Publications by authors named "Brian Scott"

358 Publications

Crystallographic characterization of (CHSiMe)U(BH).

Acta Crystallogr E Crystallogr Commun 2021 Apr 12;77(Pt 4):383-389. Epub 2021 Mar 12.

Department of Chemistry, University of California, Irvine, California 92697, USA.

New syntheses have been developed for the synthesis of (borohydrido-κ)tris-[η-(tri-methyl-sil-yl)cyclo-penta-dien-yl]uranium(IV), [U(BH)(CHSi)] or Cp'U(BH) (Cp' = CHSiMe) and its structure has been determined by single-crystal X-ray crystallography. This compound crystallized in the space group and the structure features three -coordinated Cp' rings and a -coordinated (BH) ligand.
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http://dx.doi.org/10.1107/S2056989021002425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025856PMC
April 2021

A lobulated mass on the upper back with prominent vasculature: A giant basal cell carcinoma.

Dermatol Reports 2021 Mar 7;13(1):9046. Epub 2021 Apr 7.

Department of Dermatology, UT Southwestern Medical Center, Dallas, TX.

Basal cell carcinoma (BCC) is characterized by slow but locally invasive growth. Although there is low metastatic potential, if not treated early, these skin cancers can lead to significant morbidity and mortality. In this case report, we present a man with a neglected BCC that developed into what is termed a giant BCC or one that is greater than 5 cm. This tumor was discovered only upon workup of orthostatic lightheadedness and iron deficiency anemia. Although rare, basal cell carcinoma must be included on the differential of a large cutaneous lesion and may be a source of significant blood loss.
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http://dx.doi.org/10.4081/dr.2021.9046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056320PMC
March 2021

Neuro-Oncologic Emergencies.

Neurol Clin 2021 05 31;39(2):545-563. Epub 2021 Mar 31.

Division of Neurohospitalist Medicine, Department of Neurology, Stanford University School of Medicine, 453 Quarry Rd, 2nd Floor, Stanford, CA 94305, USA. Electronic address:

Cancer and cancer therapies have the potential to affect the nervous system in a host of different ways. Cerebral edema, increased intracranial pressure, cerebrovascular events, status epilepticus, and epidural spinal cord compression are among those most often presenting as emergencies. Neurologic side-effects of cancer therapies are often mild, but occasionally result in serious illness. Immunotherapies cause autoimmune-related neurologic side-effects that are generally responsive to immunosuppressive therapies. Emergency management of neuro-oncologic problems benefits from early identification and close collaboration among interdisciplinary team members and patients or surrogate decision-makers.
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http://dx.doi.org/10.1016/j.ncl.2021.01.012DOI Listing
May 2021

Effects of cannabidiol and Δ9-tetrahydrocannabinol in the elevated plus maze in mice.

Behav Pharmacol 2021 Apr 19. Epub 2021 Apr 19.

Department of Pharmacology and Toxicology EpLink, The Epilepsy Research Program of the Ontario Brain Institute, University of Toronto, Toronto, Canada.

The present study tested the effects of cannabidiol (CBD) alone, Δ-9-tetrahydrocannabinol (THC) alone, and CBD and THC in combination (15:1 ratio) in the elevated plus maze (EPM), a test useful for the study of anxiety. In dose-response studies, adult, male CD1 mice were injected intraperitoneally with (1) CBD alone (0-96 mg/kg), (2) THC alone (0-6.4 mg/kg) or (3) CBD+THC in a 15:1 combination (0.0 + 0.0 mg/kg to 96.0 + 6.4 mg/kg). Diazepam (2.5 mg/kg) was also tested as a positive control. It was found that diazepam significantly increased open arm time in the EPM. CBD alone had no significant effect at any dose or injection-test interval. THC alone, however, caused a significant increase in open arm time at 3.2 and 6.4 mg/kg - doses which did not affect locomotion as measured by closed-arm entries. The effect of the combination of CBD and THC was not significantly different than the effect of THC alone. CBD alone did not have anxiolytic-like effects. THC had anxiolytic-like effects at nontoxic doses. No interaction between THC and CBD was seen when the two were combined.
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http://dx.doi.org/10.1097/FBP.0000000000000636DOI Listing
April 2021

Autologous Fat Grafting in Facial Cosmetic Surgery: A National Survey.

Facial Plast Surg 2021 Feb 12;37(1):136-138. Epub 2021 Apr 12.

Department of Otolaryngology - Head and Neck Surgery, Oregon Health and Science University, Portland, Oregon.

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http://dx.doi.org/10.1055/s-0040-1721098DOI Listing
February 2021

Expanding the Nonaqueous Chemistry of Neptunium: Synthesis and Structural Characterization of [Np(NR)Cl], [Np(NR)Cl], and [Np{(R)(SiMeH)}(NR)] (R = SiMe).

Inorg Chem 2021 Feb 4;60(4):2740-2748. Epub 2021 Feb 4.

Department of Chemistry and Biochemistry, University of California, Santa Barbara, Santa Barbara, California 93106, United States.

Reaction of 3 equiv of NaNR (R = SiMe) with NpCl(DME) in THF afforded the Np(IV) silylamide complex, [Np(NR)Cl] (), in good yield. Reaction of with 1.5 equiv of KC in THF, in the presence of 1 equiv of dibenzo-18-crown-6, resulted in formation of [{K(DB-18-C-6)(THF)}(μ-Cl)][Np(NR)Cl] (), also in good yield. Complex represents the first structurally characterized Np(III) amide. Finally, reaction of NpCl(DME) with 5 equiv of NaNR and 1 equiv of dibenzo-18-crown-6 afforded the Np(IV) bis(metallacycle), [{Na(DB-18-C-6)(EtO)(κ-DME)}(μ-DME)][Np{(R)(SiMeH)}(NR)] (), in moderate yield. Complex was characterized by H NMR spectroscopy and X-ray crystallography and represents a rare example of a structurally characterized neptunium-hydrocarbyl complex. To support these studies, we also synthesized the uranium analogues of and , namely, [K(2,2,2-cryptand)][U(NR)Cl] (), [K(DB-18-C-6)(THF)][U(NR)Cl] (), [Na(DME)][U{(R)(SiMeH)}(NR)] (), and [{Na(DB-18-C-6)(EtO)(κ-DME)}(μ-DME)][U{(R)(SiMeH)}(NR)] (). Complexes , , , and were characterized by a number of techniques, including NMR spectroscopy and X-ray crystallography.
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http://dx.doi.org/10.1021/acs.inorgchem.0c03616DOI Listing
February 2021

Structural and Spectroscopic Comparison of Soft-Se vs. Hard-O Donor Bonding in Trivalent Americium/Neodymium Molecules.

Angew Chem Int Ed Engl 2021 Apr 10;60(17):9459-9466. Epub 2021 Mar 10.

Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM, 87545, USA.

Covalency is often considered to be an influential factor in driving An vs. Ln selectivity invoked by soft donor ligands. This is intensely debated, particularly the extent to which An /Ln covalency differences prevail and manifest as the f-block is traversed, and the effects of periodic breaks beyond Pu. Herein, two Am complexes, [Am{N(E=PPh ) } ] (1-Am, E=Se; 2-Am, E=O) are compared to isoradial [Nd{N(E=PPh ) } ] (1-Nd, 2-Nd) complexes. Covalent contributions are assessed and compared to U/La and Pu/Ce analogues. Through ab initio calculations grounded in UV-vis-NIR spectroscopy and single-crystal X-ray structures, we observe differences in f orbital involvement between Am-Se and Nd-Se bonds, which are not present in O-donor congeners.
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http://dx.doi.org/10.1002/anie.202017186DOI Listing
April 2021

Monolithic Nanoporous Gold Foams with Catalytic Activity for Chemical Vapor Deposition Growth of Carbon Nanostructures.

ACS Appl Mater Interfaces 2021 Jan 24;13(1):1204-1213. Epub 2020 Dec 24.

Los Alamos National Laboratory MS J964, Los Alamos, New Mexico 87545, United States.

While bulk gold is generally considered to be a catalytically inactive material, nanostructured forms of gold can in fact be highly catalytically active. However, few methods exist for preparing high-purity macroscopic forms of catalytically active gold. In this work, we describe the synthesis of catalytically active macroscopic nanoporous gold foams via combustion synthesis of gold bis(tetrazolato)amine complexes. The resulting metallically pure porous gold nanoarchitectures exhibit bulk densities of <0.1 g/cm and Brunauer-Emmett-Teller (BET) surface areas as high as 10.9 m/g, making them among the lowest-density and highest-surface-area monolithic forms of gold produced to date. Thanks to the presence of a highly nanostructured gold surface, such gold nanofoams have also been found to be highly catalytically active toward thermal chemical vapor deposition (CVD) growth of carbon nanotubes, providing a novel method for direct synthesis of carbon nanostructures on macroscopic gold substrates. In contrast, analogous copper nanofoams were found to be catalytically inactive toward the growth of graphitic nanostructures under the same synthesis conditions, highlighting the unusually high catalytic propensity of this form factor of gold. The combustion synthesis process described herein represents a never-wet approach for directly synthesizing macroscopic catalytically active gold. Unlike sol-gel and dealloying approaches, combustion synthesis eliminates the time-consuming diffusion-mediated steps associated with previous methods and offers multiple degrees of freedom for tuning morphology, electrical conductivity, and mechanical properties.
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http://dx.doi.org/10.1021/acsami.0c17624DOI Listing
January 2021

Low-spin 1,1'-diphosphametallocenates of chromium and iron.

Chem Commun (Camb) 2021 Jan;57(5):595-598

Chemistry Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA. and Department of Chemistry, School of Natural Sciences, The University of Manchester, Oxford Road, Manchester, M13 9PL, UK.

We report two anionic diphosphametallocenates, [K(2.2.2-crypt)][M(PC4Me4)2] (M = Cr, 2-Cr; Fe, 2-Fe). Both are low-spin (S = ½) by EPR spectroscopy and SQUID magnetometry. This contrasts the high-spin (S = 3/2) ferrocenate, [K(2.2.2-crypt)][Fe(C5H2-1,2,4-tBu)2] (4-Fe). Quantum chemical calculations suggest this is due to significant differences in ligand field splitting of the d-orbitals which also explain structural features in the 2-M complexes.
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http://dx.doi.org/10.1039/d0cc06518hDOI Listing
January 2021

Ncor2/PPARα-Dependent Upregulation of MCUb in the Type 2 Diabetic Heart Impacts Cardiac Metabolic Flexibility and Function.

Diabetes 2021 Mar 10;70(3):665-679. Epub 2020 Dec 10.

Department of Medicine, University of California, San Diego, La Jolla, CA

The contribution of altered mitochondrial Ca handling to metabolic and functional defects in type 2 diabetic (T2D) mouse hearts is not well understood. In this study, we show that the T2D heart is metabolically inflexible and almost exclusively dependent on mitochondrial fatty acid oxidation as a consequence of mitochondrial calcium uniporter complex (MCUC) inhibitory subunit MCUb overexpression. Using a recombinant endonuclease-deficient Cas9-based gene promoter pulldown approach coupled with mass spectrometry, we found that MCUb is upregulated in the T2D heart due to loss of glucose homeostasis regulator nuclear receptor corepressor 2 repression, and chromatin immunoprecipitation assays identified peroxisome proliferator-activated receptor α as a mediator of MCUb gene expression in T2D cardiomyocytes. Upregulation of MCUb limits mitochondrial matrix Ca uptake and impairs mitochondrial energy production via glucose oxidation by depressing pyruvate dehydrogenase complex activity. Gene therapy displacement of endogenous MCUb with a dominant-negative MCUb transgene (MCUb) in vivo rescued T2D cardiomyocytes from metabolic inflexibility and stimulated cardiac contractile function and adrenergic responsiveness by enhancing phospholamban phosphorylation via protein kinase A. We conclude that MCUb represents one newly discovered molecular effector at the interface of metabolism and cardiac function, and its repression improves the outcome of the chronically stressed diabetic heart.
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http://dx.doi.org/10.2337/db20-0779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897348PMC
March 2021

Lanthanide Complexes of Bis(tetrazolato)amine: A Route to Lanthanide Nitride Foams.

Inorg Chem 2020 Nov 4;59(22):16109-16116. Epub 2020 Nov 4.

Naval Research Laboratory, Code 6030, Washington, D.C. 20375, United States.

Metal nitrides are strong refractory ceramic materials known for applications in the coatings, catalysis, and semiconductor industries. Lanthanide nitrides are difficult to prepare in high purity and often require high temperatures and sophisticated equipment. In this work, we present an approach to the synthesis of high-purity f-element nitrides through the use of simple lanthanide salts and the nitrogen-rich ligand 5,5'-bis(1H-tetrazolyl)amine (HBTA) to form lanthanide complexes of 5,5'-bis(tetrazolato)amine (BTA). We have demonstrated that, when dehydrated, these types of complexes undergo a self-sustained combustion reaction under an inert atmosphere to yield nanostructured f-element nitride foams for lanthanum and cerium. The synthesis, characterization, and single-crystal X-ray crystallography of the BTA complexes of lanthanum, cerium, praseodymium, neodymium, and europium are also discussed.
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http://dx.doi.org/10.1021/acs.inorgchem.0c02480DOI Listing
November 2020

Case Report of Delayed Auricular Reconstruction Using a Porous Polyethylene Implant for an Advanced Skin Cancer.

Ear Nose Throat J 2020 Aug 18:145561320950500. Epub 2020 Aug 18.

Department of Otolaryngology-Head and Neck Surgery, 6684Oregon Health & Science University, Portland, OR, USA.

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http://dx.doi.org/10.1177/0145561320950500DOI Listing
August 2020

Design, Synthesis, and Preclinical Evaluation of 3-Methyl-6-(5-thiophenyl)-1,3-dihydro-imidazo[4,5-]pyridin-2-ones as Selective GluN2B Negative Allosteric Modulators for the Treatment of Mood Disorders.

J Med Chem 2020 09 28;63(17):9181-9196. Epub 2020 Aug 28.

Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, California 92121-1126, United States.

Selective inhibitors of the GluN2B subunit of -methyl-d-aspartate receptors in the ionotropic glutamate receptor superfamily have been targeted for the treatment of mood disorders. We sought to identify structurally novel, brain penetrant, GluN2B-selective inhibitors suitable for evaluation in a clinical setting in patients with major depressive disorder. We identified a new class of negative allosteric modulators of GluN2B that contain a 1,3-dihydro-imidazo[4,5-]pyridin-2-one core. This series of compounds had poor solubility properties and poor permeability, which was addressed utilizing two approaches. First, a series of structural modifications was conducted which included replacing hydrogen bond donor groups. Second, enabling formulation development was undertaken in which a stable nanosuspension was identified for lead compound . Compound was found to have robust target engagement in rat with an ED of 1.4 mg/kg. The nanosuspension enabled sufficient margins in preclinical toleration studies to nominate for progression into advanced good laboratory practice studies.
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http://dx.doi.org/10.1021/acs.jmedchem.9b02113DOI Listing
September 2020

Heteroarylureas with fused bicyclic diamine cores as inhibitors of fatty acid amide hydrolase.

Bioorg Med Chem Lett 2020 10 9;30(20):127463. Epub 2020 Aug 9.

Janssen Pharmaceutical Companies of Johnson & Johnson, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

A series of mechanism-based heteroaryl urea fatty acid amide hydrolase (FAAH) inhibitors with fused bicyclic diamine cores is described. In contrast to compounds built around a piperazine core, most of the fused bicyclic diamine bearing analogs prepared exhibited greater potency against rFAAH than the human enzyme. Several compounds equipotent against both species were identified and profiled in vivo.
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http://dx.doi.org/10.1016/j.bmcl.2020.127463DOI Listing
October 2020

Hydration of α-UO following storage under controlled conditions of temperature and relative humidity.

Dalton Trans 2020 Aug 17;49(30):10452-10462. Epub 2020 Jul 17.

Los Alamos National Laboratory, Los Alamos, New Mexico 87545, USA.

Changes in chemical speciation of uranium oxides following storage under varied conditions of temperature and relative humidity are valuable for characterizing material provenance. In this study, subsamples of high purity α-UO were stored under four sets of controlled conditions of temperature and relative humidity over several years, and then measured periodically for chemical speciation. Powder X-ray diffraction (XRD) analysis and extended X-ray absorption fine structure spectroscopy confirm hydration of α-UO to a schoepite-like end product following storage under each of the varied storage conditions, but the species formed during exposure to the lower relative humidity and lower temperature condition follows different trends from those formed under the other three storage conditions (high relative humidity with high or low temperatures, and low relative humidity with a high temperature). Thermogravimetry coupled with XRD analysis was carried out to distinguish desorption pathways of water from the hydrated end products. Density functional theory calculations discern changes in the structure of α-UO following incorporation of 1, 2 or 3 HO molecules or 1, 2 or 3 OH groups into the orthorhombic lattice, revealing differences in lattice constants, U-O bond lengths, and U-U distances. The collective results from this analysis are in contrast to analogous studies that report that UO is oxidized and hydrated in air during storage under high relative humidity conditions.
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http://dx.doi.org/10.1039/d0dt01852jDOI Listing
August 2020

Employing Lewis Acidity to Generate Bimetallic Lanthanide Complexes.

Inorg Chem 2020 Jul 17;59(13):8642-8646. Epub 2020 Jun 17.

Los Alamos National Laboratory (LANL), Los Alamos, New Mexico 87544, United States.

With the advent of lanthanide-based technologies, there is a clear need to advance the fundamental understanding of 4f-element chelation chemistry. Herein, we contribute to a growing body of lanthanide chelation chemistry and report the synthesis of bimetallic 4f-element complexes within an imine/hemiacetalate framework, [Ln = lanthanide; TPT = tris(pyridineimine)(Tren)tris(methoxyhemiacetalate); Tren = tris(2-aminoethylamine)]. These products are generated from hydrolysis and methanolysis of the cage ligand tris(pyridinediimine)bis(Tren) (; Tadanobu et al. , (5), 859-862) likely facilitated by inductive effects stemming from the Lewis acidic lanthanide cations. These complexes are interesting because they result from imine cleavage to generate two metal binding sites: one pocketed site within the macrocycle and the other terminal site capping a hemiacetalate moiety. A clear demarcation in reactivity is observed between samarium and europium, where the lighter and larger lanthanides generate a mixture of products, and . Meanwhile, the heavier and smaller lanthanides generate exclusively bimetallic . The cleavage reactivity to form was extended beyond methanol to include other primary alcohols.
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http://dx.doi.org/10.1021/acs.inorgchem.0c00775DOI Listing
July 2020

Optimization and biological evaluation of thiazole-bis-amide inverse agonists of RORγt.

Bioorg Med Chem Lett 2020 06 21;30(12):127205. Epub 2020 Apr 21.

Janssen Research and Development, LLC, San Diego, CA 92121, USA. Electronic address:

The nuclear receptor retinoic acid receptor-related orphan receptor gamma t (RORγt) is a transcription factor that drives Th17 cell differentiation and IL-17 production in both innate and adaptive immune cells. The IL-23/IL-17 pathway is implicated in major autoimmune and inflammatory diseases. RORγt lies at the core of this pathway and represents an attractive opportunity for intervention with small molecule therapeutics. Despite diverse chemical series having been reported, combining high potency and nuclear receptor selectivity with good physicochemical properties remains a challenging endeavor in the field of RORγt drug discovery. We recently described the discovery and evaluation of a new class of potent and selective RORγt inverse agonists based on a thiazole scaffold. Herein we describe the successful optimization of this class by incorporation of an additional amide moiety at the 4-position of the thiazole core. In several optimization cycles, we have reduced human PXR activation, improved solubility, and increased potency while maintaining nuclear receptor selectivity. X-ray crystallographic analysis of compound 1g bound in the sterol binding site of the ligand binding domain of RORγt was largely consistent with an earlier structure, guiding further insight into the molecular mechanism for RORγt inhibition with this series. Compound 1g is orally bioavailable, potent in a human whole blood assay and proved to be efficacious in an ex-vivo IL-17A assay, and was selected for preclinical evaluation.
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http://dx.doi.org/10.1016/j.bmcl.2020.127205DOI Listing
June 2020

Discovery and optimization of new oxadiazole substituted thiazole RORγt inverse agonists through a bioisosteric amide replacement approach.

Bioorg Med Chem Lett 2020 06 7;30(12):127174. Epub 2020 Apr 7.

Janssen Research and Development, LLC, San Diego, CA 92121, USA. Electronic address:

Starting from previously identified thiazole-2-carboxamides exemplified by compound 1/6, two new series of RORγt inverse agonists with significantly improved aqueous solubility, ADME parameters and oral PK properties were discovered. These scaffolds were identified from a bioisosteric amide replacement approach. Amongst the variety of heterocycles explored, a 1,3,4-oxadiazole led to compounds with the best overall profile for SAR development and in vivo exploration. In an ex vivo mouse PD model, concentration dependent efficacy was demonstrated and compounds 3/5 and 6/3 were profiled in a 5-day rat tolerability study.
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http://dx.doi.org/10.1016/j.bmcl.2020.127174DOI Listing
June 2020

A sensitive and robust thin-film x-ray detector using 2D layered perovskite diodes.

Sci Adv 2020 Apr 10;6(15):eaay0815. Epub 2020 Apr 10.

Materials Physics and Applications Division, Los Alamos National Laboratory, Los Alamos, NM 87544, USA.

Solid-state radiation detectors, using crystalline semiconductors to convert radiation photons to electrical charges, outperform other technologies with high detectivity and sensitivity. Here, we demonstrate a thin-film x-ray detector comprised with highly crystalline two-dimensional Ruddlesden-Popper phase layered perovskites fabricated in a fully depleted - architecture. It shows high diode resistivity of 10 ohm·cm in reverse-bias regime leading to a high x-ray detecting sensitivity up to 0.276 C Gy cm. Such high signal is collected by the built-in potential underpinning operation of primary photocurrent device with robust operation. The detectors generate substantial x-ray photon-induced open-circuit voltages that offer an alternative detecting mechanism. Our findings suggest a new generation of x-ray detectors based on low-cost layered perovskite thin films for future x-ray imaging technologies.
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http://dx.doi.org/10.1126/sciadv.aay0815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7148088PMC
April 2020

Violaceous nodules in an HIV-positive man.

Dermatol Online J 2020 Feb 15;26(2). Epub 2020 Feb 15.

University of Texas Southwestern Medical Center, Dallas, TX.

Plasmablastic lymphoma (PBL) is a rare and aggressive malignancy associated with immunosuppression and the oncogenic effects of the Epstein-Barr virus (EBV). We present an HIV-positive man with PBL that presented as ulcers and violaceous exophytic nodules on the legs. The clinical features, histologic appearance, and differential diagnosis of this malignancy are briefly reviewed.
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February 2020

Actinide 2-metallabiphenylenes that satisfy Hückel's rule.

Nature 2020 02 26;578(7796):563-567. Epub 2020 Feb 26.

Chemistry Division, Los Alamos National Laboratory, Los Alamos, NM, USA.

Aromaticity and antiaromaticity, as defined by Hückel's rule, are key ideas in organic chemistry, and are both exemplified in biphenylene-a molecule that consists of two benzene rings joined by a four-membered ring at its core. Biphenylene analogues in which one of the benzene rings has been replaced by a different (4n + 2) π-electron system have so far been associated only with organic compounds. In addition, efforts to prepare a zirconabiphenylene compound resulted in the isolation of a bis(alkyne) zirconocene complex instead. Here we report the synthesis and characterization of, to our knowledge, the first 2-metallabiphenylene compounds. Single-crystal X-ray diffraction studies reveal that these complexes have nearly planar, 11-membered metallatricycles with metrical parameters that compare well with those reported for biphenylene. Nuclear magnetic resonance spectroscopy, in addition to nucleus-independent chemical shift calculations, provides evidence that these complexes contain an antiaromatic cyclobutadiene ring and an aromatic benzene ring. Furthermore, spectroscopic evidence, Kohn-Sham molecular orbital compositions and natural bond orbital calculations suggest covalency and delocalization of the uranium f electrons with the carbon-containing ligand.
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http://dx.doi.org/10.1038/s41586-020-2004-7DOI Listing
February 2020

Advancing Chelation Chemistry for Actinium and Other +3 f-Elements, Am, Cm, and La.

J Am Chem Soc 2019 12 3;141(49):19404-19414. Epub 2019 Dec 3.

Los Alamos National Laboratory , Los Alamos , New Mexico 87545 , United States of America.

A major chemical challenge facing implementation of Ac in targeted alpha therapy-an emerging technology that has potential for treatment of disease-is identifying an Ac chelator that is compatible with applications. It is unclear how to tailor a chelator for Ac binding because Ac coordination chemistry is poorly defined. Most Ac chemistry is inferred from radiochemical experiments carried out on microscopic scales. Of the few Ac compounds that have been characterized spectroscopically, success has only been reported for simple inorganic ligands. Toward advancing understanding in Ac chelation chemistry, we have developed a method for characterizing Ac complexes that contain highly complex chelating agents using small quantities (μg) of Ac. We successfully characterized the chelation of Ac by DOTP using EXAFS, NMR, and DFT techniques. To develop confidence and credibility in the Ac results, comparisons with +3 cations (Am, Cm, and La) that could be handled on the mg scale were carried out. We discovered that all M cations (M = Ac, Am, Cm, La) were completely encapsulated within the binding pocket of the DOTP macrocycle. The computational results highlighted the stability of the M(DOTP) complexes.
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http://dx.doi.org/10.1021/jacs.9b10354DOI Listing
December 2019

Overexpression of p53 due to excess protein O-GlcNAcylation is associated with coronary microvascular disease in type 2 diabetes.

Cardiovasc Res 2020 05;116(6):1186-1198

Department of Physiology, The University of Arizona, 1501 N. Campbell Ave., Tucson, AZ 85724, USA.

Aims: We previously reported that increased protein O-GlcNAcylation in diabetic mice led to vascular rarefaction in the heart. In this study, we aimed to investigate whether and how coronary endothelial cell (EC) apoptosis is enhanced by protein O-GlcNAcylation and thus induces coronary microvascular disease (CMD) and subsequent cardiac dysfunction in diabetes. We hypothesize that excessive protein O-GlcNAcylation increases p53 that leads to CMD and reduced cardiac contractility.

Methods And Results: We conducted in vivo functional experiments in control mice, TALLYHO/Jng (TH) mice, a polygenic type 2 diabetic (T2D) model, and EC-specific O-GlcNAcase (OGA, an enzyme that catalyzes the removal of O-GlcNAc from proteins)-overexpressing TH mice, as well as in vitro experiments in isolated ECs from these mice. TH mice exhibited a significant increase in coronary EC apoptosis and reduction of coronary flow velocity reserve (CFVR), an assessment of coronary microvascular function, in comparison to wild-type mice. The decreased CFVR, due at least partially to EC apoptosis, was associated with decreased cardiac contractility in TH mice. Western blot experiments showed that p53 protein level was significantly higher in coronary ECs from TH mice and T2D patients than in control ECs. High glucose treatment also increased p53 protein level in control ECs. Furthermore, overexpression of OGA decreased protein O-GlcNAcylation and down-regulated p53 in coronary ECs, and conferred a protective effect on cardiac function in TH mice. Inhibition of p53 with pifithrin-α attenuated coronary EC apoptosis and restored CFVR and cardiac contractility in TH mice.

Conclusions: The data from this study indicate that inhibition of p53 or down-regulation of p53 by OGA overexpression attenuates coronary EC apoptosis and improves CFVR and cardiac function in diabetes. Lowering coronary endothelial p53 levels via OGA overexpression could be a potential therapeutic approach for CMD in diabetes.
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http://dx.doi.org/10.1093/cvr/cvz216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177511PMC
May 2020

Magnetoelectric behavior via a spin state transition.

Nat Commun 2019 Sep 6;10(1):4043. Epub 2019 Sep 6.

National High Magnetic Field Lab (NHMFL), Los Alamos National Lab (LANL), Los Alamos, NM, 87545, USA.

In magnetoelectric materials, magnetic and dielectric/ferroelectric properties couple to each other. This coupling could enable lower power consumption and new functionalities in devices such as sensors, memories and transducers, since voltages instead of electric currents are sensing and controlling the magnetic state. We explore a different approach to magnetoelectric coupling in which we use the magnetic spin state instead of the more traditional ferro or antiferromagnetic order to couple to electric properties. In our molecular compound, magnetic field induces a spin crossover from the S = 1 to the S = 2 state of Mn, which in turn generates molecular distortions and electric dipoles. These dipoles couple to the magnetic easy axis, and form different polar, antipolar and paraelectric phases vs magnetic field and temperature. Spin crossover compounds are a large class of materials where the spin state can modify the structure, and here we demonstrate that this is a route to magnetoelectric coupling.
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http://dx.doi.org/10.1038/s41467-019-11967-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731214PMC
September 2019

Laryngeal Trauma in a 7-Year-Old Child.

Ear Nose Throat J 2019 Jul 21;98(6):326-327. Epub 2019 Feb 21.

1 Department of Otolaryngology-Head and Neck Surgery, University of Texas Southwestern Medical Center and Children's Health, Dallas, TX, USA.

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http://dx.doi.org/10.1177/0145561318823974DOI Listing
July 2019

[Am(C Me H) ]: An Organometallic Americium Complex.

Angew Chem Int Ed Engl 2019 Aug 25;58(34):11695-11699. Epub 2019 Jul 25.

Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM, 87545, USA.

We report the small-scale synthesis, isolated yield, single-crystal X-ray structure, H NMR solution spectroscopy /solid-state UV/Vis-nIR spectroscopy, and density functional theory (DFT)/ab initio wave function theory calculations on an Am organometallic complex, [Am(C Me H) ] (1). This constitutes the first quantitative data on Am-C bonding in a molecular species.
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http://dx.doi.org/10.1002/anie.201905225DOI Listing
August 2019

Laryngomalacia and Swallow Dysfunction.

Ear Nose Throat J 2019 Dec 23;98(10):613-616. Epub 2019 May 23.

Department of Otolaryngology-Head and Neck Surgery, Oregon Health & Science University, Portland, OR, USA.

Objectives: Laryngomalacia is an established cause of stridor and sleep-disordered breathing in children. However, the relationship between laryngomalacia and dysphagia has not been well characterized. The objectives of this study were to (1) describe the patient characteristics, symptoms, and prevalence of dysphagia in children with laryngomalacia and (2) examine the effectiveness of supraglottoplasty in improving feeding.

Methods: This was a retrospective study of patients with laryngomalacia who underwent a modified barium swallow study (MBSS) at a tertiary academic pediatric medical center between March 1, 2014, and March 1, 2018. Patients were excluded if they did not undergo a MBSS. Comorbidities, airway and feedings symptoms, MBSS results, and surgical history were recorded from each patient's electronic medical record.

Results: Forty-four children met inclusion/exclusion criteria. The median age at presentation was 96 days. There was a male predominance (66%). About one-third had a genetic or neuromuscular comorbidity. Most children had stridor (93%) and feeding difficulty (86%), while 50% had parent-reported poor weight gain. Fifty-seven percent of patients had evidence of penetration or aspiration on MBSS. All patients with a positive MBSS had dysphagia symptoms. Fifty-seven percent of patients underwent supraglottoplasty. Postoperatively, 92% reported improvement in dysphagia symptoms.

Conclusion: Dysphagia is prevalent among a subset of children with laryngomalacia. Symptomatic children may benefit from a swallow evaluation to help determine the need for further intervention. Children who undergo supraglottoplasty for laryngomalacia have improved dysphagia at follow-up, though the amount of improvement directly attributable to surgery is unclear and warrants further investigation.
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http://dx.doi.org/10.1177/0145561319847459DOI Listing
December 2019

Oxidation of uranium(iv) mixed imido-amido complexes with PhEEPh and to generate uranium(vi) bis(imido) dichalcogenolates, U(NR)(EPh)(L).

Dalton Trans 2019 Aug 3;48(29):10865-10873. Epub 2019 May 3.

Chemistry Division, Los Alamos National Laboratory, MS J514, Los Alamos, New Mexico 87545, USA.

This work provides new routes for the conversion of U(iv) into U(vi) bis(imido) complexes and offers new information on the manner in which the U(vi) compounds form. Many compounds from the series described by the general formula U(NR)(EPh)(L) (R = 2,6-diisopropylphenyl, tert-butyl; E = S, Se, Te; L = py, EPh) were synthesized via oxidation of an in situ generated U(iv) amido-imido species with PhE. This synthetic sequence provides a general route into bis(imido) U(vi) chalcogenolate complexes, circumventing the need to perform problematic salt metathesis reactions on U(vi) iodides. Investigation into the speciation of the U(iv) complexes that form prior to oxidation found a significant dependence on the identity of the ancillary ligands, with Bubpy forming the isolable imido-(bis)amido complex, U(NDipp)(NHDipp)(Bubpy). Together, these data are consistent with the view that the bis(imido) U(vi) motif - much like the uranyl ion, UO- is a thermodynamic sink into which simple ligand frameworks are unable to prevent uranium from falling when in the presence of a suitable retinue of imido proligands.
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http://dx.doi.org/10.1039/c9dt00680jDOI Listing
August 2019

3-Substituted Quinolines as RORγt Inverse Agonists.

Bioorg Med Chem Lett 2019 06 12;29(12):1463-1470. Epub 2019 Apr 12.

Discovery Product Development and Supply, Janssen Research and Development, Welsh and McKean Roads, Spring House, PA 19477, United States.

We have previously reported the syntheses of a series of 3,6-disubstituted quinolines as modulators of the retinoic acid receptor-related orphan receptor gamma t (RORγt). These molecules are potent binders but are high molecular weight and they exhibited poor solubility at pH 2 and pH 7. This manuscript details our efforts at improving physical chemical properties for this series of compounds by increasing the diversity at the 3-position (i.e. introducing heteroatoms and lowering the molecular weight). These efforts have led to molecules which are potent binders with improved solubility.
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http://dx.doi.org/10.1016/j.bmcl.2019.04.021DOI Listing
June 2019

Encapsulated Sinonasal Schwannoma.

Ear Nose Throat J 2019 Apr-May;98(4):205-206. Epub 2019 Mar 5.

1 Division of Facial Plastic and Reconstructive Surgery, Department of Otolaryngology-Head & Neck Surgery, Oregon Health & Science University, Portland, OR, USA.

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http://dx.doi.org/10.1177/0145561318823321DOI Listing
December 2019