Alkaline Ceramidase 2 (ACER2) and Its Product Dihydrosphingosine Mediate the Cytotoxicity of N-(4-Hydroxyphenyl)retinamide in Tumor Cells

Increased generation of dihydrosphingosine (DHS), a bioactive sphingolipid, has been implicated in the cytotoxicity of the synthetic retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) in tumor cells. However, how 4-HPR increases DHS remains unclear. Here we demonstrate that 4-HPR increases the expression of ACER2, which catalyzes the hydrolysis of dihydroceramides to generate DHS, and that ACER2 up-regulation plays a key role in mediating the 4-HPR-induced generation of DHS as well as the cytotoxicity of 4-HPR in tumor cells. Treatment with 4-HPR induced the accumulation of dihydroceramides (DHCs) in tumor cells by inhibiting dihydroceramide desaturase (DES) activity, which catalyzes the conversion of DHCs to ceramides. Treatment with 4-HPR also increased ACER2 expression through a retinoic acid receptor-independent and caspase-dependent manner. Overexpression of ACER2 augmented the 4-HPR-induced generation of DHS as well as 4-HPR cytotoxicity, and 4-HPR-induced death in tumor cells, whereas knocking down ACER2 had the opposite effects. ACER2 overexpression, along with treatment with GT11, another DES inhibitor, markedly increased cellular DHS, leading to tumor cell death, whereas ACER2 overexpression or GT11 treatment alone failed to do so, suggesting that both ACER2 up-regulation and DES inhibition are necessary and sufficient to mediate 4-HPR-induced DHS accumulation, cytotoxicity, and death in tumor cells. Taken together, these results suggest that up-regulation of the ACER2/DHS pathway mediates the cytotoxicity of 4-HPR in tumor cells and that up-regulating or activating ACER2 may improve the anti-cancer activity of 4-HRR and other DHC-inducing agents.     

Sphingosine kinase: Role in regulation of bioactive sphingolipid mediators in inflammation

Sphingolipids and their synthetic enzymes are emerging as important mediators in inflammatory responses and as regulators of immune cell functions. In particular, sphingosine kinase (SK) and its product sphingosine-1-phosphate (S1P) have been extensively implicated in these processes. SK catalyzes the phosphorylation of sphingosine to S1P and exists as two isoforms, SK1 and SK2. SK1 has been shown to be activated by cytokines including tumor necrosis factor-alpha (TNF-α) and interleukin1-β (IL1-β). The activation of SK1 in this pathway has been shown to be, at least in part, required for mediating TNF-α and IL1-β inflammatory responses in cells, including induction of cyclo-oxygenase 2 (COX2). In addition to their role in inflammatory signaling, SK and S1P have also been implicated in various immune cell functions including, mast cell degranulation, migration of neutrophils, and migration and maturation of lymphocytes. The involvement of sphingolipids and sphingolipid metabolizing enzymes in inflammatory signaling and immune cell functions has implicated these mediators in numerous inflammatory disease states as well. The contribution of these mediators, specifically SK1 and S1P, to inflammation and disease are discussed in this review.     

Evaluation of a 3-amino-8-azabicyclo[3.2.1]octane replacement in the CCR5 antagonist maraviroc

The bicyclic 5-amino-3-azabicyclo[3.3.0]octanes were shown to be effective replacements for the 3-amino-8-azabicyclo[3.2.1]octane found in the CCR5 antagonist maraviroc.     

Delusions of grandeur: Seed count is not a good fitness proxy under individual variation in phenology

The concept of fitness is central to evolutionary biology, yet it is difficult to define and to measure. In plant biology, fitness is often measured as seed count. However, under an array of circumstances, seed count may be a biased proxy of fitness, for example when individuals vary in allocation to sexual versus asexual reproduction. A more subtle example, but also likely to be important in natural populations, is when interindividual variation in conditions during development results in variation in offspring quality among seed parents. In monocarpic (semelparous) plants, this is expected to result from variation in effective season length experienced among individuals that reach reproductive maturity at different times. Here, we manipulate growing season length to ask whether seed count is an accurate representation of parental fitness in the monocarpic herb Lobelia inflata. Simple seed count suggests a paradoxical fitness advantage under constrained‐season length. However, we find that the apparent fitness advantage of a constrained‐season length is overridden by low relative per‐seed fitness. Furthermore, the fitness deficit in the constrained environment is associated primarily with an accelerating decrease in viability and seedling survival in seeds derived from fruits produced progressively later in the season. In this study, the overall fitness value of a seed under a constrained season is 0.774 of that observed under a long season.     

Silencing of lncRNA UCA1 curbs proliferation and accelerates apoptosis by repressing SIRT1 signals by targeting miR‐204 in pediatric AML

The long noncoding RNA urothelial carcinoma‐associated 1 (UCA1) has been reported to sustain the proliferation of acute myeloid leukemia (AML) cells through downregulating cell cycle regulators p27^kip1. Yet, the foundational mechanism of UCA1 in AML pathologies remains unclear. Herein, we found an escalation of UCA1 expression and suppression of miR‐204 expression in pediatric AML patients and cells. UCA1 silencing suppressed cell proliferative abilities, promoted apoptotic rates, decreased Ki67, and increased cleaved caspase‐3 in AML cells. Moreover, UCA1 sponged miR‐204 and suppressed its expression. UCA1 overexpression inversed the miR‐204 suppressed proliferation and promoted apoptosis. UCA1 also boosted the expression of SIRT1, a miR‐204 target, via the sponging interaction. Furthermore, miR‐204 inhibited inducible nitric oxide synthase and cyclooxygenase‐2 expression, while UCA1 overexpression inversed the inhibitory effects in AML cells. Our findings concluded that UCA1 downregulation repressed cell proliferation and promoted apoptosis through inactivating SIRT1 signals by upregulating miR‐204 in pediatric AML.     

An unhealing wound and subcutaneous nodules due to Sporothrix globosa after a cat bite

A 51-year-old man with 3-month unhealing cat bite wound was diagnosed with sporotrichosis, a subacute-to-chronic infection caused by the worldwide endemic, dimorphic fungus Sporothrix globosa. The case would help clinicians to raise awareness of human sporotrichosis due to cat bites, which remains rare and is likely to be underrecognized and misdiagnosed.     

A life cycle model for high-speed rail infrastructure: environmental inventories and assessment of the Tours-Bordeaux railway in France

Purpose

The objective of the study is to progress towards a comprehensive component-based Life Cycle Assessment model with clear and reusable Life Cycle Inventories (LCIs) for high-speed rail (HSR) infrastructure components, and to assess the main environmental impacts of HSR infrastructure over its lifespan, to finally determine environmental hotpots and good practices.

Methods

A process-based LCA compliant with ISO 14040 and 14044 is performed. Construction-stage LCIs rely on data collection conducted with the concessionaire of the HSR line combined with EcoInvent 3.1 inventories. Use and End-of-Life stages LCIs rest on expert feedback scenarios and field data. A set of 13 midpoint indicators is proposed to capture the diversity of the environmental damage: climate change, consumptions of primary energy and non-renewable resources, human toxicity and ecotoxicities, eutrophication, acidification, radioactive and bulk wastes, stratospheric ozone depletion, and summer smog. Three characterization methods are used: the “Cumulative Energy Demand” method to quantify energy demand, the EDIP method for waste productions, and the CML method for the rest.

Results and discussion

The study shows major contributions to environmental impact from rails (10–71%), roadbed (3–48%), and civil engineering structures (4–28%). More limited impact is noted from ballast (1–22%), building machines (0–17%), sleepers (4–11%), and power supply system (2–12%). The two last components, chairs and fasteners, have negligible impact (max. 1 and 3% of total contributions, respectively). Direct transportation can contribute up to 18% of total impact. The production and maintenance stages contribute roughly equally to environmental deterioration (respectively average of 62 and 59%). Because the End-of-Life (EoL) mainly includes recycling with environmental credit accounted for in our 100:100 approach, this stage has globally a positive impact (??9 to ??98%) on all the impact categories except terrestrial ecotoxicity (58%), radioactive waste (11%), and ozone depletion (8%). Contribution analyses show that if concrete production is one of the important contributing processes over the construction stage, primary steel production is unquestionably the most important process on all the impact categories over the entire life cycle.

Conclusions

These results are of interest for public authorities and the rail industry, in order to consider the full life cycle impacts of transportation infrastructure in a decision-making process with better understanding and inclusion of the environmental constraints. Suggestions are provided in this way for life cycle good practices—for instance as regards gravel recycling choices—and additional research to reduce the impact of current major contributors.

     

华北民族融合进程中人群生存方式及对健康的影响——以北京延庆西屯村墓地为例

探讨农耕民族与游牧民族之间的相互交融和融合,对揭示中华民族的形成和发展过程极具重要意义。目前,历史文献与人群体质特征的研究,为了解华北地区东周以后人群的混合和交流提供了丰富的线索,但在民族交融过程中生存方式的转变及其对人群健康的影响尚缺乏细致地研究。为此,本文以北京延庆西屯村墓地汉魏时期的人骨为对象,对其开展C、N稳定同位素分析,并紧密结合体质人类学研究成果及历史文献,揭示自汉至北朝期间先民生存方式的变迁及对人群健康状况的影响。研究表明,先民食物中包含大量的C₄类,反映了粟黍农作物种植业在先民生存方式中占有重要地位;自汉至北朝,先民的δ ¹³C值明显升高,可能与民族融合进程中统治阶级对农业经济的重视和多项利农措施的实施密切相关;而北朝时期人群死亡高峰的推后及女性平均身高的增高,则可能与农业经济的发展改善人群的营养健康相关。本文通过对人骨稳定同位素的分析与人骨体质特征的有机结合,为揭示我国民族间融合进程中人群生存方式的变迁及健康状况提供了新的研究视角。