5 research outputs found
Toward a Social-Ecological Theory of Forest Macrosystems for Improved Ecosystem Management
The implications of cumulative land-use decisions and shifting climate on forests, require us to integrate our understanding of ecosystems, markets, policy, and resource management into a social-ecological system. Humans play a central role in macrosystem dynamics, which complicates ecological theories that do not explicitly include human interactions. These dynamics also impact ecological services and related markets, which challenges economic theory. Here, we use two forest macroscale management initiatives to develop a theoretical understanding of how management interacts with ecological functions and services at these scales and how the multiple large-scale management goals work either in consort or conflict with other forest functions and services. We suggest that calling upon theories developed for organismal ecology, ecosystem ecology, and ecological economics adds to our understanding of social-ecological macrosystems. To initiate progress, we propose future research questions to add rigor to macrosystem-scale studies: (1) What are the ecosystem functions that operate at macroscales, their necessary structural components, and how do we observe them? (2) How do systems at one scale respond if altered at another scale? (3) How do we both effectively measure these components and interactions, and communicate that information in a meaningful manner for policy and management across different scales
Latent Warheads for Targeted Cancer Therapy: Design and Synthesis of pro-Pyrrolobenzodiazepines and Conjugates
Pyrrolobenzodiazepines
(PBDs) and their dimers (bis-PBDs) have
emerged as some of the most potent chemotherapeutic compounds, and
are currently under development as novel payloads in antibody–drug
conjugates (ADCs). However, when used as stand-alone therapeutics
or as warheads for small molecule drug conjugates (SMDCs), dose-limiting
toxicities are often observed. As an elegant solution to this inherent
problem, we designed diazepine-ring-opened conjugated prodrugs lacking
the imine moiety. Once the prodrug (pro-PBD) conjugate enters a targeted
cell, cleavage of the linker system triggers the generation of a reactive
intermediate possessing an aldehyde and aromatic amine. An intramolecular
ring-closing reaction subsequently takes place as the aromatic amine
adds to the aldehyde with the loss of water to give the imine and,
as a result, the diazepine ring. In our pro-PBDs, we mask the aldehyde
as a hydrolytically sensitive oxazolidine moiety which in turn is
a part of a reductively labile self-immolative linker system. To prove
the range of applications for this new class of latent DNA-alkylators,
we designed and synthesized several novel latent warheads: pro-PBD
dimers and hybrids of pro-PBD with other sequence-selective DNA minor
groove binders. Preliminary preclinical pharmacology studies showed
excellent biological activity and specificity