How far does a researcher's responsibility extend when an incidental finding is identified? Balancing pertinent ethical principles such as beneficence, respect for persons, and duty to rescue is not ...always straightforward, particularly in neuroimaging research where empirical data that might help guide decision making are lacking. We conducted a systematic survey of perceptions and preferences of 396 investigators, research participants, and Institutional Review Board members at our institution. Using the partial entrustment model as described by Richardson, we argue that our data supports universal reading by a neuroradiologist of all research MRI scans for incidental findings and providing full disclosure to all participants.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Bacteria continue to evade existing antibiotics by acquiring resistance by various mechanisms, leading to loss of antibiotic effectiveness. To avoid an epidemic from infections of incurable ...drug-resistant bacteria, new antibiotics with new modes of action are desperately needed. Using a genome-wide mechanism of action-guided whole cell screening approach based on antisense Staphylococcus aureus fitness test technology, we report herein the discovery of altersolanol P (1), a new tetrahydroanthraquinone from an unknown fungus from the Hypocreales isolated from forest litter collected in Puerto Rico. The structure was elucidated by high-resolution mass spectrometry and 2D NMR spectroscopy. Relative stereochemistry was established by NOESY correlations, and absolute configuration was deduced by the application of MPA ester-based methodology. Observed 1H and 13C NMR shifts were well aligned with the corresponding chemical shifts predicted by DFT calculations. Altersolanol P exhibited Gram-positive antibacterial activity (MIC range 1–8 μg/mL) and inhibited the growth of Gram-negative Haemophilus influenzae (MIC 2 μg/mL). The isolation, structure elucidation, and antibacterial activity of altersolanol P are described.
ABSTRACT
Idiopathic pulmonary fibrosis (IPF) is characterized by interstitial lung infiltrates, dyspnea, and progressive respiratory failure. Reports linking telomerase mutations to familial ...interstitial pneumonia (FIP) suggest that telomerase activity and telomere length maintenance are important in disease pathogenesis. To investigate the role of telomerase in lung fibrotic remodeling, intratracheal bleomycin was administered to mice deficient in telomerase reverse transcriptase (TERT) or telomerase RNA component (TERC) and to wild-type controls. TERT-deficient and TERC-deficient mice were interbred to the F6 and F4 generation, respectively, when they developed skin manifestations and infertility. Fibrosis was scored using a semiquantitative scale and total lung collagen was measured using a hydroxyprolinemicroplate assay. Telomere lengths were measured in peripheral blood leukocytes and isolated type II alveolar epithelial cells (AECs). Telomerase activity in type II AECs was measured using a real-time polymerase chain reaction (PCR)-based system. Following bleomycin, TERT-deficient and TERC-deficient mice developed an equivalent inflammatory response and similar lung fibrosis (by scoring of lung sections and total lung collagen content) compared to controls, a pattern seen in both early (F1) and later (F6 TERT and F4 TERC) generations. Telomere lengths were reduced in peripheral blood leukocytes and isolated type II AECs from F6 TERT-deficient and F4 TERC-deficient mice compared to controls. Telomerase deficiency in a murine model leads to telomere shortening, but does not predispose to enhanced bleomycin-induced lung fibrosis. Additional genetic or environmental factors may be necessary for development of fibrosis in the presence of telomerase deficiency.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Issue editors Amanda M. Smith and Alfredo Franco have assembled an impressive array of critical and creative works that speak to swelling popularity and power of Latinx narratives. By way of critical ...articles or interviews, we also gain insights into the dazzling literary minds of Héctor Tobar, Pedro Pietri, Giannina Braschi, and Claudia Nina. John Nieto-Phlllips is Associate Professor of History and Latino Studies at Indiana University.
Abstract Cortical development in the first years of age for children with very low birth weight is not well characterized. We obtained high-resolution structural magnetic resonance images from ...children aged 18-22 months (16 very low birth weight/7 term) and 3-4 years (12 very low birth weight/8 term). Cortical surface area and thickness of the brain were assessed using the FreeSurfer data analysis program, and manually inspected for accuracy. For children with very low birth weight, a negative correlation was evident between birth weight and cortical thickness at 18-22 months ( P = 0.04), and a positive correlation with cortical surface area at 3-4 years ( P = 0.02). Between groups, children with very low birth weight demonstrated a consistent trend for thicker cortices and reduced surface area, compared with control term children (18-22 month surface area, P = 0.08; thickness, P = 0.11; 3-4 year surface area, P = 0.73; thickness, P = 0.14). The normal processes of cortical thinning and surface area expansion in the first several years of age may be delayed by premature delivery, a potentially more prominent effect with greater degrees of prematurity.
Hairpin pyrrole-imidazole (Py-Im) polyamides are programmable oligomers that bind the DNA minor groove in a sequence-specific manner with affinities comparable to those of natural DNA-binding ...proteins. These cell-permeable small molecules have been shown to enter the nuclei of live cells and downregulate endogenous gene expression. We complete here a library of 27 hairpin Py-Im polyamides, which bind seven-base-pair sequences of the general form 5′-WWGNNNW-3′ (where W=A or T, N=W, G, or C). Their equilibrium association constants (
K
a) range from
K
a=1×10
8 to 4×10
10
M
−1 with good sequence specificity. A table of binding affinities and sequence contexts for this completed 27-member library has been assembled for the benefit of the chemical biology community interested in molecular control of transcription.
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Iron and oxygen are essential but potentially toxic constituents of most organisms, and their transport is meticulously regulated
both at the cellular and systemic levels. Compartmentalization may be ...a homeostatic mechanism for isolating these biological
reactants in cells. To investigate this hypothesis, we have undertaken a genetic analysis of the interaction between iron
and oxygen metabolism in Drosophila . We show that Drosophila iron regulatory protein-1 (IRP1) registers cytosolic iron and oxidative stress through its labile iron sulfur cluster by
switching between cytosolic aconitase and RNA-binding functions. IRP1 is strongly activated by silencing and genetic mutation
of the cytosolic superoxide dismutase ( Sod1 ), but is unaffected by silencing of mitochondrial Sod2 . Conversely, mitochondrial aconitase activity is relatively insensitive to loss of Sod1 function, but drops dramatically if Sod2 activity is impaired. This strongly suggests that the mitochondrial boundary limits the range of superoxide reactivity in vivo . We also find that exposure of adults to paraquat converts cytosolic aconitase to IRP1 but has no affect on mitochondrial
aconitase, indicating that paraquat generates superoxide in the cytosol but not in mitochondria. Accordingly, we find that
transgene-mediated overexpression of Sod2 neither enhances paraquat resistance in Sod1 + flies nor compensates for lack of SOD1 activity in Sod1 -null mutants. We conclude that in vivo , superoxide is confined to the subcellular compartment in which it is formed, and that the mitochondrial and cytosolic SODs
provide independent protection to compartment-specific protein iron-sulfur clusters against attack by superoxide generated
under oxidative stress within those compartments.
Uroporphyrinogen III synthase (U3S) catalyzes the asymmetrical cyclization of a linear tetrapyrrole to form the physiologically relevant uroporphyrinogen III (uro’gen III) isomer during heme ...biosynthesis. Here, we report four apoenzyme and one product complex crystal structures of the Thermus thermophilus (HB27) U3S protein. The overlay of eight crystallographically unique U3S molecules reveals a huge range of conformational flexibility, including a “closed” product complex. The product, uro’gen III, binds between the two domains and is held in place by a network of hydrogen bonds between the product’s side chain carboxylates and the protein’s main chain amides. Interactions of the product A and B ring carboxylate side chains with both structural domains of U3S appear to dictate the relative orientation of the domains in the closed enzyme conformation and likely remain intact during catalysis. The product C and D rings are less constrained in the structure, consistent with the conformational changes required for the catalytic cyclization with inversion of D ring orientation. A conserved tyrosine residue is potentially positioned to facilitate loss of a hydroxyl from the substrate to initiate the catalytic reaction.
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