Non-Adiabatic Vibrational Damping of Molecular Adsorbates: Insights into Electronic Friction and the Role of Electronic Coherence

We present a perturbation approach rooted in time-dependent density-functional theory to calculate electron hole (eh)-pair excitation spectra during the non-adiabatic vibrational damping of adsorbates on metal surfaces. Our analysis for the benchmark systems CO on Cu(100) and Pt(111) elucidates the surprisingly strong influence of rather short electronic coherence times. We demonstrate how in the limit of short electronic coherence times, as implicitly assumed in prevalent quantum nuclear theories for the vibrational lifetimes as well as electronic friction, band structure effects are washed out. Our results suggest that more accurate lifetime or chemicurrent-like experimental measurements could characterize the electronic coherence.Comment: Article as accepted for publication in Physical Review Letter

Electronic friction-based vibrational lifetimes of molecular adsorbates: Beyond the independent atom approximation

We assess the accuracy of vibrational damping rates of diatomic adsorbates on metal surfaces as calculated within the local-density friction approximation (LDFA). An atoms-in-molecules (AIM) type charge partitioning scheme accounts for intra-molecular contributions and overcomes the systematic underestimation of the non-adiabatic losses obtained within the prevalent independent atom approximation. The quantitative agreement obtained with theoretical and experimental benchmark data suggests the LDFA-AIM as an efficient and reliable approach to account for electronic dissipation in ab initio molecular dynamics simulations of surface chemical reactions.Comment: 5 pages including 2 figure

Age-related cellular copper dynamics in the fungal ageing model Podospora anserina and in ageing human fibroblasts

In previous investigations an impact of cellular copper homeostasis on ageing of the ascomycete Podospora anserina has been demonstrated. Here we provide new data indicating that mitochondria play a major role in this process. Determination of copper in the cytosolic fraction using total reflection X-ray fluorescence spectroscopy analysis and eGfp reporter gene studies indicate an age-related increase of cytosolic copper levels. We show that components of the mitochondrial matrix (i.e. eGFP targeted to mitochondria) become released from the organelle during ageing. Decreasing the accessibility of mitochondrial copper in P. anserina via targeting a copper metallothionein to the mitochondrial matrix was found to result in a switch from a copper-dependent cytochrome-c oxidase to a copper-independent alternative oxidase type of respiration and results in lifespan extension. In addition, we demonstrate that increased copper concentrations in the culture medium lead to the appearance of senescence biomarkers in human diploid fibroblasts (HDFs). Significantly, expression of copper-regulated genes is induced during in vitro ageing in medium devoid of excess copper suggesting that cytosolic copper levels also increase during senescence of HDFs. These data suggest that the identified molecular pathway of age-dependent copper dynamics may not be restricted to P. anserina but may be conserved from lower eukaryotes to humans

The effect of PD-L1 testing on the cost-effectiveness and economic impact of immune checkpoint inhibitors for the second-line treatment of NSCLC

Background: Immune checkpoint inhibitors improve outcomes compared with chemotherapy in lung cancer. Tumor PD-L1 receptor expression is being studied as a predictive biomarker. The objective of this study was to assess the cost-effectiveness and economic impact of second-line treatment with nivolumab, pembrolizumab, and atezolizumab with and without the use of PD-L1 testing for patient selection. Design: We developed a decision-analytic model to determine the cost-effectiveness of PD-L1 assessment and second-line immunotherapy versus docetaxel. The model used outcomes data from randomized clinical trials (RCTs) and drug acquisition costs from the United States. Thereafter, we used epidemiologic data to estimate the economic impact of the treatment. Results: We included four RCTs (2 with nivolumab, 1 with pembrolizumab, and 1 with atezolizumab). The incremental quality-adjusted life year (QALY) for nivolumab was 0.417 among squamous tumors and 0.287 among non-squamous tumors and the incremental cost-effectiveness ratio (ICER) were $155 605 and$187 685, respectively. The QALY gain in the base case for atezolizumab was 0.354 and the ICER was $215 802. Compared with treating all patients, the selection of patients by PD-L1 expression improved incremental QALY by up to 183$98 421. Patient selection also reduced the budget impact of immunotherapy. Conclusion: The use of PD-L1 expression as a biomarker increases cost-effectiveness of immunotherapy but also diminishes the number of potential life-years saved.info:eu-repo/semantics/publishedVersio

Systematics and Species Delimitation in New Guinea Skink Species Complexes (Squamata: Scincidae)

Though among the most controversial topics in systematic and evolutionary biology, species are a fundamental unit in biology, and are utilized by and critical to a wide variety of studies in the life sciences. Despite this importance, little work has focused on developing and examining objective methods for species delimitation until recently. Further, New Guinea and the surrounding regions are among the most diverse and geologically complex regions globally, yet the region remains poorly explored biologically, and little work has examined the evolutionary history of the fauna in the region. To investigate the influence of factors such as sampling intensity, species richness, and phylogenetic structure on discovery methods for species delimitation, I combine simulated and empirical data. In Chapter 1, I use simulated data to examine the accuracy of three discovery methods for species delimitation under a variety of different sampling strategies. I find that genetic clustering algorithms, such as Structurama, can be highly accurate in identifying even recent divergences with limited sampling of individuals and of loci, and that Gaussian clustering can be similarly accurate, though somewhat less sensitive to detecting recent divergences. However, my results show that nonparametric delimitation is highly sensitive to errors in gene genealogy estimation, and generally fails to delimit species accurately when true coalescent gene genealogies are unknown, as in empirical applications. In Chapters 3 and 4, I apply these methods empirically to examine the species boundaries, as well as the phylogeny and other aspects of the evolutionary history of, scincid lizards of the C. bicarinata and C. fusca groups, respectively. My results in Chapter 3 indicate that species delimitation analyses may be prone to underestimating the number of species by identifying only higher levels of clustering in systems with deep phylogenetic structure. I additionally find evidence for several cryptic species in the group, including deep, species-level divergence among the populations of C. storri from Australia, the Aru Islands, and New Guinea, despite their recent connectivity via Sahul Shelf emergence during Pleistocene glaciations. Through also examining niche evolution in the group, I find evidence for niche conservatism among most species in the group, but two species, C. bicarinata and C. sp. Amau from eastern Papua New Guinea, show evidence for environmental niche divergence. Analyses of the C. fusca group in Chapter 4 provide further evidence for a tendency of discovery methods for species delimitation to under-detect species in groups with high diversity or deep phylogenetic structure. Genetic clustering algorithms based on the complete dataset only identify a small number of clusters that correspond largely to deep phylogenetic clades, but when restricted to within these clades, this method identifies clusters that correspond well to finer, putative species-level structure. I also find evidence for extensive cryptic diversity in this group, identifying 28 distinct species among my sampling of 16 currently recognized species, as well as other incongruence with current taxonomy, including synonymous species and mis-assigned populations, supporting previous evidence of the need for extensive taxonomic revision in the C. fusca group. My biogeographic analyses also providence evidence that the C. fusca group likely evolved in Australia or Australia and New Guinea before diversifying in New Guinea, dispersing at least twice across Lydekker’s line into Wallacea, and possibly also recolonizing Australia. Finally, in Chapter 5, I take a more comprehensive approach, and combine genomic and morphological data to test the validity of and examine the demographic history of two putative species of Tribolonotus from the islands of Buka and Bougainville in the northwestern Solomon Archipelogo. I use next-generation sequencing to collect a genomic dataset of several thousand loci, and apply species discovery (genetic clustering algorithms) and species validation (Bayes factor delimitations) to test for speciation between these populations. My results support this speciation event, despite the recent connectivity between these islands. I also collect a suite of morphological characters for this group and provide evidence for morphological divergence and diagnosibility. Demographic analyses applied using approximate Bayesian computation and diffusion analysis further provide evidence for a complex demographic scenario in which migration between these populations continued for some time following their initial divergence, but subsequently decreased in rate or ceased entirely. Combined, these results yield extensive insight into the utility of several methods for species delimitation, the taxonomy and systematics of Carlia and Tribolonotus in New Guinea and the surrounding regions, and the complex processes responsible for driving the generation and maintenance of the phenomenal diversity in the Sahul shelf region

Exo70-Mediated Recruitment of Nucleoporin Nup62 at the Leading Edge of Migrating Cells is Required for Cell Migration

Nucleoporin Nup62 localizes at the central channel of the nuclear pore complex and is essential for nucleocytoplasmic transport. Through its FG-repeat domain, Nup62 regulates nuclear pore permeability and binds nuclear transport receptors. Here, we report that Nup62 interacts directly with Exo70 and colocalizes with Exo70 at the leading edge of migrating cells. Nup62 binds the N-terminal domain of Exo70 through its coiled-coil domain but not through its FG-repeat domain. Selective inhibition of leading edge Nup62 using RNA interference significantly reduces cell migration. Furthermore, Exo70 recruits Nup62 at the plasma membrane and at filopodia. Removal of the Exo70-binding domain of Nup62 prevents leading edge localization of Nup62. Analogous to Exo70, Nup62 cycles between the plasma membrane and the perinuclear recycling compartment. Altogether, we propose that Nup62 not solely regulates access to the cell nucleus, but additionally functions in conjunction with Exo70, a key regulator of exocytosis and actin dynamics, at the leading edge of migrating cells

Beneficial autoimmunity at body surfaces – immune surveillance and rapid type 2 immunity regulate tissue homeostasis and cancer

Epithelial cells line body surface tissues and provide a physicochemical barrier to the external environment. Frequent microbial and non-microbial challenges such as those imposed by mechanical disruption, injury or exposure to noxious environmental substances including chemicals, carcinogens, ultraviolet-irradiation or toxins cause activation of epithelial cells with release of cytokines and chemokines as well as alterations in the expression of cell surface ligands. Such display of epithelial stress is rapidly sensed by tissue resident immunocytes, which can directly interact with self-moieties on epithelial cells and initiate both local and systemic immune responses. Epithelial cells are thus key drivers of immune surveillance at body surface tissues. However, epithelial cells have a propensity to drive type 2 immunity (rather than type 1) upon non-invasive challenge or stress – a type of immunity whose regulation and function still remain enigmatic. Here we review the induction and possible role of type 2 immunity in epithelial tissues and propose that rapid immune surveillance and type 2 immunity are key regulators of tissue homeostasis and carcinogenesis

Preliminary observations of skeletal UV fluorescence in fresh and preserved snakes

Biofluorescent tissues in vertebrates are commonly observed phenomena that have been found in a widevariety of taxonomic groups. The fluorescence of bone has recently been found visible through the skin in some squamates,although its function is poorly known. While this phenomenon has been observed in lizards, no publishedrecords of ultraviolet (UV)-based fluorescence exist for snakes. We present the first published record of bone-basedfluorescence of snakes using museum skeletal specimens and fresh dead-on-the-road (DOR) specimens (24–48 h postmortem)gathered during field observations. Nine of 11 families tested fluoresced in the presence of a UV alternativelight source. We found that snake bones emitted brighter blue/green light in DOR specimens than the dull green colorin older museum specimens. Fluorescence, though brighter in fresh specimens, was still observed in museum specimensas old as 95 years. We herein present observations to provide baseline data for fluorescence-related studies in snakes.We remain uncertain if the light emitted from bones is visible through the skin and scales of living snakes and identifythis as an important area for future investigations

Energy dissipation at metal surfaces

Conversion of energy at the gas–solid interface lies at the heart of many industrial applications such as heterogeneous catalysis. Dissipation of parts of this energy into the substrate bulk drives the thermalization of surface species, but also constitutes a potentially unwanted loss channel. At present, little is known about the underlying microscopic dissipation mechanisms and their (relative) efficiency. At metal surfaces, prominent such mechanisms are the generation of substrate phonons and the electronically non-adiabatic excitation of electron–hole pairs. In recent years, dedicated surface science experiments at defined single-crystal surfaces and predictive-quality first-principles simulations have increasingly been used to analyze these dissipation mechanisms in prototypical surface dynamical processes such as gas-phase scattering and adsorption, diffusion, vibration, and surface reactions. In this topical review we provide an overview of modeling approaches to incorporate dissipation into corresponding dynamical simulations starting from coarse-grained effective theories to increasingly sophisticated methods. We illustrate these at the level of individual elementary processes through applications found in the literature, while specifically highlighting the persisting difficulty of gauging their performance based on experimentally accessible observables