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1.
Chemistry ; 28(9): e202104293, 2022 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-34932229

RESUMO

To investigate how remotely induced changes in ligand folding might affect catalysis by organometallic complexes, dynamic α-amino-iso-butyric acid (Aib) peptide foldamers bearing rhodium(I) N-heterocyclic carbene (NHC) complexes have been synthesized and studied. X-ray crystallography of a foldamer with an N-terminal azide and a C-terminal Rh(NHC)(Cl)(diene) complex showed a racemate with a chiral axis in the Rh(NHC) complex and a distorted 310 helical body. Replacing the azide with either one or two chiral L-α-methylvaline (L-αMeVal) residues gave diastereoisomeric foldamers that each possessed point, helical and axial chirality. NMR spectroscopy revealed an unequal ratio of diastereoisomers for some foldamers, indicating that the chiral conformational preference of the N-terminal residue(s) was relayed down the 1 nm helical body to the axially chiral Rh(NHC) complex. Although the remote chiral residue(s) did not affect the stereoselectivity of hydrosilylation reactions catalysed by these foldamers, these studies suggest a potential pathway towards remote conformational control of organometallic catalysts.


Assuntos
Compostos Heterocíclicos , Compostos Organometálicos , Ródio , Ácido Butírico , Catálise , Compostos Heterocíclicos/química , Irídio/química , Metano/análogos & derivados , Modelos Moleculares , Estrutura Molecular , Compostos Organometálicos/química , Ródio/química , Estereoisomerismo
2.
Chembiochem ; 22(9): 1656-1667, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33411956

RESUMO

The increase in resistant bacterial strains necessitates the identification of new antimicrobial molecules. Antimicrobial peptides (AMPs) are an attractive option because of evidence that bacteria cannot easily develop resistance to AMPs. The peptaibols, a class of naturally occurring AMPs, have shown particular promise as antimicrobial drugs, but their development has been hindered by their mechanism of action not being clearly understood. To explore how peptaibols might interact with membranes, circular dichroism, vibrational circular dichroism, linear dichroism, Raman spectroscopy, Raman optical activity, neutron reflectivity and molecular dynamics simulations have been used to study a small library of peptaibol mimics, the Aib-rich peptides. All the peptides studied quickly partitioned and oriented in membranes, and we found evidence of chiral interactions between the phospholipids and membrane-embedded peptides. The protocols presented in this paper open new ground by showing how chiro-optical spectroscopies can throw light on the mechanism of action of AMPs.


Assuntos
Peptídeos Catiônicos Antimicrobianos/metabolismo , Bicamadas Lipídicas/metabolismo , Simulação de Dinâmica Molecular , Peptídeos Catiônicos Antimicrobianos/química , Dicroísmo Circular , Bicamadas Lipídicas/química , Peptaibols/química , Peptaibols/metabolismo , Fosfatidilcolinas/química , Estereoisomerismo
3.
Angew Chem Int Ed Engl ; 58(27): 9171-9173, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31066186

RESUMO

Unusual demethylenation reactions of cyclopropanes under UV-light irradiation were found within a cavity of a photoactive coordination cage. The reaction proceeded via a guest-to-host electron transfer owing to the highly electron-deficient nature of the cage. The reactions were highly chemoselective and enabled late-stage derivatization of a steroid molecule, which led to a totally new un-natural steroid.

4.
J Am Chem Soc ; 140(8): 2821-2828, 2018 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-29412665

RESUMO

The Kemp elimination (reaction of benzisoxazole with base to give 2-cyanophenolate) is catalyzed in the cavity of a cubic M8L12 coordination cage because of a combination of (i) benzisoxazole binding in the cage cavity driven by the hydrophobic effect, and (ii) accumulation of hydroxide ions around the 16+ cage surface driven by ion-pairing. Here we show how reaction of the cavity-bound guest is modified by the presence of other anions which can also accumulate around the cage surface and displace hydroxide, inhibiting catalysis of the cage-based reaction. Addition of chloride or fluoride inhibits the reaction with hydroxide to the extent that a new autocatalytic pathway becomes apparent, resulting in a sigmoidal reaction profile. In this pathway the product 2-cyanophenolate itself accumulates around the cationic cage surface, acting as the base for the next reaction cycle. The affinity of different anions for the cage surface is therefore 2-cyanophenolate (generating autocatalysis) > chloride > fluoride (which both inhibit the reaction with hydroxide but cannot deprotonate the benzisoxazole guest) > hydroxide (default reaction pathway). The presence of this autocatalytic pathway demonstrates that a reaction of a cavity-bound guest can be induced with different anions around the cage surface in a controllable way; this was confirmed by adding different phenolates to the reaction, which accelerate the Kemp elimination to different extents depending on their basicity. This represents a significant step toward the goal of using the cage as a catalyst for bimolecular reactions between a cavity-bound guest and anions accumulated around the surface.

5.
Chemistry ; 24(7): 1554-1560, 2018 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-29083066

RESUMO

The cavity of an M8 L12 cubic coordination cage can accommodate a cluster of ten water molecules in which the average number of hydrogen bonds per water molecule is 0.5 H-bonds less than it would be in the bulk solution. The presence of these "hydrogen-bond frustrated" or "high-energy" water molecules in the cavity results in the hydrophobic effect associated with guest binding being predominantly enthalpy-based, as these water molecules can improve their hydrogen-bonding environment on release. This contrasts with the classical form of the hydrophobic effect in which the favourable entropy change associated with release of ordered molecules from hydrophobic surfaces dominates. For several guests Van't Hoff plots showed that the free energy of binding in water is primarily enthalpy driven. For five homologous pairs of guests related by the presence or absence of a CH2 group, the incremental changes to ΔH and TΔS for guest binding-that is, ΔΔH and TΔΔS, the difference in contributions arising from the CH2 group-are consistently 5(±1) kJ mol-1 for ΔΔH and 0(±1) kJ mol-1 for TΔΔS. This systematic dominance of ΔH in the binding of hydrophobic guests is consistent with the view that guest binding is dominated by release of "high energy" water molecules into a more favourable solvation environment, as has been demonstrated recently for some members of the cucurbituril family.

6.
Chemistry ; 23(1): 206-213, 2017 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-27879015

RESUMO

We have performed a systematic investigation of the effects of guest flexibility on their ability to bind in the cavity of a coordination cage host in water, using two sets of isomeric aliphatic ketones that differ only in the branching patterns of their alkyl chains. Apart from the expected increase in binding strength for C9 over C7 ketones associated with their greater hydrophobic surface area, within each isomeric set there is a clear inverse correlation between binding free energy and guest flexibility, associated with loss of conformational entropy. This can be parameterized by the number of rotatable C-C bonds in the guest, with each additional rotatable bond resulting in a penalty of around 2 kJ mol-1 in the binding free energy, in good agreement with values obtained from protein/ligand binding studies. We used the binding data for the new flexible guests to improve the scoring function that we had previously developed that allowed us to predict binding constants of relatively rigid guests in the cage cavity using the molecular docking programme GOLD (Genetic Optimisation of Ligand Docking). This improved scoring function resulted in a significant improvement in the ability of GOLD to predict binding constants for flexible guests, without any detriment to its ability to predict binding for more rigid guests.

7.
Gen Comp Endocrinol ; 234: 133-41, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-26393310

RESUMO

Arsenic contaminates water surface and groundwater worldwide. Several studies have suggested that arsenic acts as an endocrine disruptor in mammalian and non-mammalian species, although its chronic effect during development remains largely unknown. To address this question, life cycle exposures to 0, 0.3 and 0.8ppm of arsenate (pentavalent arsenic; As(V)) were performed in the Western clawed frog (Silurana tropicalis) from the gastrulae stage (developmental stage Nieuwkoop-Faber; NF12) until metamorphosis (NF66). Tissue samples were collected at the beginning of feeding (NF46; whole body), sexual development (NF56; liver), and at metamorphosis completion (NF66; liver and gonadal mesonephros complex). Real-time RT-PCR analysis quantified decreases in mRNA levels of genes related to estrogen- (estrogen receptor alpha and aromatase), androgen- (androgen receptor and steroid 5-alpha-reductase type 2), and cholesterol metabolism- (steroidogenic acute regulatory protein) at stage NF46. Similarly, arsenate decreased steroid 5-alpha-reductase type 2 expression in stage NF56 livers, but transcript increases were observed for both estrogen receptor alpha and steroidogenic acute regulatory protein at this stage. Given the changes observed in the expression of genes essential for proper sexual development, gonadal histological analysis was carried out in stage NF66 animals. Arsenate treatments did not alter sex ratio or produce testicular oocytes. On the other hand, arsenate interfered with thyroid hormone-related transcripts at NF66. Specifically, thyroid hormone receptor beta and deiodinase type 2 mRNA levels were significantly reduced after arsenate treatment in the gonadal mesonephros complex. This reduction in thyroid hormone-related gene expression, however, was not accompanied by any morphological changes measured. In summary, environmentally relevant concentrations of As(V) altered steroidogenesis-, sex steroid signaling- and thyroid hormone-related gene expression, although transcriptional changes varied among tissues and developmental stages.


Assuntos
Arseniatos/metabolismo , Ranidae/metabolismo , Hormônios Tireóideos/metabolismo , Animais , Estágios do Ciclo de Vida , Masculino
8.
J Environ Sci (China) ; 49: 7-27, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28007181

RESUMO

Hundreds of millions of people around the world are exposed to elevated concentrations of inorganic and organic arsenic compounds, increasing the risk of a wide range of health effects. Studies of the environmental fate and human health effects of arsenic require authentic arsenic compounds. We summarize here the synthesis and characterization of more than a dozen methylated and thiolated arsenic compounds that are not commercially available. We discuss the methods of synthesis for the following 14 trivalent (III) and pentavalent (V) arsenic compounds: monomethylarsonous acid (MMAIII), dicysteinylmethyldithioarsenite (MMAIII(Cys)2), monomethylarsonic acid (MMAV), monomethylmonothioarsonic acid (MMMTAV) or monothio-MMAV, monomethyldithioarsonic acid (MMDTAV) or dithio-MMAV, monomethyltrithioarsonate (MMTTAV) or trithio-MMAV, dimethylarsinous acid (DMAIII), dimethylarsino-glutathione (DMAIII(SG)), dimethylarsinic acid (DMAV), dimethylmonothioarsinic acid (DMMTAV) or monothio-DMAV, dimethyldithioarsinic acid (DMDTAV) or dithio-DMAV, trimethylarsine oxide (TMAOV), arsenobetaine (AsB), and an arsenicin-A model compound. We have reviewed and compared the available methods, synthesized the arsenic compounds in our laboratories, and provided characterization information. On the basis of reaction yield, ease of synthesis and purification of product, safety considerations, and our experience, we recommend a method for the synthesis of each of these arsenic compounds.


Assuntos
Arsênio/química , Arsenicais/química , Segurança Química , Saúde Ambiental , Substâncias Perigosas/química , Ecologia
9.
Small ; 11(37): 4946-58, 2015 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-26182911

RESUMO

A carbon-nanotube-enabling scanning probe technique/nanotechnology for manipulating and measuring lithium at the nano/mesoscale is introduced. Scanning Li-nanopipette and probe microscopy (SLi-NPM) is based on a conductive atomic force microscope (AFM) cantilever with an open-ended multi-walled carbon nanotube (MWCNT) affixed to its apex. SLi-NPM operation is demonstrated with a model system consisting of a Li thin film on a Si(111) substrate. By control of bias, separation distance, and contact time, attograms of Li can be controllably pipetted to or from the MWCNT tip. Patterned surface Li features are then directly probed via noncontact AFM measurements with the MWCNT tip. The subsequent decay of Li features is simulated with a mesoscale continuum model, developed here. The Li surface diffusion coefficient for a four (two) Li layer thick film is measured as D=8(±1.2)×10(-15) cm(2) s(-1) (D=1.75(±0.15)×10(-15) cm(2) s(-1)). Dual-Li pipetting/measuring with SLi-NPM enables a broad range of time-dependent Li and nanoelectrode characterization studies of fundamental importance to energy-storage research.

10.
Inorg Chem ; 54(6): 2626-37, 2015 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-25700155

RESUMO

The self-assembly between a water-soluble bis-bidentate ligand L(18w) and Co(II) salts in water affords three high-spin Co(II) products: a dinuclear meso-helicate [Co2(L(18w))3]X4; a tetrahedral cage [Co4(L(18w))6]X8; and a dodecanuclear truncated-tetrahedral cage [Co12(L(18w))18]X24 (X = BF4 or ClO4). All three products were crystallized under different conditions and structurally characterized. In [Co2(L(18w))3]X4 all three bridging ligands span a pair of metal ions; in the two larger products, there is a metal ion at each vertex of the Co4 or Co12 polyhedral cage array with a bridging ligand spanning a pair of metal ions along every edge. All three structural types are known: what is unusual here is the presence of all three from the same reaction. The assemblies Co2, Co4, and Co12 are in slow equilibrium (hours/days) in aqueous solution, and this can be conveniently monitored by (1)H NMR spectroscopy because (i) the paramagnetism of Co(II) disperses the signals over a range of ca. 200 ppm and (ii) the different symmetries of the three species give characteristically different numbers of independent (1)H NMR signals, which makes identification easy. From temperature- and concentration-dependent (1)H NMR studies it is clear that increasing temperature and increasing dilution favors fragmentation to give a larger proportion of the smaller assemblies for entropic reasons. High concentrations and low temperature favor the larger assembly despite the unfavorable entropic and electrostatic factors associated with its formation. We suggest that this arises from the hydrophobic effect: reorganization of several smaller complexes into one larger one results in a smaller proportion of the hydrophobic ligand surface being exposed to water, with a larger proportion of the ligand surface protected in the interior of the assembly. In agreement with this, (1)H NMR spectra in a nonaqueous solvent (MeNO2) show formation of only [Co2(L(18w))3]X4 because the driving force for reorganization into larger assemblies is now absent. Thus, we can identify the contributions of temperature, concentration, and solvent on the result of the metal/ligand self-assembly process and have determined the speciation behavior of the Co2/Co4/Co12 system in aqueous solution.


Assuntos
Compostos Organometálicos/química , Solventes/química , Temperatura , Cobalto/química , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Modelos Moleculares , Conformação Molecular , Água/química
11.
J Am Chem Soc ; 136(23): 8475-83, 2014 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-24841689

RESUMO

Size and shape criteria for guest binding inside the cavity of an octanuclear cubic coordination cage in water have been established using a new fluorescence displacement assay to quantify guest binding. For aliphatic cyclic ketones of increasing size (from C5 to C11), there is a linear relationship between ΔG for guest binding and the guest's surface area: the change in ΔG for binding is 0.3 kJ mol(-1) Å(-2), corresponding to 5 kJ mol(-1) for each additional CH2 group in the guest, in good agreement with expectations based on hydrophobic desolvation. The highest association constant is K = 1.2 × 10(6) M(-1) for cycloundecanone, whose volume is approximately 50% of the cavity volume; for larger C12 and C13 cyclic ketones, the association constant progressively decreases as the guests become too large. For a series of C10 aliphatic ketones differing in shape but not size, ΔG for guest binding showed no correlation with surface area. These guests are close to the volume limit of the cavity (cf. Rebek's 55% rule), so the association constant is sensitive to shape complementarity, with small changes in guest structure resulting in large changes in binding affinity. The most flexible members of this series (linear aliphatic ketones) did not bind, whereas the more preorganized cyclic ketones all have association constants of 10(4)-10(5) M(-1). A crystal structure of the cage·cycloundecanone complex shows that the guest carbonyl oxygen is directed into a binding pocket defined by a convergent set of CH groups, which act as weak hydrogen-bond donors, and also shows close contacts between the exterior surface of the disc-shaped guest and the interior surface of the pseudospherical cage cavity despite the slight mismatch in shape.

12.
Chem Res Toxicol ; 27(4): 457-61, 2014 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-24517124

RESUMO

The bioconversion of inorganic arsenic to methylated metabolites affects the tissue distribution and retention of arsenic and its actions as a toxicant or carcinogen. Although enzymes that catalyze the methylation of arsenicals have been identified in all branches of the tree of life, fundamental questions persist about the chemical processes that underlie reactions that methylate this metalloid. Here, several reaction schemes for arsenic methylation are considered to encourage careful consideration of the chemical plausibility of these schemes.


Assuntos
Arsênio/metabolismo , Metilação
13.
Nano Lett ; 13(8): 3576-80, 2013 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-23879288

RESUMO

Kelvin probe microscopy in ultrahigh vacuum is used to image the local electrostatic potential fluctuations above hexagonal boron nitride (h-BN) and SiO2, common substrates for graphene. Results are compared to a model of randomly distributed charges in a two-dimensional (2D) plane. For SiO2, the results are well modeled by 2D charge densities ranging from 0.24 to 2.7 × 10(11) cm(-2), while h-BN displays potential fluctuations 1-2 orders of magnitude lower than SiO2, consistent with the improvement in charge carrier mobility for graphene on h-BN compared to SiO2. Electron beam exposure of SiO2 increases the charge density fluctuations, creating long-lived metastable charge populations of ~2 × 10(11) cm(-2) at room temperature, which can be reversed by heating.

14.
Nano Lett ; 12(6): 2859-64, 2012 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-22563861

RESUMO

Nanoscale structure-electric potential relations in films of the organic molecular semiconductors C(60) and titanyl phthalocyanine (TiOPc) on Ag(111) have been measured under UHV conditions. Noncontact force methods were utilized to image domain structures and boundaries with molecular resolution, while simultaneously quantifying the local surface electric potential. Sensitivity and spatial resolution for the local potential measurement were first established on Ag(111) through direct observation of the electrical dipole and potential step, φ(step) = 10 ± 3 mV, of monatomic crystallographic steps. A local surface potential increase of 27 ± 11 mV occurs upon crossing the boundary between the neat Ag(111) surface and C(60) islands. Potential steps in binary C(60)-TiOPc films, nanophase-separated into crystalline C(60) and TiOPc domains, were then mapped quantitatively. The 207 ± 66 mV potential step across the C(60)-to-TiOPc domain boundary exhibits a 3.6 nm width that reflects the spatial resolution for electric potential across a material interface. The absence of potential asymmetry across this lateral interface sets the upper bound for the C(60)-TiOPc interface dipole moment as 0.012 e nm.


Assuntos
Nanopartículas Metálicas/química , Nanopartículas Metálicas/ultraestrutura , Microscopia de Varredura por Sonda/métodos , Teste de Materiais , Tamanho da Partícula , Vácuo
15.
Nat Med ; 11(5): 556-61, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15834427

RESUMO

One of the most clinically advanced forms of experimental disease-modifying treatment for Alzheimer disease is immunization against the amyloid beta protein (Abeta), but how this may prevent cognitive impairment is unclear. We hypothesized that antibodies to Abeta could exert a beneficial action by directly neutralizing potentially synaptotoxic soluble Abeta species in the brain. Intracerebroventricular injection of naturally secreted human Abeta inhibited long-term potentiation (LTP), a correlate of learning and memory, in rat hippocampus in vivo but a monoclonal antibody to Abeta completely prevented the inhibition of LTP when injected after Abeta. Size fractionation showed that Abeta oligomers, not monomers or fibrils, were responsible for inhibiting LTP, and an Abeta antibody again prevented such inhibition. Active immunization against Abeta was partially effective, and the effects correlated positively with levels of antibodies to Abeta oligomers. The ability of exogenous and endogenous antibodies to rapidly neutralize soluble Abeta oligomers that disrupt synaptic plasticity in vivo suggests that treatment with such antibodies might show reversible cognitive deficits in early Alzheimer disease.


Assuntos
Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/imunologia , Anticorpos Monoclonais/imunologia , Hipocampo/metabolismo , Imunização/métodos , Fragmentos de Peptídeos/imunologia , Doença de Alzheimer/imunologia , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/farmacologia , Animais , Anticorpos Monoclonais/metabolismo , Células CHO , Cromatografia em Gel , Cricetinae , Cricetulus , Eletrofisiologia , Ensaio de Imunoadsorção Enzimática , Imuno-Histoquímica , Imunoprecipitação , Potenciação de Longa Duração/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Testes de Neutralização , Fragmentos de Peptídeos/farmacologia , Ratos , Sinapses/fisiologia
16.
J Environ Monit ; 14(3): 743-51, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22193982

RESUMO

Terrestrial snails are consumed by humans occasionally and they are an important food source for many creatures including fish and birds. Little is known about arsenic speciation in these gastropods, let alone life cycle variations. Here we report on the arsenic speciation in freshwater snails from Pender Island and Vancouver Island, B.C., Canada, which was determined on methanol/water extracts (43-59% extraction efficiency) by using high performance liquid chromatography-inductively coupled plasma-mass spectrometry (HPLC-ICP-MS) and HPLC-electrospray tandem mass spectrometry. The tetramethylarsonium ion, oxo-arsenosugars and thio-arsenosugars are the main arsenic species encountered. Arsenobetaine, which is commonly found in the marine environment, is minor. Live bearing snails Viviparidae sp. from Pender Island were maintained in aquaria and the arsenic speciation in the unborn, newly born, and adult animals was monitored. Oxo-arsenosugars predominate in the adults, whereas thio-arsenosugars seem to predominate in juveniles, suggesting that these arsenicals are snail metabolites.


Assuntos
Arsênio/metabolismo , Caramujos/metabolismo , Poluentes Químicos da Água/metabolismo , Animais , Arsênio/análise , Colúmbia Britânica , Monitoramento Ambiental , Água Doce/química , Estágios do Ciclo de Vida , Poluentes Químicos da Água/análise
17.
Proc Natl Acad Sci U S A ; 105(43): 16418-25, 2008 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-18765797

RESUMO

Low-dimensional boundaries between phases and domains in organic thin films are important in charge transport and recombination. Here, fluctuations of interfacial boundaries in an organic thin film, acridine-9-carboxylic acid on Ag(111), have been visualized in real time and measured quantitatively using scanning tunneling microscopy. The boundaries fluctuate via molecular exchange with exchange time constants of 10-30 ms at room temperature, with length-mode fluctuations that should yield characteristic f(-1/2) signatures for frequencies less than approximately 100 Hz. Although acridine-9-carboxylic acid has highly anisotropic intermolecular interactions, it forms islands that are compact in shape with crystallographically distinct boundaries that have essentially identical thermodynamic and kinetic properties. The physical basis of the modified symmetry is shown to arise from significantly different substrate interactions induced by alternating orientations of successive molecules in the condensed phase. Incorporating this additional set of interactions in a lattice-gas model leads to effective multicomponent behavior, as in the Blume-Emery-Griffiths model, and can straightforwardly reproduce the experimentally observed isotropic behavior. The general multicomponent description allows the domain shapes and boundary fluctuations to be tuned from isotropic to highly anisotropic in terms of the balance between intermolecular interactions and molecule-substrate interactions.

19.
Rev Sci Instrum ; 91(7): 071101, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32752869

RESUMO

Research in new quantum materials requires multi-mode measurements spanning length scales, correlations of atomic-scale variables with a macroscopic function, and spectroscopic energy resolution obtainable only at millikelvin temperatures, typically in a dilution refrigerator. In this article, we describe a multi-mode instrument achieving a µeV tunneling resolution with in-operando measurement capabilities of scanning tunneling microscopy, atomic force microscopy, and magnetotransport inside a dilution refrigerator operating at 10 mK. We describe the system in detail including a new scanning probe microscope module design and sample and tip transport systems, along with wiring, radio-frequency filtering, and electronics. Extensive benchmarking measurements were performed using superconductor-insulator-superconductor tunnel junctions, with Josephson tunneling as a noise metering detector. After extensive testing and optimization, we have achieved less than 8 µeV instrument resolving capability for tunneling spectroscopy, which is 5-10 times better than previous instrument reports and comparable to the quantum and thermal limits set by the operating temperature at 10 mK.

20.
J Neurosci ; 28(16): 4231-7, 2008 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-18417702

RESUMO

The current development of immunotherapy for Alzheimer's disease is based on the assumption that human-derived amyloid beta protein (Abeta) can be targeted in a similar manner to animal cell-derived or synthetic Abeta. Because the structure of Abeta depends on its source and the presence of cofactors, it is of great interest to determine whether human-derived oligomeric Abeta species impair brain function and, if so, whether or not their disruptive effects can be prevented using antibodies. We report that untreated ex vivo human CSF that contains Abeta dimers rapidly inhibits hippocampal long-term potentiation in vivo and that acute systemic infusion of an anti-Abeta monoclonal antibody can prevent this disruption of synaptic plasticity. Abeta monomer isolated from human CSF did not affect long-term potentiation. These results strongly support a strategy of passive immunization against soluble Abeta oligomers in early Alzheimer's disease.


Assuntos
Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/imunologia , Imunização Passiva/métodos , Plasticidade Neuronal/imunologia , Sinapses/imunologia , Doença de Alzheimer/imunologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/administração & dosagem , Animais , Anticorpos Monoclonais/administração & dosagem , Células CHO , Cricetinae , Cricetulus , Dimerização , Humanos , Potenciação de Longa Duração/imunologia , Masculino , Ratos , Ratos Wistar
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