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Mechanisms of chlorate toxicity and resistance in Pseudomonas aeruginosa
No full textPseudomonas aeruginosa is an opportunistic bacterial pathogen that often encounters hypoxic/anoxic environments within the host, which increases its tolerance to many conventional antibiotics. Towards identifying novel treatments, we explored the therapeutic potential of chlorate, a pro-drug that kills hypoxic/anoxic, antibiotic-tolerant P. aeruginosa populations. While chlorate itself is relatively nontoxic, it is enzymatically reduced to the toxic oxidizing agent, chlorite, by hypoxically-induced nitrate reductase. To better assess chlorate’s therapeutic potential, we investigated mechanisms of chlorate toxicity and resistance in P. aeruginosa. We used transposon mutagenesis to identify genes that alter P. aeruginosa fitness during chlorate treatment, finding that methionine sulfoxide reductases (Msr), which repair oxidized methionine residues, support survival during chlorate stress. Chlorate treatment leads to proteome-wide methionine oxidation, which is exacerbated in a ∆msrA∆msrB strain. In response to chlorate, P. aeruginosa upregulates proteins involved in a wide range of functions, including metabolism, DNA replication/repair, protein repair, transcription, and translation, and these newly synthesized proteins are particularly vulnerable to methionine oxidation. The addition of exogenous methionine partially rescues P. aeruginosa survival during chlorate treatment, suggesting that widespread methionine oxidation contributes to death. Finally, we found that mutations that decrease nitrate reductase activity are a common mechanism of chlorate resistance
The Role of Water Vapor in the Response of the Extratropical Circulation of Earth‐like Planets to Obliquity Changes
No full textIn this study we use idealized aquaplanet simulations of Earth-like planets to explore the large-scale atmospheric circulation’s response to changes in shortwave radiation, through changes in the planet obliquity, and in longwave radiation, through changes in the prescribed optical depth. We primarily focus on the extratropical circulation and the counter-intuitive weakening of extratropical eddy activity, and associated precipitating storm tracks, with increased obliquity. We show that on high obliquity planets with a small surface thermal inertia, net energy deficit during the winter months is primarily balanced by the latent energy component of the atmospheric heat capacity, which buffers any significant atmospheric cooling. As temperatures finally start to decrease, condensational latent heat release of atmospheric moisture further slows down the cooling and keeps the winter pole warmer than the mid latitudes until after the winter solstice. This prevents vigorous baroclinic eddy activity, which lives off the potential energy stored in the sloping isopycnals, as well as the development of a Ferrel cell and storm track. For planets with larger surface heat capacity, we see a similar suppression, with the energy storage in the ocean surface, rather than atmospheric latent energy storage, primarily balancing the net energy loss during the winter months. These results suggest that, regardless of surface thermal inertia, water-covered high obliquity Earth-like planets would not experience significant extratropical storm activity and highlight the need for a proper characterization of polar properties in planetary modeling and observational investigations
The metric theory of the pair correlation function for small non‐integer powers
No full textFor 0 < θ < 1, we show that for almost all α, the pair correlation function of the sequence of fractional parts of {α_n^θ : n ≥ 1} is Poissonian
Random Magnetic Field and the Dirac Fermi Surface
No full textWe study a single 2d Dirac fermion at finite density, subject to a quenched random magnetic field. At low energies and sufficiently weak disorder, the theory maps onto an infinite collection of 1d chiral fermions (associated to each point on the Fermi surface) coupled by a random vector potential. This low-energy theory exhibits an exactly solvable random fixed line, along which we directly compute various disorder-averaged observables without the need for the usual replica, supersymmetry, or Keldysh techniques. We find the longitudinal dc conductivity in the collisionless ℏω/k_BT → ∞ limit to be nonuniversal and to vary continuously along the fixed line
Engineering viral genomics and nano-liposomes in microfluidic platforms for patient-specific analysis of SARS-CoV-2 variants
No full textNew variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are continuing to spread globally, contributing to the persistence of the COVID-19 pandemic. Increasing resources have been focused on developing vaccines and therapeutics that target the Spike glycoprotein of SARS-CoV-2. Recent advances in microfluidics have the potential to recapitulate viral infection in the organ-specific platforms, known as organ-on-a-chip (OoC), in which binding of SARS-CoV-2 Spike protein to the angiotensin-converting enzyme 2 (ACE2) of the host cells occurs. As the COVID-19 pandemic lingers, there remains an unmet need to screen emerging mutations, to predict viral transmissibility and pathogenicity, and to assess the strength of neutralizing antibodies following vaccination or reinfection. Conventional detection of SARS-CoV-2 variants relies on two-dimensional (2-D) cell culture methods, whereas simulating the micro-environment requires three-dimensional (3-D) systems. To this end, analyzing SARS-CoV-2-mediated pathogenicity via microfluidic platforms minimizes the experimental cost, duration, and optimization needed for animal studies, and obviates the ethical concerns associated with the use of primates. In this context, this review highlights the state-of-the-art strategy to engineer the nano-liposomes that can be conjugated with SARS-CoV-2 Spike mutations or genomic sequences in the microfluidic platforms; thereby, allowing for screening the rising SARS-CoV-2 variants and predicting COVID-19-associated coagulation. Furthermore, introducing viral genomics to the patient-specific blood accelerates the discovery of therapeutic targets in the face of evolving viral variants, including B1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta), c.37 (Lambda), and B.1.1.529 (Omicron). Thus, engineering nano-liposomes to encapsulate SARS-CoV-2 viral genomic sequences enables rapid detection of SARS-CoV-2 variants in the long COVID-19 era
Enzymatic Nitrogen Insertion into Unactivated C-H Bonds
No full textSelective functionalization of aliphatic C–H bonds, ubiquitous in molecular structures, could allow ready access to diverse chemical products. While enzymatic oxygenation of C–H bonds is well established, the analogous enzymatic nitrogen functionalization is still unknown; nature is reliant on preoxidized compounds for nitrogen incorporation. Likewise, synthetic methods for selective nitrogen derivatization of unbiased C–H bonds remain elusive. In this work, new-to-nature heme-containing nitrene transferases were used as starting points for the directed evolution of enzymes to selectively aminate and amidate unactivated C(sp³)–H sites. The desymmetrization of methyl- and ethylcyclohexane with divergent site selectivity is offered as demonstration. The evolved enzymes in these lineages are highly promiscuous and show activity toward a wide array of substrates, providing a foundation for further evolution of nitrene transferase function. Computational studies and kinetic isotope effects (KIEs) are consistent with a stepwise radical pathway involving an irreversible, enantiodetermining hydrogen atom transfer (HAT), followed by a lower-barrier diastereoselectivity-determining radical rebound step. In-enzyme molecular dynamics (MD) simulations reveal a predominantly hydrophobic pocket with favorable dispersion interactions with the substrate. By offering a direct path from saturated precursors, these enzymes present a new biochemical logic for accessing nitrogen-containing compounds
General-relativistic precession in a black-hole binary
No full textThe general-relativistic phenomenon of spin-induced orbital precession has not yet been observed in strong-field gravity. Gravitational-wave observations of binary black holes (BBHs) are prime candidates, as we expect the astrophysical binary population to contain precessing binaries. Imprints of precession have been investigated in several signals, but no definitive identification of orbital precession has been reported in any of the 84 BBH observations so far by the Advanced LIGO and Virgo detectors. Here we report the measurement of strong-field precession in the LIGO–Virgo–Kagra gravitational-wave signal GW200129. The binary’s orbit precesses at a rate ten orders of magnitude faster than previous weak-field measurements from binary pulsars. We also find that the primary black hole is probably highly spinning. According to current binary population estimates, a GW200129-like signal is extremely unlikely, and therefore presents a direct challenge to many current binary-formation models
Euclid: Fast two-point correlation function covariance through linear construction
No full textWe present a method for fast evaluation of the covariance matrix for a two-point galaxy correlation function (2PCF) measured with the Landy–Szalay estimator. The standard way of evaluating the covariance matrix consists in running the estimator on a large number of mock catalogs, and evaluating their sample covariance. With large random catalog sizes (random-to-data objects' ratio M ≫ 1) the computational cost of the standard method is dominated by that of counting the data-random and random-random pairs, while the uncertainty of the estimate is dominated by that of data-data pairs. We present a method called Linear Construction (LC), where the covariance is estimated for small random catalogs with a size of M = 1 and M = 2, and the covariance for arbitrary M is constructed as a linear combination of the two. We show that the LC covariance estimate is unbiased. We validated the method with PINOCCHIO simulations in the range r = 20 − 200 h⁻¹ Mpc. With M = 50 and with 2 h⁻¹ Mpc bins, the theoretical speedup of the method is a factor of 14. We discuss the impact on the precision matrix and parameter estimation, and present a formula for the covariance of covariance
Operator spectroscopy for 4d SCFTs with a=c
No full textWe study a rich set of four-dimensional superconformal field theories (SCFTs) with both central charges identical: a=c. These are constructed via the diagonal N=2 or N=1 gauging of the flavor symmetry G of a collection of N=2 Argyres-Douglas theories of type Dp(G), with or without adjoint chiral multiplets, in arXiv:2106.12579 and arXiv:2111.12092. We compute superconformal indices of some theories where the rank of G is low, performing a refined test for unitarity, and further determine the relevant and marginal operator content in detail. We find that most of these theories flow to interacting SCFTs with a=c in the infrared
Continuum source catalog for the first APERTIF data release
No full textThe first data release from Apertif survey contains 3074 radio continuum images, covering a thousand square degrees of the sky. The observations were performed between August 2019 and July 2020. The continuum images were produced at a central frequency 1355 MHz, with a bandwidth of ~150 MHz and angular resolution of up to 10″. In this work, we introduce and apply a new method to obtain a primary beam model based on a machine-learning approach, namely, Gaussian process regression. The primary beam models obtained with this method have been published, along with the data products for the first Apertif data release. We applied the method to the continuum images, carried out a mosaicking process on their basis, and extracted the source catalog. The catalog contains 249672 radio sources, many of which have been detected for the first time at these frequencies. We cross-matched the coordinates with the NVSS, LOFAR/DR1/value-added, and LOFAR/DR2 catalogs – resulting in 44523, 22825, and 152824 common sources, respectively. The first sample provides a unique opportunity for detecting long-term transient sources, which have significantly changed their flux density over the past 25 yr. A combination of the second and the third samples provides valuable information on the spectral properties of the sources in addition to redshift estimates