关键词： alternative splicing   vascular smooth muscle cells   gene expression   cardiovascular disease   splicing-modulating therapies  

摘要： Vascular smooth muscle cells (VSMCs) display extraordinary phenotypic plasticity. This allows them to differentiate or dedifferentiate, depending on environmental cues. The ability to 'switch' between a quiescent contractile phenotype to a highly proliferative synthetic state renders VSMCs as primary mediators of vascular repair and remodelling. When their plasticity is pathological, it can lead to cardiovascular diseases such as atherosclerosis and restenosis. Coinciding with significant technological and conceptual innovations in RNA biology, there has been a growing focus on the role of alternative splicing in VSMC gene expression regulation. Herein, we review how alternative splicing and its regulatory factors are involved in generating protein diversity and altering gene expression levels in VSMC plasticity. Moreover, we explore how recent advancements in the development of splicing-modulating therapies may be applied to VSMC-related pathologies.

关键词： Ultrasound   Water soaking   Reducing sugars   Acrylamide   5-hydroxymethylfurfural   Potato chips  

摘要： The effect of ultrasound (480 W, 40 kHz) on the leaching of reducing sugars during the water soaking of potatoes slices (60, 70 and 80 degrees C-1, 8 and 15 min) was investigated to reduce the formation of acrylamide (AA) and 5-hydroxymethylfurfural (5-HMF) in potato chips. Ultrasound (US) influenced abruptly the reducing sugar leaching during the first 15 min, significantly increasing their extraction rate (glucose: 60%, fructose: 30%) at all evaluated temperatures. When potato slices were treated with US, the formation of AA (-95%) and 5-HMF (-96%) were reduced significantly after frying. Although AA content did not correlate with glucose and fructose concentrations, 5-HMF did (r2: 0.80 and 0.83, respectively), probably because reducing sugars are their main precursors. The AA and 5-HMF concentrations of potato chips presented good correlation coefficient (r2:0.76), suggesting the use of 5-hydroxymethylfurfural as an acrylamide indicator for potato chips.

摘要： OBJECTIVE To describe the patterns of complementary and alternative medicine (CAM) among patients with kidney stones and analyze the alkali content of commonly used CAM therapies. METHODS We prospectively conducted structured interviews with patients who presented to a specialty stone clinic for the management of kidney stones. Open-ended questions were used to elicit information regarding CAM knowledge, formulation/dosing, and patterns of use. Several common CAM therapies were then analyzed for their alkali, organic anion, and sugar content. RESULTS Of 103 subjects, 82 (80%) patients reported knowledge of CAM and 52 (50%) reported using CAM. Patients with recurrent kidney stones were more likely to report using CAM than patients with first-time episodes (56% vs 26%, P = 0.04). Some respondents reported their condition decreased in severity or frequency since starting CAM therapy (17%) and improvements in pain (12%). Total alkali content per serving of the tested supplements was 0 mEq (Stonebreaker), 1.5 mEq (Ocean Spray Cranberry Juice Cocktail), 4.7 mEq (Lakewood Pure Cranberry Juice), 0.6 mEq (Braggs Apple Cider Vinegar), 11.9 mEq (LithoBalance), 9.5 mEq (Simply Grapefruit Juice), 19.8 mEq (KSP-Key Lime), and 20.2 mEq (KSP-Very Berry). CONCLUSION Patients with kidney stones may use CAM to alleviate symptoms or prevent recurrence. Commercially available CAM therapies may contain comparable alkali content to commonly prescribed citrate therapy. These data suggest that providers should be prepared to discuss the role of CAM with their patients. (C) 2021 Elsevier Inc.

关键词： Curcin   Type 1 RIP   RRNA-N-glycosidase   Jatropha curcas seed cake  

摘要： Jatropha curcas seed cake is a byproduct of oil extraction from biodiesel industry. Although it has high protein content, its valorization is hampered by its toxicity. Curcin is a type 1 ribosome-inactivating protein (type 1 RIP) that contributes to the Jatropha seed cake toxicity. The present study aimed to evaluate the feasibility of using Jatropha seed cake as an alternative source to obtain bioactive curcin. Extracts from the seed cake stored for 15, 30, 45, 60, 75, and 90 days were used to produce protein fractions (JcPFC15, JcPFC30, JcPFC45, JcPFC60, JcPFC75, and JcPFC90), which were further used in purifying curcin via size exclusion chromatography. All JcPFCs comprised curcin. The purified JcPFC curcins apparently had a molecular mass of 28 kDa, which was similar to the seed curcin. Western blot using antibody anti-curcin revealed a single band, corresponding to curcin. No significant differences were observed in the curcin concentrations in all JcPFCs throughout storage. Furthermore, JcPFCs' curcins presented conformational similarities to those of seed curcin, on evaluation by circular dichroism and intrinsic fluorescence spectroscopy. The RIP characteristic activity was assayed by rRNA-N-glycosidase activity test and in vitro protein synthesis inhibition assay, which revealed that the enzymatic activity was maintained in all JcPFCs' curcins. Moreover, the toxicity test did not indicate significant differences between JcPFCs' curcins and seed curcin. Accordingly, based on the results obtained, it is possible to affirm that J. curcas seed cake is a viable source of active curcin even after 90 days of storage. [GRAPHICS] .

关键词： alternative to animal testing   amino acid derivative reactivity assay–   organic solvent (ADRA‐   OS) reaction system   in chemico   skin sensitization   octanol   water partition coefficient (logKow)  

摘要： The amino acid derivative reactivity assay (ADRA) is an in chemico alternative to animal testing that focuses on protein binding. The ADRA is a skin sensitization test that solves problems associated with the direct peptide reactivity assay. However, when utilizing the ADRA to evaluate highly hydrophobic substances with octanol/water partition coefficients (logKow) of >6, the test substances may not dissolve in the reaction solution, which can prevent the accurate assessment of skin sensitization. Therefore, we developed the ADRA-organic solvent (ADRA-OS) reaction system, which is a novel skin sensitization test that enables the assessment of highly hydrophobic substances with a logKow of >6. We discovered that the organic solvent ratio, the triethylamine concentration, and the ethylenediaminetetraacetic acid disodium salt dihydrate concentration participate in reactions with the nucleophile N-(2-(1-naphthyl)acetyl)-l-cysteine (NAC) and sensitizers that are used in ADRA and in stabilizing NAC. Thus, we determined the optimal reaction composition of the ADRA-OS according to L-9 (3(3)) orthogonal array experiments. Using this test, we assessed 14 types of highly hydrophobic substances. When we compared the results with ADRA, we found that ADRA-OS reaction system has high solubility for highly hydrophobic substances and that it has a high predictive capacity (sensitivity: 63%, specificity: 100%, accuracy: 79%). The implication of the results is that the novel ADRA-OS reaction system should provide a useful method for assessing the skin sensitization of highly hydrophobic substances with a logKow of >6.

关键词： Pediatrics   Pediatric Surgery   Maternal and Child Health  

关键词： Standard test   Standard test extension   Alternative test   Regulation   Advanced materials   Omics   Terrestrial   Soil   Weight of evidence   Mechanisms   AOP  

摘要： The outstanding work performed by standardization organizations for guidelines to assess hazards, e.g., OECD (Organisation for Economic Co-operation and Development), is clearly visible by the currently available number and broad coverage, from aquatic to terrestrial organisms dealing with environmental relevant issues. Nevertheless, novel materials challenge the adequateness and fit-for-purpose of such standards, as the standards were developed to assess hazards of "conventional" chemical substances and not advanced materials (e.g. materials that may deliberately change behaviour). While standardization is a well-known process that requires extended time before reaching implementation stage, there is strong support from regulatory bodies for the development of New Approach Methodologies (NAMs) (e.g., up-dating of current guidelines, development of novel omics-, in vitro-, and in silico-tests including modelling and read-across) that meet regulatory preparedness (i.e. have considered issues important for regulatory testing). There are currently several NAMs available, complying with high quality standards and relevancy, which should be adopted. In the current review, we collected the available literature on NAMs to assess hazards of Nanomaterials (NMs), focusing on the terrestrial environment, and critically discuss the ad-vantages, challenges and gaps. Tests were grouped into 1) Standard tests (OECD/ISO), 2) Standard tests (OECD/ISO) extensions: time course or prolonged exposures and/or multigenerational, and 3) Alternative tests, beyond current OECD/ISO: omics, biomarkers, in vitro, in silico and modelling. The goal is to provide guidance on the best practices and test designs focusing on the specificities of testing NMs, outlining re-commendations and way forward. (c) 2021 The Author(s). Published by Elsevier Ltd. CC_BY_NC_ND_4.0

关键词： adaptation   alternative options   hazards   traditional irrigation challenges   water lifting  

摘要： In the glaciated mountains of the Upper Indus Basin of Pakistan, glacier- and snowmelt- based irrigation systems have been established over several centuries to secure water for cultivation. However, these systems are now facing several challenges, being sensitive to climate change and thus exposed to the resulting extreme events such as glacial lake outburst floods (GLOFs) and flash floods, also difficult terrain and access paths, male outmigration, limited technical capacity and a weak policy and governance system. Hence, exploring the potential options for overcoming the challenges and irrigating arable barren land could lead to economic prosperity and environmental gains. A literature review, stakeholder consultation and semi-structured questionnaire survey in two villages of the Hunza River basin was conducted to synthesize information in different domains. Information on the irrigation system and its sources, water distribution/allocation system, challenges and adaptation strategies were collected, and based on community preferences, an alternative irrigation technological package was established to overcome the challenges and irrigate barren land. A customized solar water lifting pump with an efficient micro-irrigation package was piloted which proved to be climate resilient. The system is simple to adopt, uses clean energy for operation and is economically feasible, with a benefit-cost ratio of 4.96 and a payback period of around 11 years.

关键词： cystectomy   neoadjuvant therapy   drug therapy   urinary bladder neoplasms  

摘要： Purpose: Patients with muscle invasive bladder cancer (MIBC) of variant histology have a poor prognosis. It is unclear if neoadjuvant chemotherapy prior to radical cystectomy is associated with pathological downstaging or improved overall survival (OS) for patients with variant histology. Our objective was to assess for associations between receipt of neoadjuvant chemotherapy, pathological downstaging and OS for patients with variant histology MIBC. Materials and Methods: Patients were identified in the National Cancer Database from 2004 to 2017 with MIBC, without metastases, who underwent radical cystectomy. Patients were stratified by histological subgroup, and receipt or nonreceipt of neoadjuvant chemotherapy. Pathological downstaging was defined as pT0N0 or pT <= 1N0, and OS from the time of diagnosis to date of death or censoring at last followup. Multivariable logistic regression analysis determined associations between neoadjuvant chemotherapy and pathological downstaging. Multivariable Cox regression analysis determined associations between neoadjuvant chemotherapy and OS. Results: A total of 31,218 patients were included in the final study population (urothelial carcinoma [UC]: 27,779;sarcomatoid UC: 501;micropapillary UC: 418;squamous cell carcinoma: 1,141;neuroendocrine carcinoma: 629;adenocarcinoma: 750). Neoadjuvant chemotherapy was associated with pathological downstaging to pT0N0 in all histological subgroups (UC: OR 5.1 [4.6-5.6];sarcomatoid UC: OR 13.8 [5.5-39.0];micropapillary UC: OR 9.7 [2.8-46.8];squamous cell carcinoma: OR 7.4 [2.1-24.5];neuroendocrine: OR 4.7 [2.6-9.2];adenocarcinoma: OR 23.3 [8.0-74.2]). Neoadjuvant chemotherapy was associated with improved OS for UC (HR 0.8 [0.77-0.84]), sarcomatoid UC (HR 0.64 [0.44-0.91]) and neuroendocrine carcinoma (HR 0.55 [0.43-0.70]). Conclusions: Neoadjuvant chemotherapy was associated with pathological downstaging for all MIBC histological variants, with improved OS for patients with UC, sarcomatoid