The tale of proteolysis targeting chimeras (PROTACs) for Leucine-Rich Repeat Kinase 2 (LRRK2)

Here we present the rational design and synthetic methodologies towards proteolysis-targeting chimeras (PROTACs) for the recently-emerged target leucine-rich repeat kinase 2 (LRRK2). Two highly potent, selective, brain-penetrating kinase inhibitors were selected, and their structure was appropriately modified to assemble a cereblon-targeting PROTAC. Biological data show strong kinase inhibition and the ability of the synthesized compounds to enter the cells. However, data regarding the degradation of the target protein are inconclusive. The reasons for the inefficient degradation of the target are further discussed.     

Environmental and individual exposure to secondhand aerosol of electronic cigarettes in confined spaces: Results from the TackSHS Project†

Secondhand electronic cigarette (e-cigarette) aerosol (SHA) might impair indoor air quality and expose bystanders. This study aims to investigate exposure to SHA in controlled conditions of enclosed settings simulating real-world scenario. An experiment was performed in a car and in a room, in which SHA was generated during a 30-minute ad libitum use of an e-cigarette. The experiment was replicated on five consecutive days in each setting. We measured PM_2.5, airborne nicotine concentrations, and biomarkers of exposure to SHA, such as nicotine metabolites, tobacco-specific nitrosamines, propylene glycol, and glycerol in bystanders’ saliva samples before, during, and after the exposure period. Self-reported health symptoms related to exposure to SHA were also recorded. The results showed that the highest median PM_2.5 concentration was recorded during the exposure period, being 21 µg/m³ in the room setting and 16 µg/m³ in the car setting—about twofold increase compared to the baseline. Most concentrations of the airborne nicotine and all biomarkers were below the limit of quantification in both settings. Bystanders in both settings experienced some short-term irritation symptoms, expressed as dry throat, nose, eyes, and phlegm. In conclusion, short-term use of an e-cigarette in confined spaces increased indoor PM_2.5 level and caused some irritation symptoms in bystanders.     

Evaluation of the PSMA-Binding Ligand 212Pb-NG001 in Multicellular Tumour Spheroid and Mouse Models of Prostate Cancer

Radioligand therapy targeting the prostate-specific membrane antigen (PSMA) is rapidly evolving as a promising treatment for metastatic castration-resistant prostate cancer. The PSMA-targeting ligand p-SCN-Bn-TCMC-PSMA (NG001) labelled with ²¹²Pb efficiently targets PSMA-positive cells in vitro and in vivo. The aim of this preclinical study was to evaluate the therapeutic potential of ²¹²Pb-NG001 in multicellular tumour spheroid and mouse models of prostate cancer. The cytotoxic effect of ²¹²Pb-NG001 was tested in human prostate C4-2 spheroids. Biodistribution at various time points and therapeutic effects of different activities of the radioligand were investigated in male athymic nude mice bearing C4-2 tumours, while long-term toxicity was studied in immunocompetent BALB/c mice. The radioligand induced a selective cytotoxic effect in spheroids at activity concentrations of 3–10 kBq/mL. In mice, the radioligand accumulated rapidly in tumours and was retained over 24 h, while it rapidly cleared from nontargeted tissues. Treatment with 0.25, 0.30 or 0.40 MBq of ²¹²Pb-NG001 significantly inhibited tumour growth and improved median survival with therapeutic indexes of 1.5, 2.3 and 2.7, respectively. In BALB/c mice, no signs of long-term radiation toxicity were observed at activities of 0.05 and 0.33 MBq. The obtained results warrant clinical studies to evaluate the biodistribution, therapeutic efficacy and toxicity of ²¹²Pb-NG001.     

基于基因组挖掘技术的新型谷氨酸脱羧酶基因挖掘及表达鉴定

采用基因组挖掘技术,以来源于Lactobacillus brevis活性较高的谷氨酸脱羧酶(glutamate decarboxylase,GAD)LbGAD为探针,从乳酸菌(Lactococcus lactis、Lactobacillus senmaizukei)和肠球菌(Enterococcus sulfureus...     

Deep Integration of Innovation and Entrepreneurship (InE) Education in Chinese University Classrooms

Recently, InE has been regarded as a popular education strategy in Chinese universities. However, problems have been exposed in the adoption of InE, for example, in InE courses and competitions. The purpose of this paper is to provide a possible solution to the problems, which is to organize effective InE courses by integrating InE with Inter-Course-level Problem-Based Learning (ICPBL). A detailed case is demonstrated by an ICPBL elective course design with deep integration of InE in the teaching, learning, and assessments. This paper contributes to a new curriculum design for promoting InE education in practically for Chinese universities.     

One-step fabrication of heterostructured CoNi-LDH@NiCo alloy for effective alkaline hydrogen evolution

Construction of heterostructured electrocatalyst with interface effect is an effective strategy for enhancing the alkaline hydrogen evolution efficiency, whereas this process often requires complex treatments. Herein, we proposed a one-step electrodeposition method to obtain heterostructured CoNi-LDH@NiCo alloy on Ni foam (NF) through a competition reduction between NO₃^? group and metal cations in the electrolyte. The HER performance for the CoNi-LDH@NiCo alloy achieved the current density of 10 mA cm^?2 at overpotential of 69 mV in 1 M KOH solution, improved 60% for η₁₀ by comparing with the pristine NiCo alloy. Utilizing the specialized adsorption of CoNi-LDH for H₂O and the featured attractiveness of NiCo alloy for H atom, the interface effect of the heterostructure electrocatalyst accelerated the dissociation of water molecules and elevated the catalytic kinetics dramatically. This work points out a potential approach towards the easy construction of inexpensive heterostructured electrocatalysts for HER activity in alkaline medium.     

Weissella cibaria short-fermented liquid sourdoughs based on quinoa or amaranth flours as fat replacer in focaccia bread formulation

Production of the traditional Italian Focaccia bread (FcBread) requires reformulation to meet the new rules for healthier foods. We tested the applicability of a short-fermented (15 h) liquid sourdough (LS) (dough yield, DY, 250), obtained using quinoa (Q) or amaranth (Am) flour fermented with a Weissella cibaria strain (C43-11) producing exopolysaccharides (EPS) as fat replacer in yeast-leavened FcBread. The LSs were applied during the FcBread-making process at industrial pilot plant, reducing the added fat amount by 20% (FcBread-QLS and FcBread-AmLS) and products were compared with reference samples not containing EPS. All the products were analysed for physico-chemical properties (pH, TTA, organic acids, protein content and profile, instrumental colour), textural properties, sensory quality and glycemic index. The application of both pseudo-cereal-based W. cibaria LSs in FcBread allowed obtaining products with a reduced amount of fat, increased protein amount, mainly due to the albumin and glutenin/glutelin fractions, reduced glycemic index, improved texture and preserved in the traditional sensory profile of ‘focaccia’.     

Juice and by-products from pomegranate to enrich pancake: characterisation and shelf-life evaluation

In this study, a fortified pancake with all parts of pomegranate as juice and by-products, added in the formulation, was designed. The influence of pomegranate addition on nutritional and sensory quality of pancake, as well as on its shelf-life, was assessed. As one would expect, the enrichment significantly improved the pancake polyphenolic content as compared to the control sample. Surprisingly, pomegranate addition did not affect its sensory quality. In fact, the enriched pancake was greatly appreciated from the sensory point of view. Results also suggested that the addition of pomegranate improved the glycemic index (GI). In fact, while a value of GI equal to 100 was obtained for the control sample, a GI of 71 was measured for the fortified sample. In terms of shelf-life, 30 days were obtained for the enriched pancake, whereas the control sample remained acceptable for about 26 days.     

Relation Between Oxidative Stability and Composition in Argentinian Olive Oils

The relation between oxidative stability and composition in 58 virgin olive oils from different cultivars and Argentinian regions was studied over four harvest years. The oxidative stability of the oils was assessed using the OSI index (110 °C, 20 L/h air flow). A multiple linear regression model is proposed using OSI values as the dependent variable (multiple R = 0.933, p = 1 × 10⁻¹⁵), with positive contributions of the independent variables: fatty acid composition [oleic acid/(linoleic acid + linolenic acid), 55.3%, p = 1 × 10⁻¹⁵], total polyphenols (24.1%, p = 1.8 × 10⁻⁹), carotenes (4.8%, p = 6.1 × 10⁻⁵), β-tocopherol (1.9%, 6.0 × 10⁻³) and other compounds (13.9%). Highly significant correlation was observed between oxidative stability indexes estimated by the compositional model and those experimentally determined by Rancimat method (b = 0.981, R = 0.924). Chlorophylls and Δ-5-avenasterol contributions to the model were non-significant when variables related with fatty acids and polyphenols were included. The results suggest that the fatty acid composition and the polyphenol content are the main factors that affect the oxidative stability of olive oils. The proposed model allows the estimation of the oxidative stability in olive oils independently of the cultivar. The model was obtained also taking into account samples that lie out of the international legal limits in some compositional values due to natural variations.