Mechanistic Studies of the Photoinduced Quinone Trimethyl Lock Decaging Process

Mechanistic studies of a general reaction that decages a wide range of substrates on exposure to visible light are described. The reaction involves a photochemically initiated reduction of a quinone mediated by an appended thioether. After reduction, a trimethyl lock system incorporated into the quinone leads to thermal decaging. The reaction could be viewed as an electron-transfer initiated reduction of the quinone or as a hydrogen abstraction—Norrish Type II—reaction. Product analysis, kinetic isotope effects, stereochemical labeling, radical clock, and transient absorption studies support the electron transfer mechanism. The differing reactivities of the singlet and triplet states are determined, and the ways in which this process deviates from typical quinone photochemistry are discussed. The mechanism suggests strategies for extending the reaction to longer wavelengths that would be of interest for applications in chemical biology and in a therapeutic setting

Fatal Outcome of Disseminated Strongyloidiasis despite Detectable Plasma and Cerebrospinal Levels of Orally Administered Ivermectin

Strongyloides stercoralis affects over 100 million people worldwide. Those people most susceptible to infection are those with an immunocompromising condition, such as cancer or human immunodeficiency virus (HIV). Local disease may spread throughout the body of the host, causing a condition termed disseminated strongyloidiasis. Standard treatment for Strongyloides stercoralis infection is oral ivermectin. We describe a patient with chronic lymphocytic leukemia diagnosed with disseminated strongyloidiasis two weeks after initial presentation. After repeated dosing of oral ivermectin with no clinical response, serum and cerebral spinal fluid (CSF) concentrations of ivermectin were measured to assess absorption. The peak serum concentration of 49.3 ng/mL correlated with a CSF concentration of 0.14 ng/mL. Despite these concentrations, the patient eventually succumbed to multi-system organ failure. We discuss the reasons for treatment failure and explore the utility of measuring ivermectin concentrations

The landscape of Saturn’s internal magnetic field from the Cassini Grand Finale

The Cassini mission entered the Grand Finale phase in April 2017 and executed 22.5 highly inclined, close-in orbits around Saturn before diving into the planet on September 15th 2017. Here we present our analysis of the Cassini Grand Finale magnetometer (MAG) dataset, focusing on Saturn’s internal magnetic field. These measurements demonstrate that Saturn’s internal magnetic field is exceptionally axisymmetric, with a dipole tilt less than 0.007 degrees (25.2 arcsecs). Saturn’s magnetic equator was directly measured to be shifted northward by ∼0.0468 ± 0.00043 (1σ) R_S, 2820 ± 26 km, at cylindrical radial distances between 1.034 and 1.069 R_S from the spin-axis. Although almost perfectly axisymmetric, Saturn’s internal magnetic field exhibits features on many characteristic length scales in the latitudinal direction. Examining B_r at the a = 0.75 R_S, c = 0.6993 R_S isobaric surface, the degree 4 to 11 contributions correspond to latitudinally banded magnetic perturbations with characteristic width ∼15∘, similar to that of the off-equatorial zonal jets observed in the atmosphere of Saturn. Saturn’s internal magnetic field beyond 60∘, in particular the small-scale features, are less well constrained by the available measurements, mainly due to incomplete spatial coverage in the polar region. Magnetic fields associated with the ionospheric Hall currents were estimated and found to contribute less than 2.5 nT to Gauss coefficients beyond degree 3. The magneto-disk field features orbit-to-orbit variations between 12 nT and 15.4 nT along the close-in part of Grand Finale orbits, offering an opportunity to measure the electromagnetic induction response from the interior of Saturn. A stably stratified layer thicker than 2500 km likely exists above Saturn’s deep dynamo to filter out the non-axisymmetric internal magnetic field. A heat transport mechanism other than pure conduction, e.g. double diffusive convection, must be operating within this layer to be compatible with Saturn’s observed luminosity. The latitudinally banded magnetic perturbations likely arise from a shallow secondary dynamo action with latitudinally banded differential rotation in the semi-conducting layer

The anatomical distribution of genetic associations

Deeper understanding of the anatomical intermediaries for disease and other complex genetic traits is essential to understanding mechanisms and developing new interventions. Existing ontology tools provide functional, curated annotations for many genes and can be used to develop mechanistic hypotheses; yet information about the spatial expression of genes may be equally useful in interpreting results and forming novel hypotheses for a trait. Therefore, we developed an approach for statistically testing the relationship between gene expression across the body and sets of candidate genes from across the genome. We validated this tool and tested its utility on three applications. First, we show that the expression of genes in associated loci from GWA studies implicates specific tissues for 57 out of 98 traits. Second, we tested the ability of the tool to identify novel relationships between gene expression and phenotypes. Specifically, we experimentally confirmed an underappreciated prediction highlighted by our tool: that white blood cell count – a quantitative trait of the immune system – is genetically modulated by genes expressed in the skin. Finally, using gene lists derived from exome sequencing data, we show that human genes under selective constraint are disproportionately expressed in nervous system tissues

A Neutron Star with a Massive Progenitor in Westerlund 1

We report the discovery of an X-ray pulsar in the young, massive Galactic star cluster Westerlund 1. We detected a coherent signal from the brightest X-ray source in the cluster, CXO J164710.2-455216, during two Chandra observations on 2005 May 22 and June 18. The period of the pulsar is 10.6107(1) s. We place an upper limit to the period derivative of Pdot<2e-10 s/s, which implies that the spin-down luminosity is Edot<3e33 erg/s. The X-ray luminosity of the pulsar is L_X = 3(+10,-2)e33 (D/5 kpc)^2 erg/s, and the spectrum can be described by a kT = 0.61+/-0.02 keV blackbody with a radius of R_bb = 0.27+/-0.03 (D/5 kpc}) km. Deep infrared observations reveal no counterpart with K1 Msun. Taken together, the properties of the pulsar indicate that it is a magnetar. The rarity of slow X-ray pulsars and the position of CXO J164710.2-455216 only 1.6' from the core of Westerlund 1 indicates that it is a member of the cluster with >99.97% confidence. Westerlund 1 contains 07V stars with initial masses M_i=35 Msun and >50 post-main-sequence stars that indicate the cluster is 4+/-1 Myr old. Therefore, the progenitor to this pulsar had an initial mass M_i>40 Msun. This is the most secure result among a handful of observational limits to the masses of the progenitors to neutron stars.Comment: 4 pages, 5 figures. Final version to match ApJL (added one figure since v2

Cancer targeting with biomolecules: a comparative study of photodynamic therapy efficacy using antibody or lectin conjugated phthalocyanine-PEG gold nanoparticles

The functionalisation of therapeutic nanoparticle constructs with cancer-specific biomolecules can enable selective tumour accumulation and targeted treatment. Water soluble gold nanoparticles (ca. 4 nm) stabilised by a mixed monolayer of a hydrophobic zinc phthalocyanine photosensitiser (C11Pc) and hydrophilic polyethylene glycol (PEG) have been prepared. The C11Pc-PEG gold nanoparticle constructs were further functionalised with jacalin, a lectin specific for the cancer-associated Thomsen–Friedenreich (T) carbohydrate antigen, or with monoclonal antibodies specific for the human epidermal growth factor receptor-2 (HER-2). The two biofunctionalised nanoparticle conjugates produced similar levels of singlet oxygen upon irradiation at 633 nm. Importantly, both nanoparticle conjugates demonstrated extensive, yet comparable, phototoxicity in HT-29 colorectal adenocarcinoma cells (80–90%) and in SK-BR-3 breast adenocarcinoma cells (>99%). Non-conjugated C11Pc-PEG gold nanoparticles were only minimally phototoxic. Lysosomal colocalisation studies performed with the HT-29 colon cancer cells and the SK-BR-3 breast cancer cells revealed that both nanoparticle conjugates were partially localised within acidic organelles, which is typical of receptor-mediated endocytosis. The similarity of the targeted PDT efficacy of the two biofunctionalised C11Pc-PEG gold nanoparticles is discussed with respect to targeting ligand binding affinity and cell surface antigen density as key determinants of targeting efficiency. This study highlights how targeting small cell-surface molecules, such as the T antigen, can mediate a selective photodynamic treatment response which is similar to that achieved when targeting overexpressed protein receptors, such as HER-2. The high prevalence of the T antigen present on the cellular surface of primary tumours emphasises the broad potential applications for lectin-targeted therapies

Reassessing the cardiac box: A comprehensive evaluation of the relationship between thoracic gunshot wounds and cardiac injury

Background: High energy missiles can cause cardiac injury regardless of entrance site. This study assesses the adequacy of the anatomic borders of the current “cardiac box” to predict cardiac injury. Methods: Retrospective autopsy review was performed to identify patients with penetrating torso gunshot wounds 2011-2013. Using a circumferential grid system around the thorax, logistic regression analysis was performed to detect differences in rates of cardiac injury from entrance/exit wounds in the “cardiac box” vs. the same for entrance/exit wounds outside the box. Analysis was repeated to identify regions to compare risk of cardiac injury between the current cardiac box and other regions of the thorax. Results: Over the study period, 263 patients (89% male, mean age = 34 years, median injuries/person = 2) sustained 735 wounds [80% gunshot wounds (GSWs], and 239 patients with 620 GSWs were identified for study. Of these, 95 (34%) injured the heart. Of the 257 GSWs entering the cardiac box, 31% caused cardiac injury while 21% GSWs outside the cardiac box (n = 67) penetrated the heart, suggesting that the current “cardiac box” is a poor predictor of cardiac injury relative to the thoracic non-"cardiac box" regions [Relative Risk (RR) 0.96; p=0.82]. The regions from the anterior to posterior midline of the left thorax provided the highest positive predictive value (41%) with high sensitivity (90%) while minimizing false positives making this region the most statistically significant discriminator of cardiac injury (RR 2.9; p=0.01). Conclusion: For GSWs, the current cardiac box is inadequate to discriminate whether a gunshot wound will cause a cardiac injury. As expected, entrance wounds nearest to the heart are the most likely to result in cardiac injury, but, from a clinical standpoint, it is best to think outside the “box” for GSWs to the thorax