Although information about climate change and its implications is becoming increasingly available to water utility managers, additional tools are needed to translate this information into secondary ...products useful for local assessments. The anticipated intensification of the hydrologic cycle makes quantifying changes to hydrologic extremes, as well as associated water quality effects, of particular concern. To this end, this paper focuses on using extreme value statistics to describe maximum monthly flow distributions at a given site, where the nonstationarity is derived from concurrent climate information. From these statistics, flow quantiles are reconstructed over the historic record and then projected to 2100. This paper extends this analysis to an associated source water quality impact, whereby the corresponding risk of exceeding a water quality threshold is examined. The approach is applied to a drinking water source in the Pacific Northwest United States that has experienced elevated turbidity values correlated with high streamflow. Results demonstrate that based on climate change information from the most recent Intergovernmental Panel on Climate Change assessment report, the variability and magnitude of extreme streamflows substantially increase over the 21st century. Consequently, the likelihood of a turbidity exceedance increases, as do the associated relative costs. The framework is general and could be applied to estimate extreme streamflow under climate change at other locations, with straightforward extensions to other water quality variables that depend on extreme hydroclimate.
To what extent can we predict how evolution occurs? Do genetic architectures and developmental processes canalize the evolution of similar outcomes in a predictable manner? Or do historical ...contingencies impose alternative pathways to answer the same challenge? Examples of Müllerian mimicry between distantly related butterfly species provide natural replicates of evolution, allowing us to test whether identical wing patterns followed parallel or novel trajectories. Here, we explore the role that the signaling ligand WntA plays in generating mimetic wing patterns in Heliconius butterflies, a group with extraordinary mimicry-related wing pattern diversity. The radiation is relatively young, and numerous cases of wing pattern mimicry have evolved within the last 2.5–4.5 Ma. WntA is an important target of natural selection and is one of four major effect loci that underlie much of the pattern variation in the group. We used CRISPR/Cas9 targeted mutagenesis to generate WntA-deficient wings in 12 species and a further 10 intraspecific variants, including three co-mimetic pairs. In all tested butterflies, WntA knockouts affect pattern broadly and cause a shift among every possible scale cell type. Interestingly, the co-mimics lacking WntA were very different, suggesting that the gene networks that pattern a wing have diverged considerably among different lineages. Thus, although natural selection channeled phenotypic convergence, divergent developmental contexts between the two major Heliconius lineages opened different developmental routes to evolve resemblance. Consequently, even under very deterministic evolutionary scenarios, our results underscore a surprising unpredictability in the developmental paths underlying convergence in a recent radiation.
Display omitted
•Mimicry in Heliconius is achieved through divergent developmental networks•WntA is a major patterning gene that is used differently in co-mimics•Regulation of WntA expression and its interaction with other genes shape diversity•WntA modulates wing-scale cell identity
Concha et al. use CRISPR/Cas9 genome editing to knock out a major wing patterning gene, WntA, in mimetic species of Heliconius butterflies and report that WntA is used in divergent gene regulatory networks in co-mimics and that resemblance is achieved through differential expression of WntA and its interaction with the specific genetic background.
The global‐scale observations of the limb and disk (GOLD) Mission images middle thermosphere temperature and the vertical column density ratio of oxygen to molecular nitrogen (ΣO/N2) using its far ...ultraviolet imaging spectrographs in geostationary orbit. Since GOLD only measures these quantities during daylight, and only over the ∼140° of longitude visible from geostationary orbit, previously developed tidal analysis techniques cannot be applied to the GOLD data set. This paper presents a novel approach that deduces two specified non‐migrating diurnal tides using simultaneous measurements of temperature and ΣO/N2. DE3 (diurnal eastward propagating wave 3) and DE2 (diurnal eastward propagating wave 2) during October 2018 and January 2020 are the focus of this paper. Sensitivity analyses using TIE‐GCM simulations reveal that our approach reliably retrieves the true phases, whereas a combination of residual contributions from secondary tides, the restriction in longitude, and random uncertainty can lead to ∼50% error in the retrieved amplitudes. Application of our approach to GOLD data during these time periods provides the first observations of non‐migrating diurnal tides in measurements taken from geostationary orbit. We identify discrepancies between GOLD observations and TIE‐GCM modeling. Retrieved tidal amplitudes from GOLD observations exceed their respective TIE‐GCM amplitudes by a factor of two in some cases.
Plain Language Summary
The uppermost region of the Earth's atmosphere, known as the thermosphere (∼80–600 km altitude), is connected to the lowermost region by planetary‐scale atmospheric waves, called non‐migrating tides, which are thermally driven and do not follow the apparent motion of the Sun across the sky. Understanding non‐migrating tides is essential to describing the global dynamics of the Earth's upper atmosphere. There is a gap in observations of these waves in the middle thermosphere temperature, around 150 km altitude. The NASA/GOLD instrument, in geostationary orbit above the mouth of the Amazon River, images the temperature and composition of the middle thermosphere. Conventional tidal analysis techniques cannot be applied to the GOLD data set, so we have designed a novel technique that infers important tides using simultaneous measurements of temperature and composition. For two separate time periods, we apply our technique to simulated observations and actual GOLD data. We find that our technique generally infers the most important tides in simulated data with high accuracy. The GOLD data reveal valuable observations of tides in the middle thermosphere as well as discrepancies with the simulated data.
Key Points
First estimates of non‐migrating diurnal tides from an observational platform in geostationary orbit using GOLD
Deduction of non‐migrating tides via known phase relationships between temperature and composition
Retrieved tidal amplitudes from GOLD observations are generally stronger than their predicted model counterparts
Oversight arrangements which articulate technical, contractual and organizational decisions in a project domain constitute project governance. In the light of rapid globalization and an increasing ...number of complex, pluralistic and heterogeneous projects, the need for contingent project governance arrangements which bridge both stability and temporality of project decisions is emphasized in the literature. Nevertheless, inadequate attention has been paid to study how these governance arrangements are actually set up on contemporary projects. We use a combination of institutions-based and practice-based lenses to develop arguments on how governance arrangements are initially selected and replicated or revised, thereby leading to the emergence of order in project governance structures. We gather empirical evidence by qualitatively studying the shaping of project governance structures in a metro rail project in India. Our data show how the project promoters drew from the Delhi Metro's governance structures to make technical, contractual and organizational decisions in the Chennai Metro, and then contested or stabilized these structures within the project field through situated interactions. Consequently, we identify 11 underlying mechanisms of sustenance and change of governance arrangements and project norms. By bridging both generic and contextual governance perspectives, the study underlines the role of situated "governing" in (re)creating governance structures.
The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of ...approximately 1800 drug targets, and nearly 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org/), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.16180. Catalytic receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, ion channels, nuclear hormone receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
Institutions are defined as systems composed of regulative, normative and cultural‐cognitive elements that act to produce meaning, stability and order. Institutional elements move from place to place ...and time to time with the help of carriers. Four types of carriers are distinguished—symbolic systems, relational systems, routines, and artifacts—and two of these—symbolic and relation systems—are described and illustrated. It is argued that carriers are not neutral vehicles but have important effects on the elements transmitted.
Piscidins are histidine-enriched antimicrobial peptides that interact with lipid bilayers as amphipathic α-helices. Their activity at acidic and basic pH in vivo makes them promising templates for ...biomedical applications. This study focuses on p1 and p3, both 22-residue-long piscidins with 68% sequence identity. They share three histidines (H3, H4, and H11), but p1, which is significantly more permeabilizing, has a fourth histidine (H17). This study investigates how variations in amphipathic character associated with histidines affect the permeabilization properties of p1 and p3. First, we show that the permeabilization ability of p3, but not p1, is strongly inhibited at pH 6.0 when the conserved histidines are partially charged and H17 is predominantly neutral. Second, our neutron diffraction measurements performed at low water content and neutral pH indicate that the average conformation of p1 is highly tilted, with its C-terminus extending into the opposite leaflet. In contrast, p3 is surface bound with its N-terminal end tilted toward the bilayer interior. The deeper membrane insertion of p1 correlates with its behavior at full hydration: an enhanced ability to tilt, bury its histidines and C-terminus, induce membrane thinning and defects, and alter membrane conductance and viscoelastic properties. Furthermore, its pH-resiliency relates to the neutral state favored by H17. Overall, these results provide mechanistic insights into how differences in the histidine content and amphipathicity of peptides can elicit different directionality of membrane insertion and pH-dependent permeabilization. This work features complementary methods, including dye leakage assays, NMR-monitored titrations, X-ray and neutron diffraction, oriented CD, molecular dynamics, electrochemical impedance spectroscopy, surface plasmon resonance, and quartz crystal microbalance with dissipation.
Highlights ► We review recent developments in therapeutic application of antimicrobial peptides. ► Host defense peptides (HDPs) may combine antibiotic with host modification activity. ► Some HDPs and ...lantibiotics have promising activity in systemic infection models. ► HDPs and non-peptidic mimics are in clinical trials for systemic infections. ► Lantibiotics are in clinical trials for Clostridium difficile infection.
Antimicrobial peptides are small cationic amphiphiles that play an important role in the innate immune system. Given their broad specificity, they appear to be ideal therapeutic agents. As a result, ...over the last decade, there has been considerable interest in developing them as intravenously administered antibiotics. However, it has proven difficult to accomplish this goal with peptide-based structures. Although it has been possible to solve some relatively simple problems such as susceptibility to proteolysis, more severe problems have included the expense of the materials, toxicity, limited efficacy, and limited tissue distribution. In an effort to overcome these problems, we developed small synthetic oligomers designed to adopt amphiphilic conformations and exhibit potent antimicrobial activity while being nontoxic to host cells. One class of these synthetic mimics of antimicrobial peptides (SMAMPs) is being developed as intravenous antibiotics.
Long-term safety of pembrolizumab in melanoma was analyzed in KEYNOTE-001, KEYNOTE-002, and KEYNOTE-006.
Analysis involved patients who received ≥1 pembrolizumab dose. Lead-time bias was addressed ...via landmark analyses in patients who were progression-free before day 147.
Adverse events (AEs) were analyzed for 1567 patients (median follow-up, 42.4 months). Most AEs were mild/moderate; grade 3/4 treatment-related AEs occurred in 17.7% of patients. Two pembrolizumab-related deaths occurred. Any-grade immune-mediated AEs (imAEs) occurred in 23.0%, most commonly hypothyroidism (9.1%), pneumonitis (3.3%), and hyperthyroidism (3.0%); grade 3/4 imAEs occurred in 6.9% of patients. Most imAEs occurred within 16 weeks of treatment. In landmark analysis, patients who did (n = 79) versus did not (n = 384) develop imAEs had similar objective response rates (ORRs) (64.6% versus 63.0%); median time to response (TTR), 5.6 months for both; median duration of response (DOR), 20.0 versus 25.3 months; median progression-free survival (PFS), 17.0 versus 17.7 months; median overall survival (OS), not reached (NR) versus 43 months (p = 0.1104). Patients who did (n = 17) versus did not (n = 62) receive systemic corticosteroids had similar ORRs (70.6% vs. 62.9%) and median TTR (6.4 vs. 5.6 months) but numerically shorter median PFS (9.9 vs. 17.0 months); median DOR, 14.2 months versus NR; median OS, NR for both.
These results enhance the knowledge base for pembrolizumab in advanced melanoma, with no new toxicity signals after lengthy follow-up of a large population. In landmark analyses, pembrolizumab efficacy was similar regardless of imAEs or systemic corticosteroid use.
NCT01295827, NCT01704287, NCT01866319.
•Long-term (3.5 years) safety analysis of pembrolizumab monotherapy in melanoma.•Data were pooled from KEYNOTE-001, KEYNOTE-002, and KEYNOTE-006 trials (N = 1567).•Treatment-related AEs and immune-mediated AEs (imAE) were generally mild/moderate.•In landmark analysis, efficacy was similar regardless of imAEs or corticosteroid use.•With no new toxicity signals, results support pembrolizumab use in advanced melanoma.