting this contention are rare, in particular for spider-venom toxins, which represent the largest diversity of ICK peptides. We used ω-hexatoxin-Hv1a (Hv1a), an insecticidal toxin from the deadly Australian funnel-web spider, as a model system to examine the contribution of the cystine knot to the stability of ICK peptides. We show that Hv1a is highly stable when subjected to temperatures up to 75 °C, pH values as low as 1, and various organic solvents. Moreover, Hv1a was highly resistant to digestion by proteinase K and when incubated in insect hemolymph and human plasma. We demonstrate that the ICK motif is essential for the remarkable stability of Hv1a, with the peptide’s stability being dramatically reduced when the disulfide bonds are eliminated. Thus, this study demonstrates that the ICK motif significantly enhances the chemical and thermal stability of spider-venom peptides and provides them with a high level of protease resistance. This study also provides guidance to the conditions under which Hv1a could be stored and deployed as a bioinsecticide.     

The in vitro effect of antimicrobial photodynamic therapy with indocyanine green on Enterococcus faecalis: Influence of a washing vs non-washing procedure

IntroductionThe purpose of this study was to evaluate the in vitro effect of washing and non-washing of indocyanine green (ICG) as photosensitizer (PS) on bacterial count, biofilm formation, development and degradation of Enterococcus faecalis.MethodsThe anti-bacterial, anti-biofilm formation, anti-biofilm development and biofilm degradation of anti-microbial photodynamic therapy (aPDT) against E. faecalis was determined at concentrations of 3 to 2000 μg/mL of ICG, subject to 18 J/cm² dose of diode laser (808 nm) in washing and non-washing producers. Bacterial viability measurements and biofilm assays were evaluated by broth microdilution method and crystal violet assays, respectively.ResultsICG-mediated aPDT, using 25 to 2000 μg/mL and 50 to 2000 μg/mL showed significant reduction in E. faecalis growth when compared to the control in non-washing and washing producers, respectively (P < 0.05). Also, ICG-mediated aPDT showed a significantly inhibitory effect on biofilm formation of E. faecalis in concentration of 6 to 2000 μg/mL and 100 to 2000 μg/mL in non-washing and washing groups (P < 0.05). The biofilm development was inhibited by concentrations of 12 to 2000 μg/mL and 100 to 2000 μg/mL in non-washing and washing groups. The biofilm degradation increased from concentrations of 12 to 2000 μg/mL and 250 to 2000 μg/mL in non-washing and washing groups, respectively.ConclusionThis study shows that the application of ICG should be accompanied by laser irradiation without being washed out to achieve better result for bacterial count reduction and anti-biofilm effects.     

Carotenoid stability during storage of yellow gari made from biofortified cassava or with palm oil

The carotenoid composition of gari made from biofortified cassava (BG) was compared to that of existing gari of similar appearance but made from white cassava with added red palm oil (RPG). Storage of both yellow gari products was modelled at ambient temperatures typical of tropical areas (19–40 °C) over a 3-month-period at constant relative humidity. Carotenoid content and hence vitamin A activity of the gari products decreased markedly with time and temperature. Trans-β-carotene degradation fitted well the kinetics predicted by the Arrhenius model, in particular for BG. Activation energies for trans-β-carotene were 60.4 and 81.0 kJ mol⁻¹ for BG and RPG respectively (R² = 0.998 and 0.997, respectively); hence the minimum energy to cause degradation of trans-β-carotene in gari was lower with BG. Rates of degradation of 9-cis-β-carotene in gari were of the same order as with trans-β-carotene. Although the initial content of trans-β-carotene was twice as high in the BG compared to RPG, trans-β-carotene in BG degraded much faster. Results showed that the average shelf life at ambient temperature for BG was significantly shorter than for RPG and therefore carotenoids in BG were less stable than in RPG.     

Effect of Scavenging Circulating Reactive Carbonyls by Oral Pyridoxamine in Uremic Rats on Peritoneal Dialysis

Pyridoxamine, a reactive carbonyl (RCO) scavenger, can ameliorate peritoneal deterioration in uremic peritoneal dialysis (PD) rats when given via dialysate. We examined the effects of scavenging circulating RCOs by oral pyridoxamine. Rats underwent nephrectomy and 3 weeks of twice daily PD either alone or with once daily oral pyridoxamine. PD solution was supplemented with methylglyoxal, a major glucose‐derived RCO, to quench intraperitoneal pyridoxamine. Oral pyridoxamine achieved comparable blood and dialysate pyridoxamine concentrations, suppressed pentosidine accumulation in the blood but not in the mesenterium or dialysate, and reduced the increases in small solute transport and mesenteric vessel densities, with no effects on submesothelial matrix layer thickening or serum creatinine. Thus, reducing circulating RCOs by giving oral pyridoxamine with PD provides limited peritoneal protection. However, orally given pyridoxamine efficiently reaches the peritoneal cavity and would eliminate intraperitoneal RCOs. Oral pyridoxamine is more clinically favorable and may be as protective as intraperitoneal administration.     

Galeterone and VNPT55 induce proteasomal degradation of AR/AR-V7, induce significant apoptosis via cytochrome c release and suppress growth of castration resistant prostate cancer xenografts in vivo

Galeterone (Gal) is a first-in-class multi-target oral small molecule that will soon enter pivotal phase III clinical trials in castration resistant prostate cancer (CRPC) patients. Gal disrupts androgen receptor (AR) signaling via inhibition of CYP17, AR antagonism and AR degradation. Resistance to current therapy is attributed to up-regulation of full-length AR (fAR), splice variants AR (AR-Vs) and AR mutations. The effects of gal and VNPT55 were analyzed on f-AR and AR-Vs (AR-V7/AR^v567es) in LNCaP, CWR22Rv1 and DU145 (transfected with AR-Vs) human PC cells in vitro and CRPC tumor xenografts. Galeterone/VNPT55 decreased fAR/AR-V7 mRNA levels and implicates Mdm2/CHIP enhanced ubiquitination of posttranslational modified receptors, targeting them for proteasomal degradation. Gal and VNPT55 also induced significant apoptosis in PC cells via increased Bax/Bcl2 ratio, cytochrome-c release with concomitant cleavage of caspase 3 and PARP. More importantly, gal and VNPT55 exhibited strong in vivo anti-CRPC activities, with no apparent host toxicities. This study demonstrate that gal and VNPT55 utilize cell-based mechanisms to deplete both fAR and AR-Vs. Importantly, the preclinical activity profiles, including profound apoptotic induction and inhibition of CRPC xenografts suggest that these agents offer considerable promise as new therapeutics for patients with CRPC and those resistant to current therapy.