Faricimab for neovascular age-related macular degeneration and diabetic macular edema: from preclinical studies to phase 3 outcomes.

Intravitreal anti-vascular endothelial growth factor (VEGF) therapy is the standard of care for diabetic macular edema (DME) and neovascular age-related macular degeneration (nAMD); however, vision gains and anatomical improvements are not sustained over longer periods of treatment, suggesting other relevant targets may be needed to optimize treatments. Additionally, frequent intravitreal injections can prove a burden for patients and caregivers. Angiopoietin-2 (Ang-2) has been explored as an additional therapeutic target, due to the involvement of Ang-2 in DME and nAMD pathogenesis. Recent evidence supports the hypothesis that targeting both VEGF and Ang-2 may improve clinical outcomes in DME and nAMD compared with targeting VEGF alone by enhancing vascular stability, resulting in reduced macular leakage, prevention of neovascularization, and diminished inflammation. Faricimab, a novel bispecific antibody that targets VEGF-A and Ang-2, has been evaluated in clinical trials for DME (YOSEMITE/RHINE) and nAMD (TENAYA/LUCERNE). These trials evaluated faricimab against the anti-VEGFA/B and anti-placental growth factor fusion protein aflibercept, both administered by intravitreal injection. In addition to faricimab efficacy, safety, and pharmacokinetics, durability was evaluated during the trials using a treat-and-extend regimen. At 1 year, faricimab demonstrated non-inferior vision gains versus aflibercept across YOSEMITE/RHINE and TENAYA/LUCERNE. In YOSEMITE/RHINE, faricimab improved anatomic parameters versus aflibercept. Reduction of central subfield thickness (CST), and absence of both DME and intraretinal fluid were greater in faricimab- versus aflibercept-treated eyes. In TENAYA/LUCERNE, CST reductions were greater for faricimab than aflibercept at the end of the head-to-head phase (0-12 weeks), and were comparable with aflibercept at year 1, but with less frequent dosing. CST and vision gains were maintained during year 2 of both YOSEMITE/RHINE and TENAYA/LUCERNE. These findings suggest that dual Ang-2/VEGF-A pathway inhibition may result in greater disease control versus anti-VEGF alone, potentially addressing the unmet needs and reducing treatment burden, and improving real-world outcomes and compliance in retinal vascular diseases. Long-term extension studies (RHONE-X, AVONELLE-X) are ongoing. Current evidence suggests that dual inhibition with faricimab heralds the beginning of multitargeted treatment strategies inhibiting multiple, independent components of retinal pathology, with faricimab providing opportunities to reduce treatment burden and improve outcomes compared with anti-VEGF monotherapy.

Modeling Sustainability: Population, Inequality, Consumption, and Bidirectional Coupling of the Earth and Human Systems.

Over the last two centuries, the impact of the Human System has grown dramatically, becoming strongly dominant within the Earth System in many different ways. Consumption, inequality, and population have increased extremely fast, especially since about 1950, threatening to overwhelm the many critical functions and ecosystems of the Earth System. Changes in the Earth System, in turn, have important feedback effects on the Human System, with costly and potentially serious consequences. However, current models do not incorporate these critical feedbacks. We argue that in order to understand the dynamics of either system, Earth System Models must be coupled with Human System Models through bidirectional couplings representing the positive, negative, and delayed feedbacks that exist in the real systems. In particular, key Human System variables, such as demographics, inequality, economic growth, and migration, are not coupled with the Earth System but are instead driven by exogenous estimates, such as UN population projections. This makes current models likely to miss important feedbacks in the real Earth-Human system, especially those that may result in unexpected or counterintuitive outcomes, and thus requiring different policy interventions from current models. The importance and imminence of sustainability challenges, the dominant role of the Human System in the Earth System, and the essential roles the Earth System plays for the Human System, all call for collaboration of natural scientists, social scientists, and engineers in multidisciplinary research and modeling to develop coupled Earth-Human system models for devising effective science-based policies and measures to benefit current and future generations.

Livability for all? Conceptual limits and practical implications.

Livability has risen, alongside sustainability, as a guiding principle for planning and policy. Promoted as the more tangible of the two concepts, livability shapes public perception and infrastructure investments in cities, as well as competition among cities for the attention of the public, investment communities, and potentially fickle and mobile human capital. This paper takes stock of the current discourse on livability, identifies two central elements that have yet to shape the assessments of livability and policies to promote it, and explores strategies for research and practice to transform the livability concept, and with it the places in which the lives and livelihoods of people unfold.

Exploring the resilience of industrial ecosystems.

Industrial ecosystems improve eco-efficiency at the system level through optimizing material and energy flows, which however raises a concern for system resilience because efficiency, as traditionally conceived, not necessarily promotes resilience. By drawing on the concept of resilience in ecological systems and in supply chains, resilience in industrial ecosystems is specified on the basis of a system's ability to maintain eco-efficient material and energy flows under disruptions. Using a network model that captures supply, asset, and organizational dependencies and propagation of disruptions among firms, the resilience, and particularly resistance as an important dimension of resilience, of two real industrial ecosystems and generalized specifications are examined. The results show that an industrial ecosystem is less resistant and less resilient with high inter-firm dependency, preferentially organized physical exchanges, and under disruptions targeted at highly connected firms. An industrial ecosystem with more firms and exchanges is less resistant, but has more eco-efficient flows and potentials, and therefore is less likely to lose its function of eco-efficiency. Taking these determinants for resilience into consideration improves the adaptability of an industrial ecosystem, which helps increase its resilience.

Growing Up and Cleaning Up: The Environmental Kuznets Curve Redux.

Borrowing from the Kuznets curve literature, researchers have coined the term "environmental Kuznets curve" or EKC to characterize the relationship between pollution levels and income: pollution levels will increase with income but some threshold of income will eventually be reached, beyond which pollution levels will decrease. The link between the original Kuznets curve, which posited a similar relationship between income and inequality, and its pollution-concerned offspring lies primarily with the shape of both curves (an upside-down U) and the central role played by income change. Although the EKC literature has burgeoned over the past several years, few concrete conclusions have been drawn, the main themes of the literature have remained constant, and no consensus has been reached regarding the existence of an environmental Kuznets curve. EKC research has used a variety of types of data and a range of geographical units to examine the effects of income levels on pollution. Changes in pollution levels might also be at least partly explained by countries' position in the demographic transition and their general population structure, however little research has included this important aspect in the analysis. In addition, few analyses confine themselves to an evaluation for one country of the long-term relationship between income and pollution. Using United States CO2 emissions as well as demographic, employment, trade and energy price data, this paper seeks to highlight the potential impact of population and economic structure in explaining the relationship between income and pollution levels.

A pentacyclic aurora kinase inhibitor (AKI-001) with high in vivo potency and oral bioavailability.

Aurora kinase inhibitors have attracted a great deal of interest as a new class of antimitotic agents. We report a novel class of Aurora inhibitors based on a pentacyclic scaffold. A prototype pentacyclic inhibitor 32 (AKI-001) derived from two early lead structures improves upon the best properties of each parent and compares favorably to a previously reported Aurora inhibitor, 39 (VX-680). The inhibitor exhibits low nanomolar potency against both Aurora A and Aurora B enzymes, excellent cellular potency (IC50 < 100 nM), and good oral bioavailability. Phenotypic cellular assays show that both Aurora A and Aurora B are inhibited at inhibitor concentrations sufficient to block proliferation. Importantly, the cellular activity translates to potent inhibition of tumor growth in vivo. An oral dose of 5 mg/kg QD is well tolerated and results in near stasis (92% TGI) in an HCT116 mouse xenograft model.

Facile synthesis of @-tide beta-strand peptidomimetics: improved assembly in solution and on solid phase.

The synthesis of @-tide beta-strand peptidomimetics has been improved such that oligomers now can be obtained from solution- and solid-phase synthesis protocols approaching the efficiency and flexibility of peptide chemistry. These methods enable the synthesis of @-tide oligomers with a variety of amino acids and with lengths up to 13 units. [reaction: see text]

Climate change policies and capital vintage effects: the cases of US pulp and paper, iron and steel, and ethylene.

Changes in material use, energy use and emissions profiles of industry are the result of complex interrelationships among a multitude of technological and economic drivers. To better understand and guide such changes requires that attention is paid to the time-varying consequences that technology and economic influences have on an industry's choice of inputs and its associated (desired and undesired) outputs. This paper lays out an approach to improving our understanding of the dynamics of large industrial systems. The approach combines engineering and econometric analysis with a detailed representation of an industry's capital stock structure. A transparent dynamic computer modeling approach is chosen to integrate information from these analyses in ways that foster participation of stakeholders from industry and government agencies in all stages of the modeling process-from problem definition and determination of system boundaries to generation of scenarios and interpretation of results. Three case studies of industrial energy use in the USA are presented-one each for the iron and steel, pulp and paper, and ethylene industry. Dynamic models of these industries are described and then used to investigate alternative carbon emissions and investment-led policies. A comparison of results clearly points towards two key issues: the need for industry specific policy approaches in order to effectively influence industrial energy use, fuel mix and carbon emissions, and the need for longer time horizons than have typically been chosen for the analysis of industrial responses to climate change policies.

Carbon emissions from U.S. ethylene production under climate change policies.

This paper presents the results from a dynamic computer model of U.S. ethylene production, designed to explore implications of alternative climate change policies for the industry's energy use and carbon emissions profiles. The model applies to the aggregate ethylene industry but distinguishes its main cracker types, fuels used as feedstocks and for process energy, as well as the industry's capital vintage structure and vintage-specific efficiencies. Results indicate that policies which increase the cost of carbon of process energy-such as carbon taxes or carbon permit systems-are relatively blunt instruments for cutting carbon emissions from ethylene production. In contrast, policies directly affecting the relative efficiencies of new to old capital-such as R&D stimuli or accelerated depreciation schedules-may be more effective in leveraging the industry's potential for carbon emissions reductions.

An Iron(III)-Catechol Complex as a Mushroom Pigment.

An iron ink has been detected as the pigment of the beautiful dark violet mushroom Cortinarius violaceus. The amino acid (R)-ß-dopa (1) is the ligand of the 1:2 Feiii -catechol complex.