Synthesis and Biological Evaluation of a Novel C8-Pyrrolobenzodiazepine (PBD) Adenosine Conjugate. A Study on the Role of the PBD Ring in the Biological Activity of PBD-Conjugates

Here we sought to evaluate the contribution of the PBD unit to the biological activity of PBD-conjugates and, to this end, an adenosine nucleoside was attached to the PBD A-ring C8 position. A convergent approach was successfully adopted for the synthesis of a novel C8-linked pyrrolo(2,1-c)(1,4)benzodiazepine(PBD)-adenosine(ADN) hybrid. The PBD and adenosine (ADN) moieties were synthesized separately and then linked through a pentynyl linker. To our knowledge, this is the first report of a PBD connected to a nucleoside. Surprisingly, the compound showed no cytotoxicity against murine cells and was inactive against Mycobacterium aurum and M. bovis strains and did not bind to guanine-containing DNA sequences, as shown by DNase I footprinting experiments. Molecular dynamics simulations revealed that the PBD–ADN conjugate was poorly accommodated in the DNA minor groove of two DNA sequences containing the AGA-PBD binding motif, with the adenosine moiety of the ligand preventing the covalent binding of the PBD unit to the guanine amino group of the DNA duplex. These interesting findings shed further light on the ability of the substituents attached at the C8 position of PBDs to a ect and modulate the biological and biophysical properties of PBD hybrids

Small molecule and peptide inhibitors of βTrCP and the βTrCP–NRF2 protein–protein interaction

The E3 ligase beta-transducin repeat-containing protein (βTrCP) is an essential component of the ubiquitin–proteasome system that is responsible for the maintenance of cellular protein levels in human cells. Key target substrates for degradation include inhibitor of nuclear factor kappa B, programmed cell death protein 4 and forkhead box protein O3, alongside the transcription factor nuclear factor erythroid-2-related factor 2 (NRF2) that is responsible for cellular protection against oxidative damage. The tumour suppressive nature of many of its substrates and the overexpression of βTrCP observed in various cancers support a potential therapeutic role for inhibitors in the treatment of cancer. A small molecule substituted pyrazolone, GS143, and the natural product erioflorin have been identified as inhibitors of βTrCP and protect its targets from proteasomal degradation. Modified peptides based on the sequences of native substrates have also been reported with KD values in the nanomolar range. This review describes the current status of inhibitors of this E3 ligase. The scope for further inhibitor design and the development of PROTAC and molecular glue-type structures is explored in the context of βTrCP as an example of WD40 domain-containing proteins that are gaining attention as drug targets

Social as much as environmental: the drivers of tree biomass in smallholder forest landscape restoration programmes

A major challenge for forest landscape restoration initiatives is the lack of quantitative evidence on how social factors drive environmental outcomes. Here we conduct an interdisciplinary quantitative analysis of the environmental and social drivers of tree biomass accumulation across 639 smallholder farms restoring native tree species in Mexico, Uganda and Mozambique. We use environmental and social data to assess the relative effects of key hypothesised drivers on aboveground biomass accumulation at the farm-level over ten years. We supplement this with a qualitative analysis of perspectives from local farmers and agroforestry technicians on the potential causal mechanisms of the observed social effects. We find that the material wellbeing of farmers (e.g. assets) and access to agroforestry knowledge explain as much variation in biomass as water availability. Local perspectives suggest that this is caused by the higher adaptive capacity of some farmers and their associated ability to respond to social-ecological shocks and stresses. Additionally, the variation in biomass between farms increased over time. Local perspectives suggested that this was caused by emergent exogenous and stochastic influences which cannot be reliably predicted in technical analyses and guidance. To deal with this persistent uncertainty, local perspectives emphasised the need for flexible and adaptive processes at the farm- and village-levels. The consistency of these findings across three countries suggests these findings are relevant to similar forest restoration interventions. Our findings provide novel quantitative evidence of a social-ecological pathway where the adaptive capacity of local land users can improve ecological processes. Our findings emphasize the need for forest restoration programmes to prioritise investment in the capabilities of local land users, and to ensure that rules support, rather than hinder, adaptive management

Confronting deep uncertainty in the forest carbon industry

Global momentum on carbon markets has the potential to direct substantial capital toward protecting the world’s forests. Yet the billion-dollar forest-carbon-offsetting industry is attracting criticism, in part from doubts about the methods used to measure and causally attribute changes in tree cover and biomass (1). Many actors in the industry are thus pursuing increasingly detailed measurement and monitoring of carbon outcomes and risks, under the assumption that this will improve accuracy and offset integrity (2). However, mounting scientific evidence (3, 4) implies that many forest landscapes are subject to “deep uncertainty” (5), such that claims of high accuracy in assessing carbon change are likely to remain inherently contestable, regardless of the technology or methodology deployed. Further, demands for such accuracy are likely to perpetuate inefficiencies and injustices among carbon suppliers (6–9). Approaches from other sectors may offer alternative ways forward in the absence of highly accurate measurements of outcomes

The current status and future prospects for therapeutic targeting of KEAP1-NRF2 and β-TrCP-NRF2 interactions in cancer chemoresistance

Drug resistance is one of the biggest challenges in cancer treatment and limits the potential to cure patients. In many tumors, sustained activation of the protein NRF2 makes tumor cells resistant to chemo- and radiotherapy. Thus, blocking inappropriate NRF2 activity in cancers has been shown to reduce resistance in models of the disease. There is a growing scientific interest in NRF2 inhibitors. However, the compounds developed so far are not target-specific and are associated with a high degree of toxicity, hampering clinical applications. Compounds that can enhance the binding of NRF2 to its ubiquitination-facilitating regulator proteins, either KEAP1 or β-TrCP, have the potential to increase NRF2 degradation and may be of value as potential chemosensitising agents in cancer treatment. Approaches based on molecular glue-type mechanisms, in which ligands stabilise a ternary complex between a protein and its binding partner have shown to enhance β-catenin degradation by stabilising its interaction with β-TrCP. This strategy could be applied to rationally discover degradative β-TrCP-NRF2 and KEAP1-NRF2 protein-protein interaction enhancers. We are proposing a novel approach to selectively suppress NRF2 activity in tumors. It is based on recent methodology and has the potential to be a promising new addition to the arsenal of anticancer agents

Shielded Cold Cathode Magnetron (SCCM)

A magnetron is a vacuum device that uses the interaction of electrons and an electric field to generate microwaves. Magnetrons are often used for radar systems. Current magnetrons create electrons by heating a tungsten wire to the point that it emits electrons. These systems waste large amounts of energy and are difficult to control. A shielded cold cathode magnetron is a new magnetron design that has the potential to greatly improve the magnetron’s efficiency. These new magnetrons utilize arrays of gated field emitters to inject the electrons into the electric field. These field emitters must be protected from electron bombardment inside of the cavity, so a ceramic structure is incorporated into the design. The field emitter structure consists of emitter tips paired with gates; the electron motion is controlled by a pusher electrode. These emitter gate pair arrays can be individually addressed, thereby allowing control of electron injection. The ceramic structure is fabricated using a Low Temperature Co-Fired Ceramic and thick film metal electrodes. This structure is designed to shield the emitters from back bombardment by electrons and ions. Performance can be measured using segmented collectors and energy analyzers. The results from the design, fabrication, and testing of a shielded cold cathode test structure will be presented

Clinical stakeholders' opinions on the use of selective decontamination of the digestive tract in critically ill patients in intensive care units : an international Delphi study

Peer reviewedPublisher PD

High stakes and low bars: How international recognition shapes the conduct of civil wars

When rebel groups engage incumbent governments in war for control of the state, questions of international recognition arise. International recognition determines which combatants can draw on state assets, receive overt military aid, and borrow as sovereigns—all of which can have profound consequences for the military balance during civil war. How do third-party states and international organizations determine whom to treat as a state's official government during civil war? Data from the sixty-one center-seeking wars initiated from 1945 to 2014 indicate that military victory is not a prerequisite for recognition. Instead, states generally rely on a simple test: control of the capital city. Seizing the capital does not foreshadow military victory. Civil wars often continue for many years after rebels take control and receive recognition. While geopolitical and economic motives outweigh the capital control test in a small number of important cases, combatants appear to anticipate that holding the capital will be sufficient for recognition. This expectation generates perverse incentives. In effect, the international community rewards combatants for capturing or holding, by any means necessary, an area with high concentrations of critical infrastructure and civilians. In the majority of cases where rebels contest the capital, more than half of its infrastructure is damaged or the majority of civilians are displaced (or both), likely fueling long-term state weakness