Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease and the main cause of motor neuron pathology. The etiology of the disease remains unknown, and no effective therapy ...exists to halt the disease or improve the quality of life. Here, we provide compelling evidence for the existence of fungal infection in ALS. Immunohistochemistry analysis using a battery of antifungal antibodies revealed fungal structures such as yeast and hyphae in the motor cortex, the medulla and the spinal cord, in eleven patients with ALS. Some fungal structures were localized intracellularly and even intranuclearly, indicating that this infection is not the result of post-mortem colonization. By contrast, this burden of fungal infection cannot be observed in several CNS areas of control subjects. PCR analysis and next generation sequencing of DNA extracted from frozen neural tissue identified a variety of fungal genera including Candida, Malassezia, Fusarium, Botrytis, Trichoderma and Cryptococcus. Overall, our present observations provide strong evidence for mixed fungal infections in ALS patients. The exact mixed infection varies from patient to patient consistent with the different evolution and severity of symptoms in each ALS patient. These novel findings provide a logical explanation for the neuropathological observations of this disease, such as neuroinflammation and elevated chitinase levels, and could help to implement appropriate therapies.
•Tissue sections from different regions of the CNS of ALS patients contain fungi.•These fungi are detected by immunohistochemistry with several antifungal antibodies.•Some fungi are intracellular indicating that this is not a post-mortem colonization.•CNS tissue from control subjects does not exhibit this burden of fungal infection.•The species present in CNS tissue have been identified by next generation sequencing.
A strategy to create cooperative hydrogen‐bonding centers by using strong and directional intramolecular hydrogen‐bonding motifs that can survive in aqueous media is presented. In particular, ...glyco–oligoamides, a family of DNA minor groove binders, with cooperative and non‐cooperative hydrogen‐bonding donor centers in the carbohydrate residues have been designed, synthesized, and studied by means of NMR spectroscopy and molecular modeling methods. Indeed, two different sugar moieties, namely, β‐D‐Man‐Py‐γ‐Py‐Ind (1; Ind=indole, Man=mannose, Py=pyrrole) and β‐D‐Tal‐Py‐γ‐Py‐Ind (2; Tal=talose), were chosen according to our design. These sugar molecules should present one‐ or two‐directional intramolecular hydrogen bonds. The challenge has been to study the conformation of the glyco–oligoamides at low temperature in physiological media by detecting the exchangeable protons (amide NH and OH resonances) by means of NMR spectroscopic analysis. In addition, two more glyco–oligoamides with non‐cooperative hydrogen‐bonding centers, that is, β‐D‐Glc‐Py‐γ‐Py‐Ind (3; Glc=glucose), β‐D‐Gal‐Py‐γ‐Py‐Ind (4; Gal=galactose), and the model compounds β‐D‐Man‐Py‐NHAc (5) and β‐D‐Tal‐Py‐NHAc (6) were synthesized and studied for comparison. We have demonstrated the existence of directional intramolecular hydrogen bonds in 1 and 2 in aqueous media. The unexpected differences in terms of stabilization of the intramolecular hydrogen bonds in 1 and 2 relative to 5 and 6 promoted us to evaluate the influence of CH—π interactions on the establishment of intramolecular hydrogen bonds by using computational methods. Initial binding studies of 1 and 2 with calf‐thymus DNA and poly(dA‐dT)2 by NMR spectroscopic analysis and molecular dynamics simulations were also carried out. Both new sugar–oligoamides are bound in the minor groove of DNA, thus keeping a stable hairpin structure, as in the free state, in which both intramolecular hydrogen‐bonding and CH—π interactions are present.
A stable influence: Glyco–oligoamides, a family of DNA minor groove binders, with cooperative and non‐cooperative hydrogen‐bonding donor centers in the carbohydrate residues have been designed, synthesized, and studied by NMR spectroscopy and molecular modeling methods. Both intramolecular hydrogen‐bonding and CH—π interactions are present in the binding of these new sugar–oligoamides.
Multiwalled carbon nanotubes grown on gold electrodes manufactured by microtechnology techniques have been used as a platform for oriented and stable immobilization of a Ni−Fe hydrogenase. ...Microscopic and electrochemical characterization of the system are presented. High-density currents due to H2 oxidation electrocatalysis, stable for over a month under continuous operational conditions, were measured. The functional properties of this nanostructured hydrogenase electrode are suitable for hydrogen biosensing and biofuel applications.
Abstract
The radio galaxy M87 is the central dominant galaxy of the Virgo Cluster. Very high-energy (VHE, ≳0.1 TeV) emission from M87 has been detected by imaging air Cherenkov telescopes. Recently, ...marginal evidence for VHE long-term emission has also been observed by the High Altitude Water Cherenkov Observatory, a gamma-ray and cosmic-ray detector array located in Puebla, Mexico. The mechanism that produces VHE emission in M87 remains unclear. This emission originates in its prominent jet, which has been spatially resolved from radio to X-rays. In this paper, we construct a spectral energy distribution from radio to gamma rays that is representative of the nonflaring activity of the source, and in order to explain the observed emission, we fit it with a lepto-hadronic emission model. We found that this model is able to explain nonflaring VHE emission of M87 as well as an orphan flare reported in 2005.
A new perovskite cathode, Sr0.95Ce0.05CoO3−δ, performs well for oxygen-reduction reactions in solid oxide fuel cells (SOFCs). We gain insight into the crystal structure of Sr1–x Ce x CoO3−δ (x = ...0.05, 0.1) and temperature-dependent structural evolution of Sr0.95Ce0.05CoO3−δ by X-ray diffraction, neutron powder diffraction, and scanning transmission electron microscopy experiments. Sr0.9Ce0.1CoO3−δ shows a perfectly cubic structure (a = a 0), with a large oxygen deficiency in a single oxygen site; however, Sr0.95Ce0.05CoO3−δ exhibits a tetragonal perovskite superstructure with a double c axis, defined in the P4/mmm space group, that contains two crystallographically different cobalt positions, with distinct oxygen environments. The structural evolution of Sr0.95Ce0.05CoO3−δ at high temperatures was further studied by in situ temperature-dependent NPD experiments. At 1100 K, the oxygen atoms in Sr0.95Ce0.05CoO3−δ show large and highly anisotropic displacement factors, suggesting a significant ionic mobility. The test cell with a La0.8Sr0.2Ga0.83Mg0.17O3−δ-electrolyte-supported (∼300 μm thickness) configuration yields peak power densities of 0.25 and 0.48 W cm–2 at temperatures of 1023 and 1073 K, respectively, with pure H2 as the fuel and ambient air as the oxidant. The electrochemical impedance spectra evolution with time of the symmetric cathode fuel cell measured at 1073 K shows that the Sr0.95Ce0.05CoO3−δ cathode possesses superior ORR catalytic activity and long-term stability. Mixed ionic–electronic conduction properties of Sr0.95Ce0.05CoO3−δ account for its good performance as an oxygen-reduction catalyst.
This paper reviews the present state of the catalytic enantioselective Reformatsky reaction. Advancements in asymmetric versions of this reaction have recently led to a considerable extension of its ...scope and applicability, principally due to the use of highly active chiral ligands and very specific reaction conditions.
This paper reviews the current status of the catalytic enantioselective Reformatsky reaction. Advancements in asymmetric versions of this reaction have recently led to a considerable extension of its scope and applicability, principally due to the use of highly active chiral ligands and very specific reaction conditions.
Detection of molecular recognition processes requires robust, specific, and easily implementable sensing methods, especially for screening applications. Here, we propose the difluoroacetamide moiety ...(an acetamide bioisoster) as a novel tag for detecting by NMR analysis those glycan–protein interactions that involve N‐acetylated sugars. Although difluoroacetamide has been used previously as a substituent in medicinal chemistry, here we employ it as a specific sensor to monitor interactions between GlcNAc‐containing glycans and a model lectin (wheat germ agglutinin). In contrast to the widely employed trifluoroacetamide group, the difluoroacetamide tag contains geminal 1H and 19F atoms that allow both 1H and 19F NMR methods for easy and robust detection of molecular recognition processes involving GlcNAc‐ (or GalNAc‐) moieties over a range of binding affinities. The CHF2CONH‐ moiety behaves in a manner that is very similar to that of the natural acetamide fragment in the involved aromatic‐sugar interactions, providing analogous binding energy and conformations, whereas the perfluorinated CF3CONH‐ analogue differs more significantly.
Monitoring glycan/protein interactions: A simple chemical tag (see figure) that can be used to monitor glycan–protein molecular recognition by NMR spectroscopic analysis has been devised. The chemical nature of the tag permits the easy and straightforward detection of interactions between the partners and allows the glycan binding epitope to be deduced.
It is widely accepted that the tumor microenvironment, particularly the extracellular matrix, plays an essential role in the development of tumors through the interaction with specific ...protein-membrane receptors. One of the most relevant proteins in this context is the transmembrane protein CD44. The role of CD44 in tumor progression, invasion, and metastasis has been well established in many cancers, although a comprehensive review concerning its role in sarcomas has not been published. CD44 is overexpressed in most sarcomas and several
in vitro
and
in vivo
experiments have shown a direct effect on tumor progression, dissemination, and drug resistance. Moreover, CD44 has been revealed as a useful marker for prognostic and diagnostic (CD44v6 isoform) in osteosarcoma. Besides, some innovative treatments such as HA-functionalized liposomes therapy have become an excellent CD44-mediated intracellular delivery system for osteosarcoma. Unfortunately, the reduced number of studies deciphering the prognostic/diagnostic value of CD44 in other sarcoma subgroups, neither than osteosarcoma, in addition to the low number of patients involved in those studies, have produced inconclusive results. In this review, we have gone through the information available on the role of CD44 in the development, maintenance, and progression of sarcomas, analyzing their implications at the prognostic, therapeutic, and mechanistic levels. Moreover, we illustrate how research involving the specific role of CD44 in the different sarcoma subgroups could suppose a chance to advance towards a more innovative perspective for novel therapies and future clinical trials.
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