Apoptosis is one type of programmed cell death. Increasingly, non-apoptotic cell death is recognized as being genetically controlled, or 'regulated'. However, the full extent and diversity of ...alternative cell death mechanisms remain uncharted. Here we surveyed the landscape of pharmacologically accessible cell death mechanisms. In an examination of 56 caspase-independent lethal compounds, modulatory profiling showed that 10 compounds induced three different types of regulated non-apoptotic cell death. Optimization of one of those ten resulted in the discovery of FIN56, a specific inducer of ferroptosis. Ferroptosis has been found to occur when the lipid-repair enzyme GPX4 is inhibited. FIN56 promoted degradation of GPX4. FIN56 also bound to and activated squalene synthase, an enzyme involved in isoprenoid biosynthesis, independent of GPX4 degradation. These discoveries show that dysregulation of lipid metabolism is associated with ferroptosis. This systematic approach is a means to discover and characterize novel cell death phenotypes.
Nanoparticles of nickel phosphide (Ni2P) have been investigated for electrocatalytic activity and stability for the hydrogen evolution reaction (HER) in acidic solutions, under which proton exchange ...membrane-based electrolysis is operational. The catalytically active Ni2P nanoparticles were hollow and faceted to expose a high density of the Ni2P(001) surface, which has previously been predicted based on theory to be an active HER catalyst. The Ni2P nanoparticles had among the highest HER activity of any non-noble metal electrocatalyst reported to date, producing H2(g) with nearly quantitative faradaic yield, while also affording stability in aqueous acidic media.
Amorphous molybdenum phosphide (MoP) nanoparticles have been synthesized and characterized as electrocatalysts for the hydrogen-evolution reaction (HER) in 0.50 M H2SO4 (pH 0.3). Amorphous MoP ...nanoparticles (having diameters of 4.2 ± 0.5 nm) formed upon heating Mo(CO)6 and trioctylphosphine in squalane at 320 °C, and the nanoparticles remained amorphous after heating at 450 °C in H2(5%)/Ar(95%) to remove the surface ligands. At mass loadings of 1 mg cm–2, MoP/Ti electrodes exhibited overpotentials of −90 and −105 mV (−110 and −140 mV without iR correction) at current densities of −10 and −20 mA cm–2, respectively. These HER overpotentials remained nearly constant over 500 cyclic voltammetric sweeps and 18 h of galvanostatic testing, indicating stability in acidic media under operating conditions. Amorphous MoP nanoparticles are therefore among the most active known molybdenum-based HER systems and are part of a growing family of active, acid-stable, non-noble-metal HER catalysts.
Nanostructured transition-metal phosphides have recently emerged as Earth-abundant alternatives to platinum for catalyzing the hydrogen-evolution reaction (HER), which is central to several clean ...energy technologies because it produces molecular hydrogen through the electrochemical reduction of water. Iron-based catalysts are very attractive targets because iron is the most abundant and least expensive transition metal. We report herein that iron phosphide (FeP), synthesized as nanoparticles having a uniform, hollow morphology, exhibits among the highest HER activities reported to date in both acidic and neutral-pH aqueous solutions. As an electrocatalyst operating at a current density of −10 mA cm–2, FeP nanoparticles deposited at a mass loading of ∼1 mg cm–2 on Ti substrates exhibited overpotentials of −50 mV in 0.50 M H2SO4 and −102 mV in 1.0 M phosphate buffered saline. The FeP nanoparticles supported sustained hydrogen production with essentially quantitative faradaic yields for extended time periods under galvanostatic control. Under UV illumination in both acidic and neutral-pH solutions, FeP nanoparticles deposited on TiO2 produced H2 at rates and amounts that begin to approach those of Pt/TiO2. FeP therefore is a highly Earth-abundant material for efficiently facilitating the HER both electrocatalytically and photocatalytically.
Using whole-genome microarray data sets of the Immunological Genome Project, we demonstrate a closer transcriptional relationship between NK cells and T cells than between any other leukocytes, ...distinguished by their shared expression of genes encoding molecules with similar signaling functions. Whereas resting NK cells are known to share expression of a few genes with cytotoxic CD8(+) T cells, our transcriptome-wide analysis demonstrates that the commonalities extend to hundreds of genes, many encoding molecules with unknown functions. Resting NK cells demonstrate a 'preprimed' state compared with naive T cells, which allows NK cells to respond more rapidly to viral infection. Collectively, our data provide a global context for known and previously unknown molecular aspects of NK cell identity and function by delineating the genome-wide repertoire of gene expression of NK cells in various states.
Tropicalization is a term used to describe the transformation of temperate ecosystems by poleward-moving tropical organisms in response to warming temperatures. In North America, decreases in the ...frequency and intensity of extreme winter cold events are expected to allow the poleward range expansion of many cold-sensitive tropical organisms, sometimes at the expense of temperate organisms. Although ecologists have long noted the critical ecological role of winter cold temperature extremes in tropical–temperate transition zones, the ecological effects of extreme cold events have been understudied, and the influence of warming winter temperatures has too often been left out of climate change vulnerability assessments. Here, we examine the influence of extreme cold events on the northward range limits of a diverse group of tropical organisms, including terrestrial plants, coastal wetland plants, coastal fishes, sea turtles, terrestrial reptiles, amphibians, manatees, and insects. For these organisms, extreme cold events can lead to major physiological damage or landscape-scale mass mortality. Conversely, the absence of extreme cold events can foster population growth, range expansion, and ecological regime shifts. We discuss the effects of warming winters on species and ecosystems in tropical–temperate transition zones. In the 21st century, climate change-induced decreases in the frequency and intensity of extreme cold events are expected to facilitate the poleward range expansion of many tropical species. Our review highlights critical knowledge gaps for advancing understanding of the ecological implications of the tropicalization of temperate ecosystems in North America.
Three Earth-sized exoplanets were recently discovered close to the habitable zone of the nearby ultracool dwarf star TRAPPIST-1 (ref. 3). The nature of these planets has yet to be determined, as ...their masses remain unmeasured and no observational constraint is available for the planetary population surrounding ultracool dwarfs, of which the TRAPPIST-1 planets are the first transiting example. Theoretical predictions span the entire atmospheric range, from depleted to extended hydrogen-dominated atmospheres. Here we report observations of the combined transmission spectrum of the two inner planets during their simultaneous transits on 4 May 2016. The lack of features in the combined spectrum rules out cloud-free hydrogen-dominated atmospheres for each planet at ≥10σ levels; TRAPPIST-1 b and c are therefore unlikely to have an extended gas envelope as they occupy a region of parameter space in which high-altitude cloud/haze formation is not expected to be significant for hydrogen-dominated atmospheres. Many denser atmospheres remain consistent with the featureless transmission spectrum-from a cloud-free water-vapour atmosphere to a Venus-like one.
Antibiotic-resistant infections kill approximately 23,000 people and cost $20,000,000,000 each year in the United States alone despite the widespread use of small-molecule antimicrobial combination ...therapy. Antibiotic combinations typically have an additive effect: the efficacy of the combination matches the sum of the efficacies of each antibiotic when used alone. Small molecules can also act synergistically when the efficacy of the combination is greater than the additive efficacy. However, synergistic combinations are rare and have been historically difficult to identify. High-throughput identification of synergistic pairs is limited by the scale of potential combinations: a modest collection of 1,000 small molecules involves 1 million pairwise combinations. Here, we describe a high-throughput method for rapid identification of synergistic small-molecule pairs, the overlap2 method (O2M). O2M extracts patterns from chemical-genetic datasets, which are created when a collection of mutants is grown in the presence of hundreds of different small molecules, producing a precise set of phenotypes induced by each small molecule across the mutant set. The identification of mutants that show the same phenotype when treated with known synergistic molecules allows us to pinpoint additional molecule combinations that also act synergistically. As a proof of concept, we focus on combinations with the antibiotics trimethoprim and sulfamethizole, which had been standard treatment against urinary tract infections until widespread resistance decreased efficacy. Using O2M, we screened a library of 2,000 small molecules and identified several that synergize with the antibiotic trimethoprim and/or sulfamethizole. The most potent of these synergistic interactions is with the antiviral drug azidothymidine (AZT). We then demonstrate that understanding the molecular mechanism underlying small-molecule synergistic interactions allows the rational design of additional combinations that bypass drug resistance. Trimethoprim and sulfamethizole are both folate biosynthesis inhibitors. We find that this activity disrupts nucleotide homeostasis, which blocks DNA replication in the presence of AZT. Building on these data, we show that other small molecules that disrupt nucleotide homeostasis through other mechanisms (hydroxyurea and floxuridine) also act synergistically with AZT. These novel combinations inhibit the growth and virulence of trimethoprim-resistant clinical Escherichia coli and Klebsiella pneumoniae isolates, suggesting that they may be able to be rapidly advanced into clinical use. In sum, we present a generalizable method to screen for novel synergistic combinations, to identify particular mechanisms resulting in synergy, and to use the mechanistic knowledge to rationally design new combinations that bypass drug resistance.
Atmospheric characterization of directly imaged planets has thus far been limited to ground-based observations of young, self-luminous, Jovian planets. Near-term space- and ground- based facilities ...like WFIRST and ELTs will be able to directly image mature Jovian planets in reflected light, a critical step in support of future facilities that aim to directly image terrestrial planets in reflected light (e.g., HabEx, LUVOIR). These future facilities are considering the use of photometry to classify planets. Here, we investigate the intricacies of using colors to classify gas-giant planets by analyzing a grid of 9120 theoretical reflected light spectra spread across different metallicities, pressure-temperature profiles, cloud properties, and phase angles. We determine how correlated these planet parameters are with the colors in the WFIRST photometric bins and other photometric bins proposed in the literature. Then we outline under what conditions giant planet populations can be classified using several supervised multivariate classification algorithms. We find that giant planets imaged in reflected light can be classified by metallicity with an accuracy of >90% if they are a prior known to not have significant cloud coverage in the visible part of the atmosphere, and at least three filter observations are available. If the presence of clouds is not known a priori, directly imaged planets can be more accurately classified by their cloud properties, as oppposed to metallicity or temperature. Furthermore, we are able to distinguish between cloudy and cloud-free populations with >90% accuracy with three filter observations. Our statistical pipeline is available on GitHub and can be extended to optimize science yield of future mission concepts.
Nature has the exquisite ability to design specific surface patterns and topologies on both the macro- and nanolength scales that relate to precise functions. Following a biomimetic approach, we have ...engineered fully synthetic nanoparticles that are able to self-organize their surface into controlled domains. We focused on polymeric vesicles or “polymersomes”; enclosed membranes formed via self-assembly of amphiphilic block copolymers in water. Exploiting the intrinsic thermodynamic tendency of dissimilar polymers to undergo phase separation, we mixed different vesicle-forming block copolymers in various proportions in order to obtain a wide range of polymersomes with differing surface domains. Using a combination of confocal laser scanning microscopy studies of micrometer-sized polymersomes, and electron microscopy, atomic force microscopy, and fluorescence spectroscopy on nanometer-sized polymersomes, we find that the domains exhibit similar shapes on both the micro- and nanolength scales, with dimensions that are linearly proportional to the vesicle diameter. Finally, we demonstrate that such control over the surface “patchiness” of these polymersomes determines their cell internalization kinetics for live cells.
PDF
