Mitochondria,sex and variation in routine metabolic rate

Variation in the metabolic costs associated with organismal maintenance may play a key role in determining fitness, and thus these differences among individuals are likely to be subject to natural selection. Although the evolvability of maintenance metabolism depends on its underlying genetic architecture, relatively little is known about the nature of genetic variation that underlies this trait. To address this, we measured variation in routine metabolic rate (?O_2routine), an index of maintenance metabolism, within and among three populations of Atlantic killifish, Fundulus heteroclitus, including a population from a region of genetic admixture between two subspecies. Polygenic association tests among individuals from the admixed population identified 54 single nucleotide polymorphisms (SNPs) that were associated with ?O_2routine, and these SNPs accounted for 43% of interindividual variation in this trait. However, genetic associations with ?O_2routine involved different SNPs if females and males were analysed separately, and there was a sex‐dependent effect of mitochondrial genotype on variation in routine metabolism. These results imply that there are sex‐specific genetic mechanisms, and potential mitonuclear interactions, that underlie variation in ?O_2routine. Additionally, there was evidence for epistatic interactions between 17% of the possible pairs of trait‐associated SNPs, suggesting that epistatic effects on ?O_2routine are common. These data demonstrate not only that phenotypic variation in this ecologically important trait has a polygenic basis with considerable epistasis among loci, but also that these underlying genetic mechanisms, and particularly the role of mitochondrial genotype, may be sex‐specific.     

Polybenzyls from Gastrodia elata,their agonistic effects on melatonin receptors and structure-activity relationships

Gastrodia elata is a famous traditional Chinese herb with medicinal and edible application. In this study, nine polybenzyls (1?9), including six new ones (2?5, 7 and 9), were isolated from the EtOAc extract of G. elata. Five compounds 1, 3, 4, 6 and 8 were found to activate melatonin receptors. Especially, compound 1 showed agonistic effects on MT₁ and MT₂ receptors with EC₅₀ values of 237 and 244 μM. For better understanding their structure-activity relationships (SARs), ten polybenzyl analogs were further synthesized and assayed for their activities on melatonin receptors. Preliminary SARs study suggested that two para-hydroxy groups were the key pharmacophore for maintaining activity. Molecular docking simulations verified that compound 1 could strongly interact with MT₂ receptor by bonding to Phe 118, Gly 121, His 208, Try 294 and Ala 297 residues.     

Design,synthesis, in vitro,and in silico studies of novel diarylimidazole-1,2,3-triazole hybrids as potent α-glucosidase inhibitors

In this work, new derivatives of diarylimidazole-1,2,3-triazole 7a-p were designed, synthesized, and evaluated for their in vitro α-glucosidase inhibitory activity. All compounds showed potent inhibitory activity in the range of IC₅₀ = 90.4–246.7 µM comparing with acarbose as the standard drug (IC₅₀ = 750.0 µM). Among the synthesized compounds, compounds 7b, 7c, and 7e were approximately 8 times more potent than acarbose. The kinetic study of those compounds indicated that they acted as the competitive inhibitors of α-glucosidase. Molecular docking studies were also carried out for compounds 7b, 7c, and 7e using modeled α-glucosidase to find the interaction modes responsible for the desired inhibitory activity.     

New amide linked dimeric 1,2,3-triazoles bearing aryloxy scaffolds as a potent antiproliferative agents and EGFR tyrosine kinase phosphorylation inhibitors

A search for potent antiproliferative agents has prompted to design and synthesize aryloxy bridged and amide linked dimeric 1,2,3-triazoles (7a–j) by using 1,3-dipolar cycloaddition reaction between 2-azido-N-phenylacetamides (4a–e) and bis(prop-2-yn-1-yloxy)benzenes (6a–b) via copper (I)-catalyzed click chemistry approach with good to excellent yields. All the newly synthesized compounds have been screened for their in vitro antiproliferative activities against two human cancer cell lines. The compounds 7d, 7e, 7h, 7i and 7j have revealed promising antiproliferative activity against human breast cancer cell line (MCF-7), whereas, the compounds 7a, 7b, 7c, 7i and 7j were observed as potent antiproliferative agents against human lung cancer cell line (A-549). The active compounds against MCF-7 have been also analysed for their mechanism of action by the enzymatic study, which shows that the compounds 7d, 7h and 7j were acts as active EGFR tyrosine kinase phosphorylation inhibitors. In support to this biological study, the molecular docking as well as in silico ADME properties of all the newly synthesized hybrids were predicted.     

From SLCA to Positive Sustainability Performance Measurement: A Two‐Tier Delphi Study

Life cycle sustainability assessment (LCSA) currently has a preoccupation with capturing and repairing negative dysfunctions and pathologies instead of fostering positive features that make a human life sustainable and worth living. With the intention to overcome this imbalance, this paper aims at transferring the shift to a positive sustainability performance measurement (PSPM) perspective in industrial ecology. We argue that positive performance is likely to develop from the lens of social life cycle assessment (SLCA), because sustainability is an anthropocentric concept that puts positive benefits to human well‐being (i.e., the social dimension of sustainability) at the center of the analysis. However, the field of SLCA is highly fragmented, without a coherent theoretical understanding and without a clear prioritization of problems and future research directions. Therefore, we engage in an extensive Delphi study with experts from academia and practice to foster a discussion of lessons learned from SLCA for PSPM. In this way, the paper contributes to a more coherent and deeper understanding of both connected fields. The results emphasize that SLCA has become a defensive risk management instrument against reputational damages, whereas PSPM offers the potential to proactively measure and manage positive contributions to sustainable development. We identify three main challenges (definitional, methodological, and managerial) and two main areas of benefits (organizational and societal) and use them to consolidate the debate on SLCA and PSPM and to provide a roadmap for future research.     

Working conditions in hydrogen production: A social life cycle assessment

Social impacts of novel technology can, parallel to environmental and economic consequences, influence its sustainability. By analyzing the case of hydrogen production by advanced alkaline water electrolysis (AEL) from a life cycle perspective, this paper illustrates the social implications of the manufacturing of the electrolyzer and hydrogen production when installed in Germany, Austria, and Spain. This paper complements previous environmental and economic assessments, which selected this set of countries based on their different structures in electricity production. The paper uses a mixed method design to analyze the social impact for the workers along the process chain. Appropriate indicators related to working conditions are selected on the basis of the UN Agenda 2030 Sustainable Development Goals. The focus on workers is chosen as a first example to test the relatively new Product Social Impact Life Cycle Assessment (PSILCA) database version 2.0. The results of the quantitative assessment are then complemented and compared through an investigation of the underlying raw data and a qualitative literature analysis. Overall, advanced AEL is found to have least social impact along the German process chain, followed by the Spanish and the Austrian. All three process chains show impacts on global upstream processes. In order to reduce social impact and ultimately contribute to Sustainable Development, policymakers and industry need to work together to further improve certain aspects of working conditions in different locations, particularly within global upstream processes.     

Formulation and evaluation of ethosomes for transdermal delivery of lamivudine

The purpose of the present research was to investigate the mechanism for improved intercellular and intracellular drug delivery from ethosomes using visualization techniques and cell line study. Ethosomal formulations were prepared using lamivudine as model drug and characterized in vitro, ex vivo and in vivo. Transmission electron microscopy, scanning electron microscopy, and fluorescence microscopy were employed to determine the effect of ethosome on ultrastructure of skin. Cytotoxicity and cellular uptake of ethosome were determined using T-lymphoid cell line (MT-2). The optimized ethosomal formulation showed 25 times higher transdermal flux (68.4 +/- 3.5 microg/cm(2)/h) across the rat skin as compared with that of lamivudine solution (2.8 +/- 0.2 microg/cm(2)/h). Microscopic studies revealed that ethosomes influenced the ultrastructure of stratum corneum. Distinct regions with lamellar stacks derived from vesicles were observed in intercellular region of deeper skin layers. Results of cellular uptake study showed significantly higher intracellular uptake of ethosomes (85.7% +/- 4.5%) as compared with drug solution (24.9% +/- 1.9%). The results of the characterization studies indicate that lipid perturbation along with elasticity of ethosomes vesicles seems to be the main contributor for improved skin permeation.