Biotransformation of 4‐fluoro‐N‐(1‐{2‐[(propan‐2‐yl)phenoxy]ethyl}‐8‐azabicyclo[3.2.1]octan‐3‐yl)‐benzenesulfonamide,a novel potent 5‐HT7 receptor antagonist with antidepressant‐like and anxiolytic properties: In vitro and in silico approach

The aim of the study was to investigate the metabolism of 4‐fluoro‐N‐(1‐{2‐[(propan‐2‐yl)phenoxy]ethyl}‐8‐azabicyclo[3.2.1]octan‐3‐yl)‐benzenesulfonamide (PZ‐1150), a novel 5‐HT₇ receptor antagonist with antidepressant‐like and anxiolytic properties, by the following three ways: in vitro with microsomes; in vitro employing Cunninghamella echinulata, and in silico using MetaSite. Biotransformation of PZ‐1150 with microsomes resulted in five metabolites, while transformation with C. echinulata afforded two metabolites. In both models, the predominant metabolite occurred due to hydroxylation of benzene ring. In silico data coincide with in vitro experiments, as three MetaSite metabolites matched compounds identified in microsomal samples. In human liver microsomes PZ‐1150 exhibited in vitro half‐life of 64 min, with microsomal intrinsic clearance of 54.1 μL/min/mg and intrinsic clearance of 48.7 mL/min/kg. Therefore, PZ‐1150 is predicted to be a high‐clearance agent. The study demonstrated the applicability of using microsomal model coupled with microbial model to elucidate the metabolic pathways of compounds and comparison with in silico metabolite predictions.     

Two closely linked tomato HKT coding genes are positional candidates for the major tomato QTL involved in Na+/K+ homeostasis

The location of major quantitative trait loci (QTL) contributing to stem and leaf [Na⁺] and [K⁺] was previously reported in chromosome 7 using two connected populations of recombinant inbred lines (RILs) of tomato. HKT1;1 and HKT1;2, two tomato Na⁺‐selective class I‐HKT transporters, were found to be closely linked, where the maximum logarithm of odds (LOD) score for these QTLs located. When a chromosome 7 linkage map based on 278 single‐nucleotide polymorphisms (SNPs) was used, the maximum LOD score position was only 35 kb from HKT1;1 and HKT1;2. Their expression patterns and phenotypic effects were further investigated in two near‐isogenic lines (NILs): 157‐14 (double homozygote for the cheesmaniae alleles) and 157‐17 (double homozygote for the lycopersicum alleles). The expression pattern for the HKT1;1 and HKT1;2 alleles was complex, possibly because of differences in their promoter sequences. High salinity had very little effect on root dry and fresh weight and consequently on the plant dry weight of NIL 157‐14 in comparison with 157‐17. A significant difference between NILs was also found for [K⁺] and the [Na⁺]/[K⁺] ratio in leaf and stem but not for [Na⁺] arising a disagreement with the corresponding RIL population. Their association with leaf [Na⁺] and salt tolerance in tomato is also discussed.     

Interaction between GAMs and Mean Flow Shear During SMBI Injection into HL-2A Tokamak

Plasma Physics Reports - The interactions among geodesic acoustic modes (GAMs), mean flow, and mean flow shear were investigated using Langmuir probe arrays under periodic supersonic molecular beam...     

协同分布式实验2.0 (CDE 2.0):生态学野外研究新方法

全球野外实验网络是近年来兴起的生态学实验方法,产生了“协同分布式实验”(CDE)、“分布式协作实验”(DCE)的野外实验网络和英国生物学记录中心(BRC)的野外观察网络等具体方法,但均存在尺度小、周期短或数据偏差问题.野外实验网络的协议设计应秉持实验优于观察测量、数据数量优于数据质量和尺度优于操作的原则.综合上述方法,本研究提出利用公众科学(citizen science)获得大范围、多尺度和长周期的数据,采用环境因子作为协变量对公众参与者的实验数据集进行验证后,将其作为后验概率与作为主观概率的生态学家实验数据集进行比对,以完成数据有效性验证,克服公众参与者数据质量瑕疵,并提出了相应的统计学模型.讨论了生态学实验数据中应用先验概率、先验与后验概率的逻辑关系以及后验概率发现演化过程新关系的可能性.这种方法更符合统计学采样规范,并增加了大尺度时空的样本量.该方法有望为生态学研究所寻找的一般性理论提供方法支持,新方法可称之为“协同分布式实验2.0”(CDE 2.0).     

Incentivising fire management in Pindan (Acacia shrubland): A proposed fuel type for Australia's Savanna burning greenhouse gas emissions abatement methodology

The Australian Government has sanctioned development of greenhouse gas emissions (GHG) abatement methodologies to meet international emissions reduction obligations. Savanna burning emissions abatement methodologies have been available since 2012, and there are currently 72 registered projects covering approximately 32 million ha. Abatement to date has exceeded 4 million tonnes of carbon dioxide equivalent (CO2‐e) principally through the application of low intensity early dry season fire management to reduce the amount of biomass combusted in higher intensity late dry season (LDS) fires. Savanna burning projects can only be conducted on areas with eligible fire‐prone vegetation fuel types where implementing the improved fire management regime is considered ecologically appropriate. This study assesses the suitability of including tall Acacia shrublands (‘Pindan’) as a new eligible fuel type. These shrublands make up 12% (~2 million ha) of the Kimberley region, Western Australia, where, on average, 32% is fire affected annually, mostly in the LDS. A standard assessment protocol was applied to describe vegetation fuel type structural and pyrolysis characteristics. We show that Pindan (i) can be identified and mapped as a unique tall Acacia shrubland vegetation fuel type, (ii) characterised by a significantly greater shrubby fuel load biomass, and (iii) the conservation status of which would benefit from imposition of strategic prescribed burning programme. Savanna burning projects in the Pindan fuel type could potentially abate up to 24.43 t.CO₂‐e/km² per year, generating significant income and employment opportunities for predominantly Indigenous land managers in the region.     

In vitro and in vivo characterization of an interleukin‐15 antagonist peptide by metabolic stability, 99mTc‐labeling,and biological activity assays

Interleukin (IL)–15 is an inflammatory cytokine that constitutes a validated therapeutic target in some immunopathologies, including rheumatoid arthritis (RA). Previously, we identified an IL‐15 antagonist peptide named [K6T]P8, with potential therapeutic application in RA. In the current work, the metabolic stability of this peptide in synovial fluids from RA patients was studied. Moreover, [K6T]P8 peptide was labeled with ^99mTc to investigate its stability in human plasma and its biodistribution pattern in healthy rats. The biological activity of [K6T]P8 peptide and its dimer was evaluated in CTLL‐2 cells, using 3 different additives to improve the solubility of these peptides. The half‐life of [K6T]P8 in human synovial fluid was 5.88 ± 1.73 minutes, and the major chemical modifications included peptide dimerization, cysteinylation, and methionine oxidation. Radiolabeling of [K6T]P8 with ^99mTc showed a yield of approximately 99.8%. The ^99mTc‐labeled peptide was stable in a 30‐fold molar excess of cysteine and in human plasma, displaying a low affinity to plasma proteins. Preliminary biodistribution studies in healthy Wistar rats suggested a slow elimination of the peptide through the renal and hepatic pathways. Although citric acid, sucrose, and Tween 80 enhanced the solubility of [K6T]P8 peptide and its dimer, only the sucrose did not interfere with the in vitro proliferation assay used to assess their biological activity. The results here presented, reinforce nonclinical characterization of the [K6T]P8 peptide, a potential agent for the treatment of RA and other diseases associated with IL‐15 overexpression.     

Daily Rhythms of P‐glycoprotein Expression in Mice

Recent studies have shown the gene expression of several transporters to be circadian rhythmic. However, it remains to be elucidated whether the expression of P‐glycoprotein, which is involved in the transport of many medications, undergoes 24 h rhythmicity. To address this issue, we investigated daily profiles of P‐glycoprotein mRNA and protein levels in peripheral mouse tissues. In the liver and intestine, but not in the kidney, Abcb1a mRNA expression showed clear 24 h rhythmicity. On the other hand, Abcb1b and Abcb4, the other P‐glycoprotein genes, did not exhibit significant rhythmic expression in the studied tissues. In the intestine, levels of whole P‐glycoprotein also exhibited a daily rhythm, with a peak occurring in the latter half of the light phase and a trough at the onset of the light phase. Consistent with the day‐night change of P‐glycoprotein level, the ex vivo accumulation of digoxin, an Abcb1a P‐glycoprotein substrate, into the intestinal segments at the onset of dark phase was significantly lower than it was at the onset of the light phase. Thus, Abcb1a P‐glycoprotein expression, and apparently its function, are 24 h rhythmic at least in mouse intestine tissue. This circadian variation might be involved in various chronopharmacological phenomena.