Asymmetric mass ratios for bright double neutron-star mergers.

The discovery of a radioactively powered kilonova associated with the binary neutron-star merger GW170817 remains the only confirmed electromagnetic counterpart to a gravitational-wave event1,2. Observations of the late-time electromagnetic emission, however, do not agree with the expectations from standard neutron-star merger models. Although the large measured ejecta mass3,4 could be explained by a progenitor system that is asymmetric in terms of the stellar component masses (that is, with a mass ratio q of 0.7 to 0.8)5, the known Galactic population of merging double neutron-star systems (that is, those that will coalesce within billions of years or less) has until now consisted only of nearly equal-mass (q > 0.9) binaries6. The pulsar PSR J1913+1102 is a double system in a five-hour, low-eccentricity (0.09) orbit, with an orbital separation of 1.8 solar radii7, and the two neutron stars are predicted to coalesce in [Formula: see text] million years owing to gravitational-wave emission. Here we report that the masses of the pulsar and the companion neutron star, as measured by a dedicated pulsar timing campaign, are 1.62 ± 0.03 and 1.27 ± 0.03 solar masses, respectively. With a measured mass ratio of q = 0.78 ± 0.03, this is the most asymmetric merging system reported so far. On the basis of this detection, our population synthesis analysis implies that such asymmetric binaries represent between 2 and 30 per cent (90 per cent confidence) of the total population of merging binaries. The coalescence of a member of this population offers a possible explanation for the anomalous properties of GW170817, including the observed kilonova emission from that event.

Inflation of 430-parsec bipolar radio bubbles in the Galactic Centre by an energetic event.

The Galactic Centre contains a supermassive black hole with a mass of four million Suns1 within an environment that differs markedly from that of the Galactic disk. Although the black hole is essentially quiescent in the broader context of active galactic nuclei, X-ray observations have provided evidence for energetic outbursts from its surroundings2. Also, although the levels of star formation in the Galactic Centre have been approximately constant over the past few hundred million years, there is evidence of increased short-duration bursts3, strongly influenced by the interaction of the black hole with the enhanced gas density present within the ring-like central molecular zone4 at Galactic longitude |l| < 0.7 degrees and latitude |b| < 0.2 degrees. The inner 200-parsec region is characterized by large amounts of warm molecular gas5, a high cosmic-ray ionization rate6, unusual gas chemistry, enhanced synchrotron emission7,8, and a multitude of radio-emitting magnetized filaments9, the origin of which has not been established. Here we report radio imaging that reveals a bipolar bubble structure, with an overall span of 1 degree by 3 degrees (140 parsecs × 430 parsecs), extending above and below the Galactic plane and apparently associated with the Galactic Centre. The structure is edge-brightened and bounded, with symmetry implying creation by an energetic event in the Galactic Centre. We estimate the age of the bubbles to be a few million years, with a total energy of 7 × 1052 ergs. We postulate that the progenitor event was a major contributor to the increased cosmic-ray density in the Galactic Centre, and is in turn the principal source of the relativistic particles required to power the synchrotron emission of the radio filaments within and in the vicinity of the bubble cavities.

NO and N2O Release from the Trityl Diazeniumdiolate Complexes [M(O2N2CPh3)3]- (M = Fe, Co).

Reaction of MBr2 with 3 equiv of [K(18-crown-6)][O2N2CPh3] generates the trityl diazeniumdiolate complexes [K(18-crown-6)][M(O2N2CPh3)3] (M = Co, 2; Fe, 3) in good yields. Irradiation of 2 and 3 using 371 nm light led to NO formation in 10 and 1% yields (calculated assuming a maximum of 6 equiv of NO produced per complex), respectively. N2O was also formed during the photolysis of 2, in 63% yield, whereas photolysis of 3 led to the formation of N2O, as well as Ph3CN(H)OCPh3, in 37 and 5% yields, respectively. These products are indicative of diazeniumdiolate fragmentation via both C-N and N-N bond cleavage pathways. In contrast, oxidation of complexes 2 and 3 with 1.2 equiv of [Ag(MeCN)4][PF6] led to N2O formation but no NO formation, suggesting that diazeniumdiolate fragmentation occurs exclusively via C-N bond cleavage under these conditions. While the photolytic yields of NO are modest, they represent a 10- to 100-fold increase compared to the previously reported Zn congener, suggesting that the presence of a redox-active metal center favors NO formation upon trityl diazeniumdiolate fragmentation.

Analysis and Discrimination of Canadian Honey Using Quantitative NMR and Multivariate Statistical Methods.

To address the growing concern of honey adulteration in Canada and globally, a quantitative NMR method was developed to analyze 424 honey samples collected across Canada as part of two surveys in 2018 and 2019 led by the Canadian Food Inspection Agency. Based on a robust and reproducible methodology, NMR data were recorded in triplicate on a 700 MHz NMR spectrometer equipped with a cryoprobe, and the data analysis led to the identification and quantification of 33 compounds characteristic of the chemical composition of honey. The high proportion of Canadian honey in the library provided a unique opportunity to apply multivariate statistical methods including PCA, PLS-DA, and SIMCA in order to differentiate Canadian samples from the rest of the world. Through satisfactory model validation, both PLS-DA as a discriminant modeling technique and SIMCA as a class modeling method proved to be reliable at differentiating Canadian honey from a diverse set of honeys with various countries of origins and floral types. The replacement method of optimization was successfully applied for variable selection, and trigonelline, proline, and ethanol at a lower extent were identified as potential chemical markers for the discrimination of Canadian and non-Canadian honeys.

Photolytic or Oxidative Fragmentation of Trityl Diazeniumdiolate (O2N2CPh3-): Evidence for Both C-N and N-N Bond Cleavage.

Exposure of [K(18-crown-6)(THF)2][CPh3] (THF = tetrahydrofuran; Ph = phenyl) to an atmosphere of nitric oxide (NO) cleanly generates [K(18-crown-6)][O2N2CPh3] (1) in excellent yields. A subsequent reaction of [ZnCl2(THF)2] with 3 equiv of 1 affords the C-diazeniumdiolate complex [K(18-crown-6)][Zn(O2N2CPh3)3] (2). Both 1 and 2 were characterized by 1H and 13C{1H} NMR spectroscopy, and their structures were confirmed by X-ray crystallography. Photolysis of 2 using 371 nm light resulted in the formation of three trityl-containing products, namely, Ph3CH, 9-phenylfluorene, and Ph3CN(H)OCPh3 (3). In addition, we detected nitrous oxide (N2O), as well as small amounts of NO in the reaction mixture. In contrast, oxidation of 2 with 1.2 equiv of [Ag(MeCN)4][PF6] resulted in the formation of O(CPh3)2 as the major trityl-containing product; N2O was also detected in the reaction mixture, but NO was not apparently formed in this case. The observation of these fragmentation products indicates that the [O2N2CPh3]- ligand is susceptible to both C-N bond and N-N bond cleavage. Moreover, the different product distributions suggest that [O2N2CPh3]- is susceptible to different modes of fragmentation.

A repeating fast radio burst.

Fast radio bursts are millisecond-duration astronomical radio pulses of unknown physical origin that appear to come from extragalactic distances. Previous follow-up observations have failed to find additional bursts at the same dispersion measure (that is, the integrated column density of free electrons between source and telescope) and sky position as the original detections. The apparent non-repeating nature of these bursts has led to the suggestion that they originate in cataclysmic events. Here we report observations of ten additional bursts from the direction of the fast radio burst FRB 121102. These bursts have dispersion measures and sky positions consistent with the original burst. This unambiguously identifies FRB 121102 as repeating and demonstrates that its source survives the energetic events that cause the bursts. Additionally, the bursts from FRB 121102 show a wide range of spectral shapes that appear to be predominantly intrinsic to the source and which vary on timescales of minutes or less. Although there may be multiple physical origins for the population of fast radio bursts, these repeat bursts with high dispersion measure and variable spectra specifically seen from the direction of FRB 121102 support an origin in a young, highly magnetized, extragalactic neutron star.

Paediatric cardiomyopathies: echocardiographic diagnosis, clinical profile, and demographic characteristics: the experience of a tertiary referral centre for Latin American paediatric cardiology.

BACKGROUND: Although multiple studies have been conducted in the adult population, there is a vast knowledge gap regarding the epidemiologic characteristics of cardiomyopathies in the paediatric population. This issue is even more crucial when the precarious situation of medical research in Latin America is considered. Given the potential impact that these disorders could have on Latin American health systems, a comprehensive epidemiologic study regarding the clinical profile and sociodemographic characteristics of these patients will influence the way we approach paediatric cardiomyopathies. METHODS: An observational retrospective study was conducted at a tertiary referral centre for Colombian and Latin American paediatric cardiology. We analysed all cases of primary cardiomyopathies in children younger than 18 years of age who presented at our institution between 2010 and 2016. Cases of cardiomyopathies were classified according to World Health Organization guidelines. RESULTS: From a total of 29,533 children who attended our institution during the study period, 89 new cases of primary cardiomyopathies were identified. The median age at diagnosis was 11 years (interquartile range 4-9). Dilated cardiomyopathy accounted for 57.3% (n = 51) of cases; hypertrophic cardiomyopathy, 12.3% (n = 11); restrictive cardiomyopathy, 8.9% (n = 8); non-compacted cardiomyopathy, 7.8% (n = 7); arrhythmogenic ventricular cardiomyopathy, 6.7% (n = 6); and unspecified cardiomyopathy, 6.7% (n = 6). Heart failure was observed in 53.93% of the patients. The overall mortality was 12.36% (n = 11), which included two of eight patients who underwent cardiac transplantation.

Incidental finding of pulmonary arterial sling during patent ductus arteriosus surgery in a patient with Mowat-Wilson syndrome.

Mowat-Wilson syndrome is a genetic condition due to a mutation in the ZEB2 gene; it affects many systems including the cardiovascular system. The pulmonary arterial sling originates from a failure of development of the proximal portion of the left sixth aortic arch, resulting in an anomalous left pulmonary artery origin from the posterior wall of the right pulmonary artery and the left pulmonary artery crossing to the left lung between the trachea and the oesophagus. We present a 4-month-old infant with Mowat-Wilson syndrome and left pulmonary arterial sling, and discuss the association of these two rare conditions. Pulmonary arterial sling is significantly more frequent in patients with Mowat-Wilson syndrome than in the general population.

N-Heterocyclic Carbene-Stabilized Boranthrene as a Metal-Free Platform for the Activation of Small Molecules.

The multielectron reduction of small molecules (e.g., CO2) is a key aspect of fuel synthesis from renewable electricity. Transition metals have been researched extensively in this role due to their intrinsic redox properties and reactivity, but more recently, strategies that forego transition metal ions for p-block elements have emerged. In this vein, we report an analogue of boranthrene (9,10-diboraanthracene) stabilized by N-heterocyclic carbenes and its one- and two-electron oxidized congeners. This platform exhibits reversible, two-electron redox chemistry at mild potentials and reacts with O2, CO2, and ethylene via formal [4+2] cycloaddition to the central diborabutadiene core. In an area traditionally dominated by transition metals, these results outline an approach for the redox activation of small molecules at mild potentials based on conjugated, light element scaffolds.

Jadomycins Inhibit Type II Topoisomerases and Promote DNA Damage and Apoptosis in Multidrug-Resistant Triple-Negative Breast Cancer Cells.

Jadomycins are natural products that kill drug-sensitive and multidrug-resistant (MDR) breast cancer cells. To date, the cytotoxic activity of jadomycins has never been tested in MDR breast cancer cells that are also triple negative. Additionally, there is only a rudimentary understanding of how jadomycins cause cancer cell death, which includes the induction of intracellular reactive oxygen species (ROS). We first created a paclitaxel-resistant, triple-negative breast cancer cell line [paclitaxel-resistant MDA-MB-231 breast cancer cells (231-TXL)] from drug-sensitive control MDA-MB-231 cells (231-CON). Using thiazolyl blue methyltetrazolium bromide cell viability-measuring assays, jadomycins B, S, and F were found to be equipotent in drug-sensitive 231-CON and MDR 231-TXL cells; and using ROS-detecting assays, these jadomycins were determined to increase ROS activity in both cell lines by up to 7.3-fold. Jadomycins caused DNA double-strand breaks in 231-CON and 231-TXL cells as measured by γH2AX Western blotting. Coincubation with the antioxidant N-acetyl cysteine or pro-oxidant auranofin did not affect jadomycin-mediated DNA damage. Jadomycins induced apoptosis in 231-CON and 231-TXL cells as measured by annexin V affinity assays, a process that was retained when ROS were inhibited. This indicated that jadomycins are capable of inducing MDA-MB-231 apoptotic cell death independently of ROS activity. Using quantitative polymerase chain reaction, Western blotting, and direct topoisomerase inhibition assays, it was determined that jadomycins inhibit type II topoisomerases and that jadomycins B and F selectively poison topoisomerase IIß We therefore propose novel mechanisms through which jadomycins induce breast cancer cell death independently of ROS activity, through inhibition or poisoning of type II topoisomerases and the induction of DNA damage and apoptosis.

JadX is a Disparate Natural Product Binding Protein.

We report that JadX, a protein of previously undetermined function coded for in the jadomycin biosynthetic gene cluster of Streptomyces venezuelae ISP5230, affects both chloramphenicol and jadomycin production levels in blocked mutants. Characterization of recombinant JadX through protein-ligand interactions by chemical shift perturbation and WaterLOGSY NMR spectroscopy resulted in the observation of binding between JadX and a series of jadomycins and between JadX and chloramphenicol, another natural product produced by S. venezuelae ISP5230. These results suggest JadX to be an unusual class of natural product binding protein involved in binding structurally disparate natural products. The ability for JadX to bind two different natural products in vitro and the ability to affect production of these secondary metabolites in vivo suggest a potential role in regulation or signaling. This is the first example of functional characterization of these JadX-like proteins, and provides insight into a previously unobserved regulatory process.

Eight-membered ring-containing jadomycins: implications for non-enzymatic natural products biosynthesis.

Jadomycin Oct (1) was isolated from Streptomyces venezuelae ISP5230 and characterized as a structurally unique eight-membered l-ornithine ring-containing jadomycin. The structure was elucidated through the semisynthetic derivatization of starting material via chemoselective acylation of the l-ornithine α-amino group using activated succinimidyl esters. Incorporation of 5-aminovaleric acid led to jadomycin AVA, a second eight-membered ring-containing jadomycin. These natural products illustrate the structural diversity permissible from a non-enzymatic step within a biosynthetic pathway and exemplifies the potential for discovery of novel scaffolds.

Investigations into the binding of jadomycin DS to human topoisomerase IIß by WaterLOGSY NMR spectroscopy.

The jadomycins are a family of secondary metabolites produced by S. venezuelae ISP5230. Specific jadomycins have been shown to possess a variety of anticancer, antifungal, and antibacterial properties, with different molecular mechanisms of action. Herein we demonstrate qualitative and quantitative direct binding between the validated anticancer target human topoisomerase IIß and jadomycin DS using WaterLOGSY NMR spectroscopy. Additionally, we report for the first time, that jadomycin DS also binds a variety of other proteins, likely in a non-specific manner. Such interactions may rationalize the potential polypharmacology of jadomycin DS.

Characterization of l-Digitoxosyl-phenanthroviridin from Streptomyces venezuelae ISP5230.

The jadomycin-derived compound l-digitoxosyl-phenanthroviridin was isolated from fermentations of Streptomyces venezuelae ISP5230 grown in nutrient-deficient media with l-lysine as the sole nitrogen source. Structural elucidation was accomplished using a combination of high-resolution MS, LC-MS/MS, and 1D- and 2D-NMR. The compound was evaluated against the National Cancer Institute (NCI) 60 human tumor cell line screen in both the one-dose and five-dose screens, and cytotoxicity was compared to a small library of jadomycin analogues to probe the structure-activity relationship.

Isolation and Synthetic Diversification of Jadomycin 4-Amino-l-phenylalanine.

Streptomyces venezuelae ISP5230 was grown in the presence of phenylalanine analogues to observe whether they could be incorporated into novel jadomycin structures. It was found that the bacteria successfully produced jadomycins incorporating 4-aminophenylalanine enantiomers. Upon isolation and characterization of jadomycin 4-amino-l-phenylalanine (1), it was synthetically derivatized, using activated succinimidyl esters, to yield a small jadomycin amide library. These are the first examples of oxazolone-ring-containing jadomycins that have incorporated an amino functionality subsequently used for derivatization.

Neutron star mass estimates from gamma-ray eclipses in spider millisecond pulsar binaries.

Reliable neutron star mass measurements are key to determining the equation of state of cold nuclear matter, but such measurements are rare. Black widows and redbacks are compact binaries consisting of millisecond pulsars and semi-degenerate companion stars. Spectroscopy of the optically bright companions can determine their radial velocities, providing inclination-dependent pulsar mass estimates. Although inclinations can be inferred from subtle features in optical light curves, such estimates may be systematically biased due to incomplete heating models and poorly understood variability. Using data from the Fermi Large Area Telescope, we have searched for gamma-ray eclipses from 49 spider systems, discovering significant eclipses in 7 systems, including the prototypical black widow PSR B1957+20. Gamma-ray eclipses require direct occultation of the pulsar by the companion, and so the detection, or significant exclusion, of a gamma-ray eclipse strictly limits the binary inclination angle, providing new robust, model-independent pulsar mass constraints. For PSR B1957+20, the eclipse implies a much lighter pulsar (1.81 ± 0.07 solar masses) than inferred from optical light curve modelling.

Transient radio bursts from rotating neutron stars.

The radio sky is relatively unexplored for transient signals, although the potential of radio-transient searches is high. This was demonstrated recently by the discovery of a previously unknown type of source, varying on timescales of minutes to hours. Here we report a search for radio sources that vary on much shorter timescales. We found eleven objects characterized by single, dispersed bursts having durations between 2 and 30 ms. The average time intervals between bursts range from 4 min to 3 h with radio emission typically detectable for <1 s per day. From an analysis of the burst arrival times, we have identified periodicities in the range 0.4-7 s for ten of the eleven sources, suggesting origins in rotating neutron stars. Despite the small number of sources detected at present, their ephemeral nature implies a total Galactic population significantly exceeding that of the regularly pulsing radio pulsars. Five of the ten sources have periods >4 s, and the rate of change of the pulse period has been measured for three of them; for one source, we have inferred a high magnetic field strength of 5 x 10(13) G. This suggests that the new population is related to other classes of isolated neutron stars observed at X-ray and gamma-ray wavelengths.

Design of chitosan nanocrystals decorated with amino acids and peptides.

Antimicrobial peptides (AMPs) offer a great promise in designing new therapeutics due to their ability to interfere in bacterial growth by penetrating the cell wall. The overuse of antibiotics has resulted into antibiotic-resistant bacteria and AMPs could be an alternative to circumvent this resistance. Chitosan nanocrystals (ChsNCs) are rod-shaped polysaccharide-based nanomaterials, formed by deacetylation of seafood waste. They possess primary amino groups on the surface of the nanoparticles which can be as used a scaffold due to the built-in morphology and ease in functionalization. Here, we developed a new methodology to functionalize ChsNCs with amino acids and peptides by using fundamentals of solid phase peptide synthesis. The resulting functionalized rod-shaped nanomaterials were characterized using nuclear magnetic resonance (NMR), dynamic light scattering (DLS), zeta potential measurements and microscopy imaging. This synthetic strategy could be used in designing ChsNC-based nanomaterials to target specific cells by attaching bioactive peptides to the nanomaterial surface.

Effect of Chiral Purity on Adjuvanticity of Archaeol-Based Glycolipids.

Archaeosomes composed of sulfated lactosyl archaeol (SLA) glycolipids from stereoisomerically pure archaeol (1) are vaccine adjuvants that can boost immunogenicity and vaccine efficacy in preclinical models. Herein, we report a new synthesis of 2,3-bis((3,7,11,15-tetramethylhexadecyl)oxy) propan-1-ol (3) by treating (±)-3-benzyloxy-1,2-propanediol with a mesylated phytol derivative through a double nucleophilic substitution reaction, followed by reductive debenzylation. Three SLA archaeosomes from archaeols of different chiral purities were prepared, and the effect of stereochemistry on their adjuvanticity toward ovalbumin was investigated. It was found that all SLA archaeosomes induced strong humoral and cell-mediated antigen-specific immune responses following immunization of C57BL/6NCrl mice, with no significant differences, irrespective of the chiral purities. The responses were comparable or better than those obtained using mimetics of approved adjuvants. The performance of SLA archaeosomes during immunization and their lack of dependence on the stereochemistry of archaeol points toward a promising, safe, scalable, and economically viable vaccine adjuvant system.

Genetic engineering of microalgae for enhanced lipid production.

Microalgae have the potential to become microbial cell factories for lipid production. Their ability to convert sunlight and CO2 into valuable lipid compounds has attracted interest from cosmetic, biofuel, food and feed industries. In order to make microalgae-derived products cost-effective and commercially competitive, enhanced growth rates and lipid productivities are needed, which require optimization of cultivation systems and strain improvement. Advances in genetic tool development and omics technologies have increased our understanding of lipid metabolism, which has opened up possibilities for targeted metabolic engineering. In this review we provide a comprehensive overview on the developments made to genetically engineer microalgal strains over the last 30 years. We focus on the strategies that lead to an increased lipid content and altered fatty acid profile. These include the genetic engineering of the fatty acid synthesis pathway, Kennedy pathway, polyunsaturated fatty acid and triacylglycerol metabolisms and fatty acid catabolism. Moreover, genetic engineering of specific transcription factors, NADPH generation and central carbon metabolism, which lead to increase of lipid accumulation are also reviewed.