Atomic-Scale Interface for Pt Nanoparticles on SrTiO3 (001).

The interfacial structure formed by Pt nanoparticles grown epitaxially on a SrTiO3 (001) surface by pulsed laser deposition was studied by X-ray standing-wave (XSW) excited core-level photoelectron emission. The XSW-generated 3D atomic map of the Pt and interfacial oxygens for the oxidized Pt/SrTiO3 interface differs significantly from that of the as-deposited interface. After oxidation, the Pt atoms shifted upward and their atomic occupation at fcc-like sites evolved as the oxidation temperature increased. Interfacial oxygen atoms were differentiated from bulk O atoms by the chemical shift in the binding energy of their 1s electrons. After oxidation, the interfacial oxygen atoms rearranged to form a TiO2 bilayer at the interface. These results provide a more complete description of the strong metal-support interaction process at the interface.

A case of immunotherapy-responsive autoimmune hemichorea.

INTRODUCTION: Subacute adult-acquired hemichorea is a striking presentation with a broad differential, including ischemic, metabolic, and inflammatory causes. CASE: We encountered a 74-year-old woman with rapid onset of hemichorea and associated encephalopathy. Following a thorough workup without identification of clear imaging or laboratory abnormalities, we empirically treated with IVIg. Her hemichorea dramatically improved. Due to relapses of hemichorea, she required repeat immunotherapy with IVIg or high dose steroids followed by maintenance mycophenolate. DISCUSSION: This case of seronegative autoimmune hemichorea highlights the importance of a high index of suspicion for an inflammatory etiology of chorea when other causes are ruled out and performing an immunotherapy trial.

Treatment of IgG4-related disease-associated hypertrophic pachymeningitis with intrathecal rituximab: a case report.

IgG4-related disease-associated hypertrophic pachymeningitis (IgG4RD-HP) is a fibroinflammatory autoimmune disorder in which diagnosis is difficult without biopsy. Guidance on management of disease refractory to glucocorticoids and intravenous rituximab is limited. We present the case of a 68-year-old woman with IgG4RD-HP who developed sensorineural hearing loss with associated bulky basilar pachymeningeal enhancement. Her cerebrospinal fluid was inflammatory and had an elevated IgG4 concentration, strongly suggestive of IgG4RD-HP. Biopsy of involved meninges was not possible due to surgical risk. Over years she developed bilateral optic neuropathies and hydrocephalus, requiring intravenous rituximab and ventriculoperitoneal shunt. Her disease was refractory to glucocorticoids. Despite maintenance intravenous rituximab, she developed slowly progressive symptoms of intracranial hypertension and hydrocephalus with persistently inflammatory spinal fluid. Switching to intrathecal rituximab therapy led to dramatic improvement in gait and headache and reduced pachymeningeal bulk and metabolic activity. In patients with IgG4RD-HP refractory to glucocorticoids and intravenous rituximab, intrathecal rituximab may be an efficacious therapy.

Stability and Thrombogenicity Analysis of Collagen/Carbon Nanotube Nanocomposite Coatings Using a Reversible Microfluidic Device.

Currently, the development of stable and antithrombogenic coatings for cardiovascular implants is socially important. This is especially important for coatings exposed to high shear stress from flowing blood, such as those on ventricular assist devices. A method of layer-by-layer formation of nanocomposite coatings based on multi-walled carbon nanotubes (MWCNT) in a collagen matrix is proposed. A reversible microfluidic device with a wide range of flow shear stresses has been developed for hemodynamic experiments. The dependence of the resistance on the presence of a cross-linking agent for collagen chains in the composition of the coating was demonstrated. Optical profilometry determined that collagen/c-MWCNT and collagen/c-MWCNT/glutaraldehyde coatings obtained sufficiently high resistance to high shear stress flow. However, the collagen/c-MWCNT/glutaraldehyde coating was almost twice as resistant to a phosphate-buffered solution flow. A reversible microfluidic device made it possible to assess the level of thrombogenicity of the coatings by the level of blood albumin protein adhesion to the coatings. Raman spectroscopy demonstrated that the adhesion of albumin to collagen/c-MWCNT and collagen/c-MWCNT/glutaraldehyde coatings is 1.7 and 1.4 times lower than the adhesion of protein to a titanium surface, widely used for ventricular assist devices. Scanning electron microscopy and energy dispersive spectroscopy determined that blood protein was least detected on the collagen/c-MWCNT coating, which contained no cross-linking agent, including in comparison with the titanium surface. Thus, a reversible microfluidic device is suitable for preliminary testing of the resistance and thrombogenicity of various coatings and membranes, and nanocomposite coatings based on collagen and c-MWCNT are suitable candidates for the development of cardiovascular devices.

Actinomycotic Osteomyelitis and Myiasis in Oroantral Communication: Clinicopathological and Tomographic Findings

Actinomycotic osteomyelitis of the maxilla presenting with oroantral communication is very rare, herein we report the first case of this condition in association with myiasis. A 50-year-old man reported chronic sinusopathy and a non-healing maxillary lesion, with 30 years of evolution, presenting occasional nasal and intraoral purulent discharge, with foul smell, and recurrent episodes of larvae presence. Cone beam computed tomography showed a large hyperdense image inside the left maxillary sinus, with focal areas with soft tissue density, and extensive discontinuity of the maxillary sinus floor, confirming the oroantral fistula. The necrotic tissue curetted during surgery presented hard consistency, and dark greenish color, and was submitted for histopathological analysis. Microscopically, necrotic bone, masses of filamentous bacteria colonie s, compatible with actinomycosis, and large rhomboidal structures surrounded by eosinophilic capsule - suggestive of larvae, were observed. The diagnosis of actinomycotic osteomyelitis with presence of structures compatible with larvae was established.

La osteomielitis actinomicótica del maxilar que se presenta con comunicación oroantral es poco frequente. En este trabajo reportamos el primer caso de esta condición en asociación con miasis. Un hombre de 50 años que refiere sinusopatía crónica y lesión maxilar que no cicatriza, de 30 años de evolución, presenta secreción ocasional purulenta nasal e intraoral, con mal olor y episodios recurrentes de presencia de larvas. La tomografía computarizada de haz cónico mostró una gran imagen hiperdensa en el interior del seno maxilar izquierdo, con áreas focales con densidad de partes blandas y una extensa discontinuidad del piso del seno maxilar, lo que confirma la fístula oroantral. El tejido necrótico legrado durante la cirugía presentó consistencia dura, coloración verdosa oscura, y fue remitido para análisis histopatológico. Microscópicamente se observó hueso necrótico, masas de colonias de bacterias filamentosas compatibles con actinomicosis y grandes estructuras romboidales rodeadas de cápsula eosinofílica sugestiva de larvas. Se estableció el diagnóstico de osteomielitis actinomicótica con presencia de estructuras compatibles con larvas.

Ischemic stroke in neurosarcoidosis: A retrospective cohort analysis.

BACKGROUND: Cerebrovascular disease is rarely reported in neurosarcoidosis and constitutes one of its least well-described forms, though recognition for it has grown in the last decade with recent studies estimating a higher frequency of occurrence than previously known. METHODS: Patients with ischemic stroke were included if the mechanism was directly attributable to sarcoidosis of the CNS. Patients were excluded if an alternative stroke etiology was of equal or higher likelihood than CNS sarcoidosis. RESULTS: Neurologic disease was the initial presenting manifestation of sarcoidosis in 8/11 (72.7%), and ischemic stroke was an inaugural manifestation of sarcoidosis in 4/11 (36.4%). Small vessel disease was the predominant ischemia subtype (10/11, 90.9%) with pontine perforating vessels (6/11, 54.5%) and lenticulostriate arteries (3/11, 27.3%) being the vasculature most often affected. Vessels with a more rostral supratentorial distribution were uncommonly affected. Common neuroinflammatory accompaniments included leptomeningitis (10/11, 90.9%) and cranial nerve disease (3/11, 27.3%). Recurrent strokes occurred in 8/11 (72.7%), and recurrent neuroinflammation occurred in 7/11 (63.6%). Antiplatelet drugs were used in 6/11 (54.5%) patients. Most (10/11, 90.9%) required at least two lines of immunosuppression to achieve inflammatory disease remission in this context; infliximab was the most successfully employed immunosuppressant (7/8 treatment courses, 87.5%). Recurrent strokes occurred in 8/11 (72.7%) patients, and a second inflammatory attack occurred in 7/11 (63.6%) patients. The presenting median modified Rankin Scale score of 4.0 improved to 2.0 over a median period of follow-up of 52.0 months. CONCLUSION: Ischemic strokes in neurosarcoidosis occur in a caudal-to-rostral distribution, tend to affect small caliber blood vessels that lack collateral blood flow, and typically associate with inflammatory leptomeningeal disease. The risk for relapse in the forms of stroke or neuroinflammation are high in this neurosarcoidosis phenotype.

Hybrid Carbon Nanotubes-Graphene Nanostructures: Modeling, Formation, Characterization.

A technology for the formation and bonding with a substrate of hybrid carbon nanostructures from single-walled carbon nanotubes (SWCNT) and reduced graphene oxide (rGO) by laser radiation is proposed. Molecular dynamics modeling by the real-time time-dependent density functional tight-binding (TD-DFTB) method made it possible to reveal the mechanism of field emission centers formation in carbon nanostructures layers. Laser radiation stimulates the formation of graphene-nanotube covalent contacts and also induces a dipole moment of hybrid nanostructures, which ensures their orientation along the force lines of the radiation field. The main mechanical and emission characteristics of the formed hybrid nanostructures were determined. By Raman spectroscopy, the effect of laser radiation energy on the defectiveness of all types of layers formed from nanostructures was determined. Laser exposure increased the hardness of all samples more than twice. Maximum hardness was obtained for hybrid nanostructure with a buffer layer (bl) of rGO and the main layer of SWCNT-rGO(bl)-SWCNT and was 54.4 GPa. In addition, the adhesion of rGO to the substrate and electron transport between the substrate and rGO(bl)-SWCNT increased. The rGO(bl)-SWCNT cathode with an area of ~1 mm2 showed a field emission current density of 562 mA/cm2 and stability for 9 h at a current of 1 mA. The developed technology for the formation of hybrid nanostructures can be used both to create high-performance and stable field emission cathodes and in other applications where nanomaterials coating with good adhesion, strength, and electrical conductivity is required.

Atomic-Site-Specific Surface Valence-Band Structure from X-Ray Standing-Wave Excited Photoemission.

X-ray standing-wave (XSW) excited photoelectron emission was used to measure the site-specific valence band (VB) for ½ monolayer (ML) Pt grown on a SrTiO_{3} (001) surface. The XSW induced modulations in the core level (CL), and VB photoemission from the surface and substrate atoms were monitored for three hkl substrate Bragg reflections. The XSW CL analysis shows the Pt to have a face-centered-cubic-like cube-on-cube epitaxy with the substrate. The XSW VB information compares well to a density functional theory calculated projected density of states from the surface and substrate atoms. Overall, this Letter represents a novel method for determining the contribution to the density of states by valence electrons from specific atomic surface sites.

Atomic-Scale View of Redox Induced Changes for Monolayer MoOx on α-TiO2(110) with Chemical-State Sensitivity.

Supported molybdenum oxide (MoOx) plays an important role in catalytic transformations from alcohol dehydrogenation to transesterification. During these reactions, molybdenum and oxygen surface species undergo structural and chemical changes. A detailed, chemical-state specific, atomic-scale structural analysis of the catalyst under redox conditions is important for improving catalytic properties. In this study, a monolayer of Mo grown on α-TiO2(110) by atomic-layer deposition is analyzed by X-ray standing wave (XSW) excited X-ray photoelectron spectroscopy (XPS). The chemical shifts for Mo 2p3/2 and O 1s peaks are used to distinguish Mo6+ from Mo4+ and surface O from bulk O. Excitation of XPS by XSW allows pinpointing the location of these surface species relative to the underlying substrate lattice. Measured 3D composite atomic density maps for the oxidized and reduced interfaces compare well with our density functional theory models and collectively create a unique view of the redox-driven dynamics for this complex catalytic structure.

A new route to obtain fluorescence X-ray absorption spectra of compounds and to remove the self-absorption induced nonlinearity in the spectra.

A new route to obtain fluorescence X-ray absorption spectra of compounds and to remove the self-absorption induced nonlinearity in the spectra is described. The fluorescent intensity If is linearly proportional to the absorption coefficient µ. For studies of surface structures around an element (κ) the fluorescence detection is often the mode of choice. However, the measurement may suffer from a self-absorption (SA) effect which nonlinearly distorts the spectra. The effect is severe when κ is concentrated or the measurements are carried out in certain geometries. Here, the correlations among emission events in compounds are examined following resonance X-ray core-electron excitation within κ. Under conditions leading to SA, If emitted from κ apparently has a conjugated relationship with the fluorescent intensities simultaneously emitted from other elements (ξ). Normalizing the former (κ) by the latter (ξ) will largely remove SA effects and reduce this nonlinear problem to a tractable linear problem. This does result in a moderate reduction of the spectral amplitude due to the so-called secondary emission from ξ excited by the emission from κ. Nonetheless, the resulting spectra will allow one to accurately determine bond distances and disorder and, in some respects, can be superior to spectra obtained via the absorption channel. For µξ < µκ and grazing incidence geometry, the amplitude reduction can be small and simple normalization is sufficient to restore the spectral integrity with remarkable accuracy. This has been instrumental in unravelling the surface and subsurface structures around cations in amorphous Ga-In-O and Zn-Sn-O films which are otherwise inaccessible due to severe SA effects. This method has also been applied to several samples with µξ ≃ µκ to examine its applicability. For these samples, the amplitude reduction is 12 ± 4% versus their standards for the data measured with the classical 45°/45° geometry. This experimental method is easy to implement. Since If from κ and ξ are measured by the same detector system, it is also superior to other methods in removing systematic errors such as detector system nonlinearity, electronic noise, and some beam instabilities, and in removing spectral imperfections due to, for example, SA effects, diffraction effects and sample inhomogeneity. The distortions resulting from the latter can be severe in the spectra measured in transmission mode.

[The ethics of fetal myelomeningocele surgery]. / Réflexions éthiques concernant la chirurgie fœtale de réparation des myéloméningocèles.

Fetal myelomeningocele surgery was introduced in France in 2014. Developments in prenatal diagnosis of neural tube defects have accompanied the development of prenatal diagnosis. This fetal surgery represents one of the three possible care paths for pregnant women faced with this prenatal diagnosis. The ethical issues of this fetal surgery are discussed and in particular regarding prenatal counselling and patient autonomy of choice.

Small Molecule SOS1 Agonists Modulate MAPK and PI3K Signaling via Independent Cellular Responses.

Activating mutations in RAS can lead to oncogenesis by enhancing downstream signaling, such as through the MAPK and PI3K pathways. Therefore, therapeutically targeting RAS may perturb multiple signaling pathways simultaneously. One method for modulating RAS signaling is to target the activity of the guanine nucleotide exchange factor SOS1. Our laboratory has discovered compounds that bind to SOS1 and activate RAS. Interestingly, these SOS1 agonist compounds elicit biphasic modulation of ERK phosphorylation and simultaneous inhibition of AKT phosphorylation levels. Here, we utilized multiple chemically distinct compounds to elucidate whether these effects on MAPK and PI3K signaling by SOS1 agonists were mechanistically linked. In addition, we used CRISPR/Cas9 gene-editing to generate clonally derived SOS1 knockout cells and identified a potent SOS1 agonist that rapidly elicited on-target molecular effects at substantially lower concentrations than those causing off-target effects. Our findings will allow us to further define the on-target utility of SOS1 agonists.

An apparatus based on an atomic force microscope for implementing tip-controlled local breakdown.

Solid-state nanopores are powerful tools for sensing of single biomolecules in solution. Fabrication of solid-state nanopores is still challenging, however; in particular, new methods are needed to facilitate the integration of pores with larger nanofluidic and electronic device architectures. We have developed the tip-controlled local breakdown (TCLB) approach, in which an atomic force microscope (AFM) tip is brought into contact with a silicon nitride membrane that is placed onto an electrolyte reservoir. The application of a voltage bias at the AFM tip induces a dielectric breakdown that leads to the formation of a nanopore at the tip position. In this work, we report on the details of the apparatus used to fabricate nanopores using the TCLB method, and we demonstrate the formation of nanopores with smaller, more controlled diameters using a current limiting circuit that zeroes the voltage upon pore formation. Additionally, we demonstrate the capability of TCLB to fabricate pores aligned to embedded topographical features on the membranes.

Diffusion tensor imaging (DTI) and Tractography of the spinal cord in pediatric population with spinal lipomas: preliminary study.

PURPOSE: Diffusion tensor imaging (DTI) allows studying the micro and macro architecture. One of the major challenges in dysraphism is to know the morphologic organization of the spinal cord. In a preliminary work, spinal lipoma was chosen for analyzing the micro-architecture parameters and fiber morphology of the spinal cord by DTI with tractography. METHODS: Twelve patients (0-8 years) related to spinal lipomas treated between May 2017 and March 2018 were included. Tractography reconstruction of the conus medullaris of 12 patients were obtained using the MedINRIA software. The diffusion parameters have been calculated by Osirix DTImap plugin. RESULTS: We found a significant difference in the FA (p = 0.024) between two age groups (< 24 months old and > 24 months old). However, no significant differences in the mean values of FA, RD, and MD between the level of the lipoma and the level above were noted. The tractography obtained in each case was coherent with morphologic sequences and reproducible. The conus medullaris was deformed and shifted. Destruction or disorganization of fibers and any passing inside the lipomas was not observed. CONCLUSIONS: Tractography of the conus medullaris in a very young pediatric population (0-8 years old) with a spinal lipoma is possible, reproductive, and allows visualization of the spinal cord within the dysraphism. Analysis of the FA shows that the presence of a lipoma seems to have an effect on the myelination of the conus medullaris. It is during the probable myelination phase that the majority of symptoms appear. Is the myelination per se the cause?

Correction to: Diffusion tensor imaging (DTI) and Tractography of the spinal cord in pediatric population with spinal lipomas: preliminary study.

The article which was recently published contained error. The figures and figure captions were interchanged during the publication process of the paper.

Discovery and Structure-Based Optimization of Benzimidazole-Derived Activators of SOS1-Mediated Nucleotide Exchange on RAS.

Son of sevenless homologue 1 (SOS1) is a guanine nucleotide exchange factor that catalyzes the exchange of GDP for GTP on RAS. In its active form, GTP-bound RAS is responsible for numerous critical cellular processes. Aberrant RAS activity is involved in ∼30% of all human cancers; hence, SOS1 is an attractive therapeutic target for its role in modulating RAS activation. Here, we describe a new series of benzimidazole-derived SOS1 agonists. Using structure-guided design, we discovered small molecules that increase nucleotide exchange on RAS in vitro at submicromolar concentrations, bind to SOS1 with low double-digit nanomolar affinity, rapidly enhance cellular RAS-GTP levels, and invoke biphasic signaling changes in phosphorylation of ERK 1/2. These compounds represent the most potent series of SOS1 agonists reported to date.

Discovery of Quinazolines That Activate SOS1-Mediated Nucleotide Exchange on RAS.

Proteins in the RAS family are important regulators of cellular signaling and, when mutated, can drive cancer pathogenesis. Despite considerable effort over the last 30 years, RAS proteins have proven to be recalcitrant therapeutic targets. One approach for modulating RAS signaling is to target proteins that interact with RAS, such as the guanine nucleotide exchange factor (GEF) son of sevenless homologue 1 (SOS1). Here, we report hit-to-lead studies on quinazoline-containing compounds that bind to SOS1 and activate nucleotide exchange on RAS. Using structure-based design, we refined the substituents attached to the quinazoline nucleus and built in additional interactions not present in the initial HTS hit. Optimized compounds activate nucleotide exchange at single-digit micromolar concentrations in vitro. In HeLa cells, these quinazolines increase the levels of RAS-GTP and cause signaling changes in the mitogen-activated protein kinase/extracellular regulated kinase (MAPK/ERK) pathway.

Discovery of Aminopiperidine Indoles That Activate the Guanine Nucleotide Exchange Factor SOS1 and Modulate RAS Signaling.

Deregulated RAS activity, often the result of mutation, is implicated in approximately 30% of all human cancers. Despite this statistic, no clinically successful treatment for RAS-driven tumors has yet been developed. One approach for modulating RAS activity is to target and affect the activity of proteins that interact with RAS, such as the guanine nucleotide exchange factor (GEF) son of sevenless homologue 1 (SOS1). Here, we report on structure-activity relationships (SAR) in an indole series of compounds. Using structure-based design, we systematically explored substitution patterns on the indole nucleus, the pendant amino acid moiety, and the linker unit that connects these two fragments. Best-in-class compounds activate the nucleotide exchange process at submicromolar concentrations in vitro, increase levels of active RAS-GTP in HeLa cells, and elicit signaling changes in the mitogen-activated protein kinase-extracellular regulated kinase (MAPK-ERK) pathway, resulting in a decrease in pERK1/2T202/Y204 protein levels at higher compound concentrations.

Small Molecule-Mediated Activation of RAS Elicits Biphasic Modulation of Phospho-ERK Levels that Are Regulated through Negative Feedback on SOS1.

Oncogenic mutation of RAS results in aberrant cellular signaling and is responsible for more than 30% of all human tumors. Therefore, pharmacologic modulation of RAS has attracted great interest as a therapeutic strategy. Our laboratory has recently discovered small molecules that activate Son of Sevenless (SOS)-catalyzed nucleotide exchange on RAS and inhibit downstream signaling. Here, we describe how pharmacologically targeting SOS1 induced biphasic modulation of RAS-GTP and ERK phosphorylation levels, which we observed in a variety of cell lines expressing different RAS-mutant isoforms. We show that compound treatment caused an increase in phosphorylation at ERK consensus motifs on SOS1 that was not observed with the expression of a non-phosphorylatable S1178A SOS1 mutant or after pretreatment with an ERK inhibitor. Phosphorylation at S1178 on SOS1 is known to inhibit the association between SOS1 and GRB2 and disrupt SOS1 membrane localization. Consistent with this, we show that wild-type SOS1 and GRB2 dissociated in a time-dependent fashion in response to compound treatment, and conversely, this interaction was enhanced with the expression of an S1178A SOS1 mutant. Furthermore, in cells expressing either S1178A SOS1 or a constitutively membrane-bound CAAX box tagged SOS1 mutant, we observed elevated RAS-GTP levels over time in response to compound, as compared with the biphasic changes in RAS-GTP exhibited in cells expressing wild-type SOS1. These results suggest that small molecule targeting of SOS1 can elicit a biphasic modulation of RAS-GTP and phospho-ERK levels through negative feedback on SOS1 that regulates the interaction between SOS1 and GRB2. Mol Cancer Ther; 17(5); 1051-60. ©2018 AACR.

Concurrent Covalent and Supramolecular Polymerization.

Covalent and supramolecular polymerizations, both of which offer their own unique advantages, have emerged as popular strategies for making artificial materials. Herein, we describe a concurrent covalent and supramolecular polymerization strategy-namely, one which utilizes 1) a bis-azide-functionalized diazaperopyrenium dication that undergoes polymeriation covalently with a bis-alkyne-functionalized biphenyl derivative in one dimension as a result of a rapid and efficient ß-cyclodextrin(CD)-accelerated, cucurbit[6]uril(CB)-templated azide-alkyne cycloaddition, while 2) the aromatic core of the dication is able to dimerize in a criss-cross fashion by dint of π-π interactions, enabling simultaneous supramolecular assembly, resulting in an extended polymer network in an orthogonal dimension.