Gold (iii) macrocycles are dna intercalators that inhibit topoisomerase i and ii

Human Topoisomerase IB (TOP1) and Topoisomerase II? (TOP2?) are essential nuclear enzymes that control DNA topology during DNA replication, gene transcription and cell division. These enzymes carry out their catalytic function by making transient single-strand (type I) or double-strand (type II) breaks in the DNA. In vivo, these complexes are short-lived but can be exploited by anti-cancer drugs to mechanistically kill cancer cells. Two general classes of compounds can kill cancer cells through a topo-targeted mechanism. Interfacial Poisons (IFPs) act at the enzyme-DNA interface to inhibit the religation reaction, resulting in the accumulation of DNA double-stand breaks (DSBs) in the genomic setting. Catalytic Inhibitor Compounds (CICs) act by interfering with other steps of the catalytic cycles such as DNA/protein binding or the cleavage reaction. In this work we identify new Au3+ macrocyclic gold complexes that act as CICs of both TOP1 and TOP2?. The complexes exhibit square planar geometry with an aromatic system that allows for DNA intercalation with binding affinities in the low micromolar range. A cytotoxicity screen across 60 human cancer cell lines performed by the National Cancer Institute (NCI, USA) reveals significant anti-tumor potential. Our lead compound (butyl gold(III) macrocycle, cmpd 3.) is currently undergoing further studies in animal models at the NCI. In vitro assays with purified DNA and enzyme reveal the Au3+ ion to be the quintessential switch that allows for DNA intercalation and subsequent inhibition of TOP1 and TOP2?

Twenty Novel Disease Group-Specific and 12 New Shared Macrophage Pathways in Eight Groups of 34 Diseases Including 24 Inflammatory Organ Diseases and 10 Types of Tumors.

The mechanisms underlying pathophysiological regulation of tissue macrophage (Mφ) subsets remain poorly understood. From the expression of 207 Mφ genes comprising 31 markers for 10 subsets, 45 transcription factors (TFs), 56 immunometabolism enzymes, 23 trained immunity (innate immune memory) enzymes, and 52 other genes in microarray data, we made the following findings. (1) When 34 inflammation diseases and tumor types were grouped into eight categories, there was differential expression of the 31 Mφ markers and 45 Mφ TFs, highlighted by 12 shared and 20 group-specific disease pathways. (2) Mφ in lung, liver, spleen, and intestine (LLSI-Mφ) express higher M1 Mφ markers than lean adipose tissue Mφ (ATMφ) physiologically. (3) Pro-adipogenic TFs C/EBPα and PPARγ and proinflammatory adipokine leptin upregulate the expression of M1 Mφ markers. (4) Among 10 immune checkpoint receptors (ICRs), LLSI-Mφ and bone marrow (BM) Mφ express higher levels of CD274 (PDL-1) than ATMφ, presumably to counteract the M1 dominant status via its reverse signaling behavior. (5) Among 24 intercellular communication exosome mediators, LLSI- and BM- Mφ prefer to use RAB27A and STX3 than RAB31 and YKT6, suggesting new inflammatory exosome mediators for propagating inflammation. (6) Mφ in peritoneal tissue and LLSI-Mφ upregulate higher levels of immunometabolism enzymes than does ATMφ. (7) Mφ from peritoneum and LLSI-Mφ upregulate more trained immunity enzyme genes than does ATMφ. Our results suggest that multiple new mechanisms including the cell surface, intracellular immunometabolism, trained immunity, and TFs may be responsible for disease group-specific and shared pathways. Our findings have provided novel insights on the pathophysiological regulation of tissue Mφ, the disease group-specific and shared pathways of Mφ, and novel therapeutic targets for cancers and inflammations

Interdependent Infrastructure as Linked Social, Ecological, and Technological Systems (SETSs) to Address Lock‐in and Enhance Resilience

Traditional infrastructure adaptation to extreme weather events (and now climate change) has typically been techno‐centric and heavily grounded in robustness—the capacity to prevent or minimize disruptions via a risk‐based approach that emphasizes control, armoring, and strengthening (e.g., raising the height of levees). However, climate and nonclimate challenges facing infrastructure are not purely technological. Ecological and social systems also warrant consideration to manage issues of overconfidence, inflexibility, interdependence, and resource utilization—among others. As a result, techno‐centric adaptation strategies can result in unwanted tradeoffs, unintended consequences, and underaddressed vulnerabilities. Techno‐centric strategies that lock‐in today\u27s infrastructure systems to vulnerable future design, management, and regulatory practices may be particularly problematic by exacerbating these ecological and social issues rather than ameliorating them. Given these challenges, we develop a conceptual model and infrastructure adaptation case studies to argue the following: (1) infrastructure systems are not simply technological and should be understood as complex and interconnected social, ecological, and technological systems (SETSs); (2) infrastructure challenges, like lock‐in, stem from SETS interactions that are often overlooked and underappreciated; (3) framing infrastructure with a SETS lens can help identify and prevent maladaptive issues like lock‐in; and (4) a SETS lens can also highlight effective infrastructure adaptation strategies that may not traditionally be considered. Ultimately, we find that treating infrastructure as SETS shows promise for increasing the adaptive capacity of infrastructure systems by highlighting how lock‐in and vulnerabilities evolve and how multidisciplinary strategies can be deployed to address these challenges by broadening the options for adaptation

Small business owners’ success criteria, a values approach to personal differences

This study of 150 Dutch small business owners, identified through business/ network directories, investigated relationships between owners’ understanding of success and their personal values. Business owners ranked 10 success criteria. Per- sonal satisfaction, profitability, and satisfied stakeholders ranked highest. Multidi- mensional scaling techniques revealed two dimensions underlying the rank order of success criteria: person-oriented (personal satisfaction versus business growth) and business-oriented (profitability versus contributing back to society). Furthermore, business growth, profitability, and innovativeness were guided by self-enhancing value orientations (power and achievement). Softer success criteria, such as having satisfied stakeholders and a good work–life balance, were guided by self-transcendent value orientations (benevolence and universalism)

Entrepreneurs’ achieved success: developing a multi-faceted measure

Firm performance is typically measured via objective financial indicators. However, researchers increasingly acknowledge that entrepreneurs do not measure their success solely in financial terms but that a range of often subjective indicators matter to them. This article contributes to the debate on entrepreneurial performance by studying how entrepreneurs assess their achieved success. ‘Entrepreneurs’ achieved success’ was conceptualized as a multi-faceted construct that includes entrepreneurs’ self-reported achievement of firm performance, workplace relationships, personal fulfilment, community impact, and personal financial rewards. It was measured via the Subjective Entrepreneurial Success–Achievement Scale (SES-AS). Over the course of three studies (N = 390) the factorial structure of ‘entrepreneurs’ achieved success’ was established and largely replicated in two cultures. Based on a nomological network, we documented relationships among ‘entrepreneurs’ achieved success’, quasi-objective indicators of firm performance, and entrepreneurs’ financial satisfaction, creativity, and health. Based on our research, we propose a new conceptual framework to study performance in the context of entrepreneurship. This framework acknowledges both the success criteria that entrepreneurs wish to achieve and those that they actually achieve, and extends our understanding of firm performance

Seriously personal:The reasons that motivate entrepreneurs to address climate change

This is the author accepted manuscript. The final version is freely available from Springer Verlag via the DOI in this record.Scholars increasingly argue that entrepreneurs and their small- and medium-sized enterprises should play a central role in reducing the rate and magnitude of climate change. However, evidence suggests that while some entrepreneurs recognize their crucial role in addressing climate change, most do not. Why some entrepreneurs nevertheless concern themselves with climate change has largely been overlooked. Some initial work in this area tentatively suggests that these entrepreneurs may engage with climate change because of their personal values, which either focus on financial or socio-ecological reasons, or a combination of both. Yet, it is unclear if all for-profit entrepreneurs engage with climate change for the same reasons, or if indeed their motivations vary across business types. Over a period of four years, we examined entrepreneurs’ motivations to engage with climate change through a variety of qualitative research methods. Our findings illustrate how entrepreneurs who address climate change have motivations specific to their business activity/industry and level of maturity. In each instance, we link these motivations to distinct conceptualizations of time and place. We contend that, through a more differentiated understanding of entrepreneurial motivations, policy-makers can draft climate change-related policies tailored to entrepreneurial needs. Policies could both increase the number of entrepreneurs who already engage in climate change mitigation and leverage the impact of those entrepreneurs already mitigating climate change.This study was funded by the European Social Fund (09099NCO5). We acknowledge with thanks the participation of the entrepreneurs and the support of Business Leaders for Low Carbon, Cornwall Council, and Cornwall Sustainable Tourism Project. The authors wish to thank Professor John Amis, Professor Kenneth Amaeshi and the anonymous reviewers who provided useful feedback on earlier versions of the article

Age and work-related motives: Results of a meta-analysis

Item does not contain fulltextAn updated literature review was conducted and a meta-analysis was performed to investigate the relationship between age and work-related motives. Building on theorizing in life span psychology, we hypothesized the existence of age-related differences in work-related motives. Specifically, we proposed an age-related increase in the strength of security and social motives, and an age-related decrease in the strength of growth motives. To investigate life span developmental theory predictions about age-related differences in control strategies, we also examined the relationship between age and intrinsic and extrinsic motives. Consistent with our predictions, meta-analytic results showed a significant positive relationship between age and intrinsic motives, and a significant negative relationship between age and strength of growth and extrinsic motives. The predicted positive relation between age and strength of social and security motives was only found among certain subgroups. Implications of these findings for work motivation and life span theories and future research are discussed