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Peptide cyclization has dramatic effects on a variety of important properties, enhancing metabolic stability, limiting conformational flexibility, and altering cellular entry and intracellular localization. The hydrophilic, polyfunctional nature of peptides creates chemoselectivity challenges in macrocyclization, especially for natural sequences without biorthogonal handles. Herein, we describe a gaseous sulfonyl chloride derived reagent that achieves amine–amine, amine–phenol, and amine–aniline crosslinking through a minimalist linchpin strategy that affords macrocyclic urea or carbamate products. The cyclization reaction is metal‐mediated and involves a novel application of sulfine species that remains unexplored in aqueous or biological contexts. The aqueous method delivers unique cyclic or bicyclic topologies directly from a variety of natural bioactive peptides without the need for protecting‐group strategies. [ABSTRACT FROM AUTHOR]

Aim: Evolutionary radiations are central to the origin and maintenance of biodiversity, yet we rarely understand how they are jointly shaped by demography and ecological opportunity. Astragalus is the largest plant genus in the world and is disproportionately comprised of rare species restricted to narrow geographic and ecological regions. Here, we explored the demographic and ecological mechanisms underlying patterns of diversification in a threatened Astragalus species complex endemic to a small desert region in the western United States. Location: Southeast Utah, USA. Methods: We used high‐throughput DNA sequencing to infer genetic structure, genetic diversity, and demographic history (i.e., the timing of population divergence, effective population sizes and gene flow) among Astragalus taxa. We performed landscape genetic analyses to quantify the relationships between genetic differentiation, geographic distance, and ecological distance based on bioclimatic and soil variables. Finally, we identified putative adaptive loci that show higher genetic differentiation between taxa than expected based on our inferred neutral demographic model. Results: We found evidence of low gene flow between three highly differentiated taxa (currently delineated as A. iselyi, A. sabulosus var. sabulosus and A. sabulosus var. vehiculus) that rapidly diverged from a small ancestral population near the beginning of the last glacial period. Genomic signatures revealed long‐term effective population sizes are 2–10× larger than recent census sizes, perhaps due to the maintenance of standing genetic variation through seed banks. Consistent with limited dispersal and local adaptation, genome‐wide patterns of differentiation are shaped by geographic distance (isolation‐by‐distance) and climate and soil variation (isolation‐by‐environment). Taxon‐specific adaptation is further supported by uncovering putative adaptive loci. Main Conclusions: Our findings suggest that interactions between demography (i.e., dispersal limitations and seeds banks) and ecological opportunity (i.e., spatial and temporal environmental heterogeneity) may promote diversification, endemism, and rarity among closely related Astragalus species and similar plant clades distributed across complex landscapes. [ABSTRACT FROM AUTHOR]

Understanding the links between genetic variation and fitness in natural populations is a central goal of evolutionary genetics. This monumental task spans the fields of classical and molecular genetics, population genetics, biochemistry, physiology, developmental biology, and ecology. Advances to our molecular and developmental toolkits are facilitating integrative approaches across these traditionally separate fields, providing a more complete picture of the genotype‐phenotype map in natural and non‐model systems. Here, we summarize research presented at the first annual symposium of the UNVEIL Network, an NSF‐funded collaboration between the University of Montana and the University of Nebraska, Lincoln, which took place from the 1st to the 3rd of June, 2018. We discuss how this body of work advances basic evolutionary science, what it implies for our ability to predict evolutionary change, and how it might inform novel conservation strategies. [ABSTRACT FROM AUTHOR]

The spatial structure of the environment (e.g. the configuration of habitat patches) may play an important role in determining the strength of local adaptation. However, previous studies of habitat heterogeneity and local adaptation have largely been limited to simple landscapes, which poorly represent the multiscale habitat structure common in nature. Here, we use simulations to pursue two goals: (i) we explore how landscape heterogeneity, dispersal ability and selection affect the strength of local adaptation, and (ii) we evaluate the performance of several genotype-environment association (GEA) methods for detecting loci involved in local adaptation. We found that the strength of local adaptation increased in spatially aggregated selection regimes, but remained strong in patchy landscapes when selection was moderate to strong. Weak selection resulted in weak local adaptation that was relatively unaffected by landscape heterogeneity. In general, the power of detection methods closely reflected levels of local adaptation. False-positive rates (FPRs), however, showed distinct differences across GEA methods based on levels of population structure. The univariate GEA approach had high FPRs (up to 55%) under limited dispersal scenarios, due to strong isolation by distance. By contrast, multivariate, ordination-based methods had uniformly low FPRs (0-2%), suggesting these approaches can effectively control for population structure. Specifically, constrained ordinations had the best balance of high detection and low FPRs and will be a useful addition to the GEA toolkit. Our results provide both theoretical and practical insights into the conditions that shape local adaptation and how these conditions impact our ability to detect selection. [ABSTRACT FROM AUTHOR]

The rapid expansion of next-generation sequencing has yielded a powerful array of tools to address fundamental biological questions at a scale that was inconceivable just a few years ago. Various genome-partitioning strategies to sequence select subsets of the genome have emerged as powerful alternatives to whole-genome sequencing in ecological and evolutionary genomic studies. High-throughput targeted capture is one such strategy that involves the parallel enrichment of preselected genomic regions of interest. The growing use of targeted capture demonstrates its potential power to address a range of research questions, yet these approaches have yet to expand broadly across laboratories focused on evolutionary and ecological genomics. In part, the use of targeted capture has been hindered by the logistics of capture design and implementation in species without established reference genomes. Here we aim to (i) increase the accessibility of targeted capture to researchers working in nonmodel taxa by discussing capture methods that circumvent the need of a reference genome, (ii) highlight the evolutionary and ecological applications where this approach is emerging as a powerful sequencing strategy and (iii) discuss the future of targeted capture and other genome-partitioning approaches in the light of the increasing accessibility of whole-genome sequencing. Given the practical advantages and increasing feasibility of high-throughput targeted capture, we anticipate an ongoing expansion of capture-based approaches in evolutionary and ecological research, synergistic with an expansion of whole-genome sequencing. [ABSTRACT FROM AUTHOR]

The environment shapes host-parasite interactions, but how environmental variation affects the diversity and composition of parasite-defense genes of hosts is unresolved. In vertebrates, the highly variable major histocompatibility complex ( MHC) gene family plays an essential role in the adaptive immune system by recognizing pathogen infection and initiating the cellular immune response. Investigating MHC-parasite associations across heterogeneous landscapes may elucidate the role of spatially fluctuating selection in the maintenance of high levels of genetic variation at the MHC. We studied patterns of association between an avian haemosporidian blood parasite and the MHC of rufous-collared sparrows ( Zonotrichia capensis) that inhabit environments with widely varying haemosporidian infection prevalence in the Peruvian Andes. MHC diversity peaked in populations with high infection prevalence, although intra-individual MHC diversity was not associated with infection status. MHC nucleotide and protein sequences associated with infection absence tended to be rare, consistent with negative frequency-dependent selection. We found an MHC variant associated with a ~26% decrease in infection probability at middle elevations (1501-3100 m) where prevalence was highest. Several other variants were associated with a significant increase in infection probability in low haemosporidian prevalence environments, which can be interpreted as susceptibility or quantitative resistance. Our study highlights important challenges in understanding MHC evolution in natural systems, but may point to a role of negative frequency-dependent selection and fluctuating spatial selection in the evolution of Z. capensis MHC. [ABSTRACT FROM AUTHOR]

Many nanoparticle adsorption processes are dictated by the collective interactions of surface-bound ligands. These adsorption processes define how nanoparticles interact with biological systems and enable the assembly of nanoparticle-based materials and devices. Herein, we present an approach for quantifying nanoparticle adsorption thermodynamics in a manner that satisfies the assumptions of the Langmuir model. Using this approach, we study the DNA-mediated adsorption of polyvalent anisotropic nanoparticles on surfaces and explore how deviations from model assumptions influence adsorption thermodynamics. Importantly, when combined with a solution-based van't Hoff analysis, we find that polyvalency plays a more important role as the individual interactions become weaker. Furthermore, we find that the free energy of anisotropic nanoparticle adsorption is consistent across multiple shapes and sizes of nanoparticles based on the surface area of the interacting facet. [ABSTRACT FROM AUTHOR]

Airway smooth muscle (ASM) cells play important physiological roles in the lung, and abnormal proliferation of ASM directly contributes to the airway remodeling during development of lung diseases such as asthma. MicroRNAs are small yet versatile gene tviners that regulate a variety of cellular processes, including cell growth and proliferation; however, little is known about the precise role of microRNAs in the proliferation of the ASM. Here we report that a specific microRNA (miR-10a) controls ASM proliferation through directly inhibiting the phosphoinositide 3-kinase (PI3K) pathway. Next-generation sequencing identified miR-10a as the most abundant microRNA expressed in primary human airway smooth muscle (HASM) cells, accounting for > 20% of all small RNA reads. Overexpression of miR-10a reduced mitogen-induced HASM proliferation by ~50%, whereas inhibition of miR-10a increased HASM proliferation by ~40%. Microarray profiling of HASM cells expressing miR-10a mimics identified 52 significantly down-regulated genes as potential targets of miR-10a, including die catalytic subunit a of PI3K (PIK3CA), the central component of the PI3K. pathway. MiR-10a directly suppresses PIK3CA expression by targeting the 3'-untranslated region (3'-UTR) of the gene. Inhibition of PIK3CA by miR-10a reduced V-akt murine thymoma viral oncogene homolog 1 (AKT) phosphorylation and blunted the expression of cyclins and cyclin-dependent kinases that are required for HASM proliferation. Together, our study identifies a novel microRNA-mediated regulatory mechanism for PI3K signaling and ASM proliferation and further suggests miR-10a as a potential therapeutic target for lung diseases whose etiology resides in abnormal ASM proliferation. [ABSTRACT FROM AUTHOR]

Dünne Filme von DNA ‐ Nanopartikel ‐ Übergittern ließen sich mithilfe eines schrittweisen Assemblierungsprozesses Schicht für Schicht auf DNA ‐ Substraten abscheiden. Ein neues Designprinzip für programmierbare Kristalle wird daraus abgeleitet: Das Übergitter nimmt eine Orientierung an, in der die komplementären DNA ‐ Wechselwirkungen mit einer gegebenen Kristallebene maximiert sind. [ABSTRACT FROM AUTHOR]

Es darf nur einen geben: Die Synthese anisotroper Nanopartikel liefert oft verunreinigte Nanostrukturen. Durch Funktionalisierung der Produkte mit DNA (Schritt 1) können die relativen Wechselwirkungsstärken zwischen den Partikeln gezielt eingestellt werden. Anschließend lassen sich die gewünschten Nanopartikel selektiv kristallisieren (Schritt 2) und abtrennen, was Proben deutlich höheren Reinheitsgrades ergibt (Schritt 3). [ABSTRACT FROM AUTHOR]

Context: Geoffrey Rose's two principal approaches to public health intervention are (1) targeted strategies focusing on individuals at a personal increased risk of disease and (2) population-wide approaches focusing on the whole population. Beyond his discussion of the strengths and weaknesses of these approaches, there is no empiric work examining the conditions under which one of these approaches may be better than the other. Methods: This article uses mathematical simulations to model the benefits and costs of the two approaches, varying the cut points for treatment, effect magnitudes, and costs of the interventions. These techniques then were applied to the specific example of an intervention on blood pressure to reduce cardiovascular disease. Findings: In the general simulation (using an inverse logit risk curve), lower costs of intervention, treating people with risk factor values at or above where the slope on the risk curve is at its steepest (for targeted interventions), and interventions with larger effects on reducing the risk factor (for population-wide interventions) provided benefit/cost advantages. In the specific blood pressure intervention example, lower-cost population-wide interventions had better benefit/cost ratios, but some targeted treatments with lower cutoffs prevented more absolute cases of disease. Conclusions: These simulations empirically evaluate some of Rose's original arguments. They can be replicated for particular interventions being considered and may be useful in helping public health decision makers assess potential intervention strategies. [ABSTRACT FROM AUTHOR]

Polyploidy is a state in which a cell contains multiple copies of its entire genome, while a normal diploid cell contains only two sets of homologous chromosomes. Although widely studied and pervasive in nature, the signals and mechanisms of polyploidization and its accompanying operational consequences are still unclear. This review focuses on relevant questions in deciphering the regulation of polyploidization of vascular smooth muscle cells (VSMC) in mammals and the role of polyploidy in various vascular pathologies, such as hypertension and aging. Additionally, we will explore new investigations in polyploidization of VSMCs involving the rapidly expanding fields of oxidative stress and senescence. J. Cell. Physiol. 215: 588–592, 2008. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

We previously reported that the frequency of polyploid aortic vascular smooth muscle cells (VSMC) serves as a biomarker of aging. Cellular senescence of somatic cells is another marker of aging that is characterized by the inability to undergo cell division. Here, we examined whether polyploidy is associated with the development of cellular senescence in vivo. Analysis of aortic tissue preparations from young and old Brown Norway rats showed that expression of senescence markers such as p16INK4a and senescence-associated β-galactosidase activity are detected primarily in the old tissues. VSMC from p16INK4a knockout and control mice display similar levels of polyploid cells. Intriguingly, senescence markers are expressed in most, but not all, polyploid VSMC. Moreover, the polyploid cells exhibit limited proliferative capacity in comparison to their diploid counterparts. This study is the first to demonstrate in vivo that polyploid VSMC adopt a senescent phenotype. [ABSTRACT FROM AUTHOR]

The cover image relates to the Research Article https://onlinelibrary.wiley.com/doi/10.1111/ddi.13288 'The demographic and ecological factors shaping diversifi cation among rare Astragalus species'. Cisco milkvetch (Astragalus sabulosus; Fabaceae), an incredibly rare,perennial forb growing in sparsely vegetated substrate near Moab, Utah (USA). [Extracted from the article]

Between February and October 2007, a time series of alkyl nitrate concentrations in the water column of a shallow freshwater lake, University of East Anglia Broad, located in southeastern England was carried out to determine whether methyl and ethyl nitrate are present in freshwater systems and to improve understanding of alkyl nitrate production mechanisms in aquatic environments. Concentrations ranged from 4.7 (± 0.5) to 53.7 (± 4.36) pmol L-1 methyl nitrate, and 2.5 (± 0.3) to 11.1 (± 0.4) pmol L-1 ethyl nitrate and were within the range of those measured previously in seawater. Peaks in the concentrations of methyl and ethyl nitrate at 4 m were observed in 9 and 6 of the 18 depth profiles measured, respectively. Gradients in concentrations within the hypolimnion suggest that the alkyl nitrates are produced in the bottom waters or sediments, are transported to the lake in groundwater, or both. Colored dissolved organic matter absorbance data suggests that the penetration of ultraviolet light was limited in the lake, so the deep maxima must be due to a non-photochemical alkyl nitrate source. [ABSTRACT FROM AUTHOR]