Phenanthroindolizidine Alkaloids Isolated from <em>Tylophora ovata</em> as Potent Inhibitors of Inflammation, Spheroid Growth, and Invasion of Triple-Negative Breast Cancer

\ua9 2022 by the authors. Triple-negative breast cancer (TNBC), representing the most aggressive form of breast cancer with currently no targeted therapy available, is characterized by an inflammatory and hypoxic tumor microenvironment. To date, a broad spectrum of anti-tumor activities has been reported for phenanthroindolizidine alkaloids (PAs), however, their mode of action in TNBC remains elusive. Thus, we investigated six naturally occurring PAs extracted from the plant Tylophora ovata: O-methyltylophorinidine (1) and its five derivatives tylophorinidine (2), tylophoridicine E (3), 2-demethoxytylophorine (4), tylophoridicine D (5), and anhydrodehydrotylophorinidine (6). In comparison to natural (1) and for more-in depth studies, we also utilized a sample of synthetic O-methyltylophorinidine (1s). Our results indicate a remarkably effective blockade of nuclear factor kappa B (NFκB) within 2 h for compounds (1) and (1s) (IC50 = 17.1 \ub1 2.0 nM and 3.3 \ub1 0.2 nM) that is different from its effect on cell viability within 24 h (IC50 = 13.6 \ub1 0.4 nM and 4.2 \ub1 1 nM). Furthermore, NFκB inhibition data for the additional five analogues indicate a structure–activity relationship (SAR). Mechanistically, NFκB is significantly blocked through the stabilization of its inhibitor protein kappa B alpha (IκBα) under normoxic as well as hypoxic conditions. To better mimic the TNBC microenvironment in vitro, we established a 3D co-culture by combining the human TNBC cell line MDA-MB-231 with primary murine cancer-associated fibroblasts (CAF) and type I collagen. Compound (1) demonstrates superiority against the therapeutic gold standard paclitaxel by diminishing spheroid growth by 40% at 100 nM. The anti-proliferative effect of (1s) is distinct from paclitaxel in that it arrests the cell cycle at the G0/G1 state, thereby mediating a time-dependent delay in cell cycle progression. Furthermore, (1s) inhibited invasion of TNBC monoculture spheroids into a matrigel\uae-based environment at 10 nM. In conclusion, PAs serve as promising agents with presumably multiple target sites to combat inflammatory and hypoxia-driven cancer, such as TNBC, with a different mode of action than the currently applied chemotherapeutic drugs

Uncertainty and Bias in Global to Regional Scale Assessments of Current and Future Coastal Flood Risk

This study provides a literature-based comparative assessment of uncertainties and biases in global to world-regional scale assessments of current and future coastal flood risks, considering mean and extreme sea-level hazards, the propagation of these into the floodplain, people and coastal assets exposed, and their vulnerability. Globally, by far the largest bias is introduced by not considering human adaptation, which can lead to an overestimation of coastal flood risk in 2100 by up to factor 1300. But even when considering adaptation, uncertainties in how coastal societies will adapt to sea-level rise dominate with a factor of up to 27 all other uncertainties. Other large uncertainties that have been quantified globally are associated with socio-economic development (factors 2.3–5.8), digital elevation data (factors 1.2–3.8), ice sheet models (factor 1.6–3.8) and greenhouse gas emissions (factors 1.6–2.1). Local uncertainties that stand out but have not been quantified globally, relate to depth-damage functions, defense failure mechanisms, surge and wave heights in areas affected by tropical cyclones (in particular for large return periods), as well as nearshore interactions between mean sea-levels, storm surges, tides and waves. Advancing the state-of-the-art requires analyzing and reporting more comprehensively on underlying uncertainties, including those in data, methods and adaptation scenarios. Epistemic uncertainties in digital elevation, coastal protection levels and depth-damage functions would be best reduced through open community-based efforts, in which many scholars work together in collecting and validating these data

Evidence from sperm whale clans of symbolic marking in non-human cultures

Culture, a pillar of the remarkable ecological success of humans, is increasingly recognized as a powerful force structuring nonhuman animal populations. A key gap between these two types of culture is quantitative evidence of symbolic markers—seemingly arbitrary traits that function as reliable indicators of cultural group membership to conspecifics. Using acoustic data collected from 23 Pacific Ocean locations, we provide quantitative evidence that certain sperm whale acoustic signals exhibit spatial patterns consistent with a symbolic marker function. Culture segments sperm whale populations into behaviorally distinct clans, which are defined based on dialects of stereotyped click patterns (codas). We classified 23,429 codas into types using contaminated mixture models and hierarchically clustered coda repertoires into seven clans based on similarities in coda usage; then we evaluated whether coda usage varied with geographic distance within clans or with spatial overlap between clans. Similarities in within-clan usage of both “identity codas” (coda types diagnostic of clan identity) and “nonidentity codas” (coda types used by multiple clans) decrease as space between repertoire recording locations increases. However, between-clan similarity in identity, but not nonidentity, coda usage decreases as clan spatial overlap increases. This matches expectations if sympatry is related to a measurable pressure to diversify to make cultural divisions sharper, thereby providing evidence that identity codas function as symbolic markers of clan identity. Our study provides quantitative evidence of arbitrary traits, resembling human ethnic markers, conveying cultural identity outside of humans, and highlights remarkable similarities in the distributions of human ethnolinguistic groups and sperm whale clans

The Dynamics of Managerial Ideology: Analyzing the Cuban Case

After the collapse of state socialism in Eastern Europe, management researchers devoted considerable energy to investigate ways to smooth transition to market economies. But one country of the former Soviet bloc, Cuba resisted transition and reaffirmed loyalty to communism. Little is known about management in Cuba on the managerial impacts of the combination of two major environmental forces: the American embargo and the Soviet Union collapse, both of which have challenged the sustainability of the communist regime. This study intends to approach one particular aspect of management in Cuba: the relationship between national ideology and management practice. To analyze these topics, direct qualitative data from focus groups with Cuban managers and management professors was obtained and complemented with documentary analysis. Results suggest that the dynamics of managerial ideology can be understood as the interplay of several processes operating at distinct levels: institutional, professional, organizational and individual. The study provides a nested, multi-level understanding of management and organization as parts of a wider institutional context, which is both a source of constraint and a non-tangible resource to be used by ideological bricoleurs. The interplay between the acceptance of ideology and its use as a practical resource is a potential source of change. As such, the same professional class (managers) may be both a source of continuity and a trigger of change - a finding that is line with institutional theory’s claim that it is necessary to understand both institutionalization and de-institutionalization for understanding organizational change and continuity.N/

Uncertainty and bias in global to regional scale assessments of current and future coastal flood risk

This study provides a literature-based comparative assessment of uncertainties and biases in global to world-regional scale assessments of current and future coastal flood risks, considering mean and extreme sea-level hazards, the propagation of these into the floodplain, people and coastal assets exposed, and their vulnerability. Globally, by far the largest bias is introduced by not considering human adaptation, which can lead to an overestimation of coastal flood risk in 2100 by up to factor 1300. But even when considering adaptation, uncertainties in how coastal societies will adapt to sea-level rise dominate with a factor of up to 27 all other uncertainties. Other large uncertainties that have been quantified globally are associated with socio-economic development (factors 2.3–5.8), digital elevation data (factors 1.2–3.8), ice sheet models (factor 1.6–3.8) and greenhouse gas emissions (factors 1.6–2.1). Local uncertainties that stand out but have not been quantified globally, relate to depth-damage functions, defense failure mechanisms, surge and wave heights in areas affected by tropical cyclones (in particular for large return periods), as well as nearshore interactions between mean sea-levels, storm surges, tides and waves. Advancing the state-of-the-art requires analyzing and reporting more comprehensively on underlying uncertainties, including those in data, methods and adaptation scenarios. Epistemic uncertainties in digital elevation, coastal protection levels and depth-damage functions would be best reduced through open community-based efforts, in which many scholars work together in collecting and validating these data