Spatial ecology and population dynamics of brown trout Salmo trutta L. in reservoirs and headwater tributaries.

This investigation compared the spatial ecology and population dynamics of brown trout Salmo trutta L. between reservoirs with (impact; Langsett Reservoir) and without (control; Grimwith Reservoir) barriers to fish movements into headwater tributaries, and the effectiveness of a fish pass intended to remediate connectivity. Passive integrated transponder (PIT) telemetry revealed that fish that emigrated from Langsett and Grimwith tributaries were 1-3 and 0-2 years old, respectively, and predominantly did so in spring and autumn-early winter in both systems. Weirs at Langsett Reservoir appeared to thwart emigration rate (26%) relative to Grimwith Reservoir (85%). Acoustic telemetry (two-dimensional positions) in the impacted reservoir revealed that the largest home range was in October-December (95% monthly activity space S.D. up to 26.9 ± 6.69 ha in November), activity was influenced by both month and time of day, and fish occupied shallow water depths (relative to reservoir depth), especially at night. Brown trout tagged in Grimwith and Langsett Reservoirs (42.9% and 64.1%, respectively) and fish tagged in the tributaries that emigrated (37.2% and 27.7%, respectively) were detected immigrating into tributaries throughout the year. At both reservoirs, peak immigration for ≥3-year-old trout occurred primarily in autumn-early winter. Overall passage efficiency went from 3% prior to remediation to 14% after and there was no significant increase in fish densities following the construction of the fish pass. Fish were attracted towards and entered the fish pass under a wide range of river levels, but only succeeded in passing upstream during low levels, which are uncommon druing the main migration period. Overall, this investigation significantly furthers our understanding of brown trout spatial ecology and population dynamics in reservoirs and headwater tributaries.

Targeting Cytotoxic Agents through EGFR-Mediated Covalent Binding and Release.

A major drawback of cytotoxic chemotherapy is the lack of selectivity toward noncancerous cells. The targeted delivery of cytotoxic drugs to tumor cells is a longstanding goal in cancer research. We proposed that covalent inhibitors could be adapted to deliver cytotoxic agents, conjugated to the ß-position of the Michael acceptor, via an addition-elimination mechanism promoted by covalent binding. Studies on model systems showed that conjugated 5-fluorouracil (5FU) could be released upon thiol addition in relevant time scales. A series of covalent epidermal growth factor receptor (EGFR) inhibitors were synthesized as their 5FU derivatives. Achieving the desired release of 5FU was demonstrated to depend on the electronics and geometry of the compounds. Mass spectrometry and NMR studies demonstrated an anilinoquinazoline acrylate ester conjugate bound to EGFR with the release of 5FU. This work establishes that acrylates can be used to release conjugated molecules upon covalent binding to proteins and could be used to develop targeted therapeutics.

Modulation of ERK5 Activity as a Therapeutic Anti-Cancer Strategy.

The extracellular signal-regulated kinase 5 (ERK5) signaling pathway is one of four conventional mitogen-activated protein (MAP) kinase pathways. Genetic perturbation of ERK5 has suggested that modulation of ERK5 activity may have therapeutic potential in cancer chemotherapy. This Miniperspective examines the evidence for ERK5 as a drug target in cancer, the structure of ERK5, and the evolution of structurally distinct chemotypes of ERK5 kinase domain inhibitors. The emerging complexities of ERK5 pharmacology are discussed, including the confounding phenomenon of paradoxical ERK5 activation by small-molecule ERK5 inhibitors. The impact of the recent development and biological evaluation of potent and selective bifunctional degraders of ERK5 and future opportunities in ERK modulation are also explored.

Simultaneous targeting of glycolysis and oxidative phosphorylation as a therapeutic strategy to treat diffuse large B-cell lymphoma.

BACKGROUND: We evaluated the therapeutic potential of combining the monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 with the mitochondrial respiratory Complex I inhibitor IACS-010759, for the treatment of diffuse large B-cell lymphoma (DLBCL), a potential clinically actionable strategy to target tumour metabolism. METHODS: AZD3965 and IACS-010759 sensitivity were determined in DLBCL cell lines and tumour xenograft models. Lactate concentrations, oxygen consumption rate and metabolomics were examined as mechanistic endpoints. In vivo plasma concentrations of IACS-010759 in mice were determined by LC-MS to select a dose that reflected clinically attainable concentrations. RESULTS: In vitro, the combination of AZD3965 and IACS-010759 is synergistic and induces DLBCL cell death, whereas monotherapy treatments induce a cytostatic response. Significant anti-tumour activity was evident in Toledo and Farage models when the two inhibitors were administered concurrently despite limited or no effect on the growth of DLBCL xenografts as monotherapies. CONCLUSIONS: This is the first study to examine a combination of two distinct approaches to targeting tumour metabolism in DLBCL xenografts. Whilst nanomolar concentrations of either AZD3965 or IACS-010759 monotherapy demonstrate anti-proliferative activity against DLBCL cell lines in vitro, appreciable clinical activity in DLBCL patients may only be realised through their combined use.

Parallel Optimization of Potency and Pharmacokinetics Leading to the Discovery of a Pyrrole Carboxamide ERK5 Kinase Domain Inhibitor.

The nonclassical extracellular signal-related kinase 5 (ERK5) mitogen-activated protein kinase pathway has been implicated in increased cellular proliferation, migration, survival, and angiogenesis; hence, ERK5 inhibition may be an attractive approach for cancer treatment. However, the development of selective ERK5 inhibitors has been challenging. Previously, we described the development of a pyrrole carboxamide high-throughput screening hit into a selective, submicromolar inhibitor of ERK5 kinase activity. Improvement in the ERK5 potency was necessary for the identification of a tool ERK5 inhibitor for target validation studies. Herein, we describe the optimization of this series to identify nanomolar pyrrole carboxamide inhibitors of ERK5 incorporating a basic center, which suffered from poor oral bioavailability. Parallel optimization of potency and in vitro pharmacokinetic parameters led to the identification of a nonbasic pyrazole analogue with an optimal balance of ERK5 inhibition and oral exposure.

Engagement in video and audio narratives: contrasting self-report and physiological measures.

Stories play a fundamental role in human culture. They provide a mechanism for sharing cultural identity, imparting knowledge, revealing beliefs, reinforcing social bonds and providing entertainment that is central to all human societies. Here we investigated the extent to which the delivery medium of a story (audio or visual) affected self-reported and physiologically measured engagement with the narrative. Although participants self-reported greater involvement for watching video relative to listening to auditory scenes, stronger physiological responses were recorded for auditory stories. Sensors placed at their wrists showed higher and more variable heart rates, greater electrodermal activity, and even higher body temperatures. We interpret these findings as evidence that the stories were more cognitively and emotionally engaging at a physiological level when presented in an auditory format. This may be because listening to a story, rather than watching a video, is a more active process of co-creation, and that this imaginative process in the listener's mind is detectable on the skin at their wrist.

Single crystal texture by directed molecular self-assembly along dual axes.

Creating well-defined single-crystal textures in materials requires the biaxial alignment of all grains into desired orientations, which is challenging to achieve in soft materials. Here we report the formation of single crystals with rigorously controlled texture over macroscopic areas (>1 cm2) in a soft mesophase of a columnar discotic liquid crystal. We use two modes of directed self-assembly, physical confinement and magnetic fields, to achieve control of the orientations of the columnar axes and the hexagonal lattice along orthogonal directions. Field control of the lattice orientation emerges in a low-temperature phase of tilted discogens that breaks the field degeneracy around the columnar axis present in non-tilted states. Conversely, column orientation is controlled by physical confinement and the resulting imposition of homeotropic anchoring at bounding surfaces. These results extend our understanding of molecular organization in tilted systems and may enable the development of a range of new materials for distinct applications.

Low Heat of Adsorption of Ethylene Achieved by Major Solid-State Structural Rearrangement of a Discrete Copper(I) Complex.

The trinuclear copper(I) pyrazolate complex [Cu3 ] rearranges to the dinuclear analogue [Cu2 ⋅(C2 H4 )2 ] when exposed to ethylene gas. Remarkably, the [Cu3 ]↔[Cu2 ⋅(C2 H4 )2 ] rearrangement occurs reversibly in the solid state. Furthermore, this transformation emulates solution chemistry. The bond-making and breaking processes associated with the rearrangement in the solid-state result in an observed heat of adsorption (-13±1 kJ mol-1 per Cu-C2 H4 interaction) significantly lower than other Cu-C2 H4 interactions (≥-24 kJ mol-1 ). The low overall heat of adsorption, "step" isotherms, high ethylene capacity (2.76 mmol g-1 ; 7.6 wt % at 293 K), and high ethylene/ethane selectivity (136:1 at 293 K) make [Cu3 ] an interesting basis for the rational design of materials for low-energy ethylene/ethane separations.

Highly Potent Clickable Probe for Cellular Imaging of MDM2 and Assessing Dynamic Responses to MDM2-p53 Inhibition.

MDM2 is a key negative regulator of the p53 tumor suppressor. Direct binding of MDM2 to p53 represses the protein's transcriptional activity and induces its polyubiquitination, targeting it for degradation by the proteasome. Consequently, small molecule inhibitors that antagonize MDM2-p53 binding, such as RG7388, have progressed into clinical development aiming to reactivate p53 function in TP53 wild-type tumors. Here, we describe the design, synthesis, and biological evaluation of a trans-cyclooctene tagged derivative of RG7388, RG7388-TCO, which showed high cellular potency and specificity for MDM2. The in-cell reaction of RG7388-TCO with a tetrazine-tagged BODIPY dye enabled fluorescence imaging of endogenous MDM2 in SJSA-1 and T778 tumor cells. RG7388-TCO was also used to pull down MDM2 by reaction with tetrazine-tagged agarose beads in SJSA-1 lysates. The data presented show that RG733-TCO enables precise imaging of MDM2 in cells and can permit a relative assessment of target engagement and MDM2-p53 antagonism in vitro.

Inhibition of monocarboxyate transporter 1 by AZD3965 as a novel therapeutic approach for diffuse large B-cell lymphoma and Burkitt lymphoma.

Inhibition of monocarboxylate transporter 1 has been proposed as a therapeutic approach to perturb lactate shuttling in tumor cells that lack monocarboxylate transporter 4. We examined the monocarboxylate transporter 1 inhibitor AZD3965, currently in phase I clinical studies, as a potential therapy for diffuse large B-cell lymphoma and Burkitt lymphoma. Whilst extensive monocarboxylate transporter 1 protein was found in 120 diffuse large B-cell lymphoma and 10 Burkitt lymphoma patients' tumors, monocarboxylate transporter 4 protein expression was undetectable in 73% of the diffuse large B-cell lymphoma samples and undetectable or negligible in each Burkitt lymphoma sample. AZD3965 treatment led to a rapid accumulation of intracellular lactate in a panel of lymphoma cell lines with low monocarboxylate transporter 4 protein expression and potently inhibited their proliferation. Metabolic changes induced by AZD3965 in lymphoma cells were consistent with a feedback inhibition of glycolysis. A profound cytostatic response was also observed in vivo: daily oral AZD3965 treatment for 24 days inhibited CA46 Burkitt lymphoma growth by 99%. Continuous exposure of CA46 cells to AZD3965 for 7 weeks in vitro resulted in a greater dependency upon oxidative phosphorylation. Combining AZD3965 with an inhibitor of mitochondrial complex I (central to oxidative phosphorylation) induced significant lymphoma cell death in vitro and reduced CA46 disease burden in vivo These data support clinical examination of AZD3965 in Burkitt lymphoma and diffuse large B-cell lymphoma patients with low tumor monocarboxylate transporter 4 expression and highlight the potential of combination strategies to optimally target the metabolic phenotype of tumors.

A thermoresponsive poly(ionic liquid) membrane enables concentration of proteins from aqueous media.

A new type of poly(ionic liquid) membrane, which shows switchable hydrated states via lower critical solution temperature-type phase behaviour, enables concentration of some water-soluble proteins from aqueous media.

Imidazolium-Based Poly(ionic liquid)/Ionic Liquid Ion-Gels with High Ionic Conductivity Prepared from a Curable Poly(ionic liquid).

Ionic liquid (IL)-based ion-gel membranes were prepared from a curable poly(IL)-based materials platform with the free ILs 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([EMIM][TFSI]), bis(fluorosulfonyl)imide ([EMIM][FSI]), 1-butylimidazolium bis(trifluoromethylsulfonyl)imide ([C4 IMH][TFSI]), and ethylmethylammonium nitrate [EAN][NO3 ] and evaluated for their ionic conductivity performance at ambient and elevated temperatures. The resulting cross-linked, free-standing ion-gel membranes were found to have less than 1 wt% water (with the exception of [EAN][NO3 ] which contained ≈20 wt% water). Increasing free IL content from 50 to 80 wt% produces materials with ionic conductivity values ≥10(-2) S cm(-1) at 25 °C and ≈10(-1) S cm(-1) at 110 °C. Additionally, ion-gels containing 70 wt% of the protic ILs [C4 IMH][TFSI] and [EMIM][FSI] display ionic conductivity values of ≈10(-3) to 10(-2) S cm(-1) over the temperature range of 25-110 °C.

Poly(ionic liquid)/Ionic Liquid Ion-Gels with High "Free" Ionic Liquid Content: Platform Membrane Materials for CO2/Light Gas Separations.

The recycling or sequestration of carbon dioxide (CO2) from the waste gas of fossil-fuel power plants is widely acknowledged as one of the most realistic strategies for delaying or avoiding the severest environmental, economic, political, and social consequences that will result from global climate change and ocean acidification. For context, in 2013 coal and natural gas power plants accounted for roughly 31% of total U.S. CO2 emissions. Recycling or sequestering this CO2 would reduce U.S. emissions by ca. 1800 million metric tons-easily meeting the U.S.'s currently stated CO2 reduction targets of ca. 17% relative to 2005 levels by 2020. This situation is similar for many developed and developing nations, many of which officially target a 20% reduction relative to 1990 baseline levels by 2020. To make CO2 recycling or sequestration processes technologically and economically viable, the CO2 must first be separated from the rest of the waste gas mixture-which is comprised mostly of nitrogen gas and water (ca. 85%). Of the many potential separation technologies available, membrane technology is particularly attractive due to its low energy operating cost, low maintenance, smaller equipment footprint, and relatively facile retrofit integration with existing power plant designs. From a techno-economic standpoint, the separation of CO2 from flue gas requires membranes that can process extremely high amounts of CO2 over a short time period, a property defined as the membrane "permeance". In contrast, the membrane's CO2/N2 selectivity has only a minor effect on the overall cost of some separation processes once a threshold permeability selectivity of ca. 20 is reached. Given the above criteria, the critical properties when developing membrane materials for postcombustion CO2 separation are CO2 permeability (i.e., the rate of CO2 transport normalized to the material thickness), a reasonable CO2/N2 selectivity (≥20), and the ability to be processed into defect-free thin-films (ca. 100-nm-thick active layer). Traditional polymeric membrane materials are limited by a trade-off between permeability and selectivity empirically described by the "Robeson upper bound"-placing the desired membrane properties beyond reach. Therefore, the investigation of advanced and composite materials that can overcome the limitations of traditional polymeric materials is the focus of significant academic and industrial research. In particular, there has been substantial work on ionic-liquid (IL)-based materials due to their gas transport properties. This review provides an overview of our collaborative work on developing poly(ionic liquid)/ionic liquid (PIL/IL) ion-gel membrane technology. We detail developmental work on the preparation of PIL/IL composites and describe how this chemical technology was adapted to allow the roll-to-roll processing and preparation of membranes with defect-free active layers ca. 100 nm thick, CO2 permeances of over 6000 GPU, and CO2/N2 selectivity of ≥20-properties with the potential to reduce the cost of CO2 removal from coal-fired power plant flue gas to ca. $15 per ton of CO2 captured. Additionally, we examine the materials developments that have produced advanced PIL/IL composite membranes. These advancements include cross-linked PIL/IL blends, step-growth PIL/IL networks with facilitated transport groups, and PIL/IL composites with microporous additives for CO2/CH4 separations.

Thin Polymer Films with Continuous Vertically Aligned 1 nm Pores Fabricated by Soft Confinement.

Membrane separations are critically important in areas ranging from health care and analytical chemistry to bioprocessing and water purification. An ideal nanoporous membrane would consist of a thin film with physically continuous and vertically aligned nanopores and would display a narrow distribution of pore sizes. However, the current state of the art departs considerably from this ideal and is beset by intrinsic trade-offs between permeability and selectivity. We demonstrate an effective and scalable method to fabricate polymer films with ideal membrane morphologies consisting of submicron thickness films with physically continuous and vertically aligned 1 nm pores. The approach is based on soft confinement to control the orientation of a cross-linkable mesophase in which the pores are produced by self-assembly. The scalability, exceptional ease of fabrication, and potential to create a new class of nanofiltration membranes stand out as compelling aspects.

High ethene/ethane selectivity in 2,2'-bipyridine-based silver(i) complexes by removal of coordinated solvent.

Following removal of coordinated CH3 CN, the resulting complexes [Ag(I) (2,2'-bipyridine)][BF4 ] (1) and [Ag(I) (6,6'-dimethyl-2,2'-bipyridine)][OTf] (2) show ethene/ethane sorption selectivities of 390 and 340, respectively, and corresponding ethene sorption capacities of 2.38 and 2.18 mmol g(-1) when tested at an applied gas pressure of 90 kPa and a temperature of (20±1) °C. These ethene/ethane selectivities are 13 times higher than those reported for known solid sorbents for ethene/ethane separation. For 2, ethene sorption reached 90 % of equilibrium capacity within 15 minutes, and this equilibrium capacity was maintained over the three sorption/desorption cycles tested. The rates of ethene sorption were also measured. To our knowledge, these are the first complexes, designed for olefin/paraffin separations, which have open silver(I) sites. The high selectivities arise from these open silver(I) sites and the relatively low molecular surface areas of the complexes.

Scalable fabrication of polymer membranes with vertically aligned 1 nm pores by magnetic field directed self-assembly.

There is long-standing interest in developing membranes possessing uniform pores with dimensions in the range of 1 nm and physical continuity in the macroscopic transport direction to meet the needs of challenging small molecule and ionic separations. Here we report facile, scalabe fabrication of polymer membranes with vertically (i.e., along the through-plane direction) aligned 1 nm pores by magnetic-field alignment and subsequent cross-linking of a liquid crystalline mesophase. We utilize a wedge-shaped amphiphilic species as the building block of a thermotropic columnar mesophase with 1 nm ionic nanochannels, and leverage the magnetic anisotropy of the amphiphile to control the alignment of these pores with a magnetic field. In situ X-ray scattering and subsequent optical microscopy reveal the formation of highly ordered nanostructured mesophases and cross-linked polymer films with orientational order parameters of ca. 0.95. High-resolution transmission electron microscopy (TEM) imaging provides direct visualization of long-range persistence of vertically aligned, hexagonally packed nanopores in unprecedented detail, demonstrating high-fidelity retention of structure and alignment after photo-cross-linking. Ionic conductivity measurements on the aligned membranes show a remarkable 85-fold enhancement of conductivity over nonaligned samples. These results provide a path to achieving the large area control of morphology and related enhancement of properties required for high-performance membranes and other applications.

A cobalt(II) bis(salicylate)-based ionic liquid that shows thermoresponsive and selective water coordination.

A metal-containing ionic liquid (MCIL) has been prepared in which the [Co(II)(salicylate)2](2-) anion is able to selectively coordinate two water molecules with a visible colour change, even in the presence of alcohols. Upon moderate heating or placement in vacuo, the hydrated MCIL undergoes reversible thermochromism by releasing the bound water molecules.

A silver(I) coordinated phenanthroline-based polymer with high ethylene/ethane adsorption selectivity.

We report a non-porous silver(i) coordinated phenanthroline-based polymer, which exhibits a high ideal ethylene/ethane adsorption selectivity (15/1) and high ethylene uptake (5.0 mmol g(-1)) at ambient temperature and pressure. Both silver(i) coordination and polymer structures are important for the high uptake of ethylene.

Ending aging in super glassy polymer membranes.

Aging in super glassy polymers such as poly(trimethylsilylpropyne) (PTMSP), poly(4-methyl-2-pentyne) (PMP), and polymers with intrinsic microporosity (PIM-1) reduces gas permeabilities and limits their application as gas-separation membranes. While super glassy polymers are initially very porous, and ultra-permeable, they quickly pack into a denser phase becoming less porous and permeable. This age-old problem has been solved by adding an ultraporous additive that maintains the low density, porous, initial stage of super glassy polymers through absorbing a portion of the polymer chains within its pores thereby holding the chains in their open position. This result is the first time that aging in super glassy polymers is inhibited whilst maintaining enhanced CO2 permeability for one year and improving CO2/N2 selectivity. This approach could allow super glassy polymers to be revisited for commercial application in gas separations.