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Alzheimer's disease is a progressive neurodegenerative disorder characterized by the abnormal processing of the Tau and the amyloid precursor proteins. The unusual aggregation of Tau is based on the formation of intermolecular β-sheets through two motifs: 275 VQIINK280 and 306 VQIVYK311 . Phenylthiazolyl-hydrazides (PTHs) are capable of inhibiting/disassembling Tau aggregates. However, the disaggregation mechanism of Tau oligomers by PTHs is still unknown. In this work, we studied the disruption of the oligomeric form of the Tau motif 306 VQIVYK311 by PTHs through molecular docking, molecular dynamics, and free energy calculations. We predicted hydrophobic interactions as the major driving forces for the stabilization of Tau oligomer, with V306 and I308 being the major contributors. Nonpolar component of the binding free energy is essential to stabilize Tau-PTH complexes. PTHs disrupted mainly the van der Waals interactions between the monomers, leading to oligomer destabilization. Destabilization of full Tau filament by PTHs and emodin was not observed in the sampled 20 ns; however, in all cases, the nonpolar component of the binding free energy is essential for the formation of Tau filament-PTH and Tau filament-emodin. These results provide useful clues for the design of more effective Tau-aggregation inhibitors.

The 1,3 dipolar cycloaddition reactions of three pentose-derived pyrroline N-oxides with mono- and disubstituted alkenes are reported. A strong dependence of the diastereoselectivity of the cycloadditions on the relative configuration of the nitrone stereocentres was observed. Further transformation of the reaction products allowed the synthesis of four new tetrahydroxylated indolizidines. Their activity as glycosidase inhibitors was evaluated against a panel of commercially available glycosidases. The specificity of inhibitory activity against amyloglucosidase and α-mannosidases depends on the configuration at C-2 of the indolizidine moiety.

Previous studies have shown that organophosphate pesticide (OP) exposure is associated with oxidative stress. Methamidophos (MET) is an OP widely used in agriculture, which is regarded as a highly toxic pesticide and it is a potent inhibitor of acetylcholinesterase. The aim of this study was to evaluate whether MET can induce oxidative stress at low concentrations in primary cultures of human peripheral blood mononuclear cells (PBMCs). PBMCs from healthy individuals were exposed to MET (0-80 mg/L) for 0-72 h. We performed the MTT and neutral-red assays to assess the cytotoxicity. As indicators of oxidative stress, the levels of reactive oxygen species (ROS) were assessed using flow cytometry, and the malondialdehyde (MDA) and reduced glutathione (GSH) levels were determined. MET decreased the viability of PBMCs in a dose-dependent manner. At concentrations of 3, 10, or 20 mg/L for 24 h, MET increased the ROS production significantly compared with the vehicle control. Similarly, MET increased the levels of MDA at the same concentrations that increased ROS (10 and 20 mg/L); however, no changes in GSH levels were observed. These results suggest that MET increased the generation of oxidative stress in PBMCs. © 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 147-155, 2017.

A general strategy for the synthesis of diversely substituted 3,4,5-trihydroxypiperidines (including two natural products), 5-amino-3,4-dihydroxypiperidines, 3,4,5-trihydroxypipecolic acids, and 2-(aminomethyl)-3,4,5-trihydroxypiperidines is reported. The procedure used a double reductive amination or a Strecker reaction, starting from differently protected aldehydes readily synthesized on a gram scale from D-mannose. The biological activities of the target compounds were evaluated, and some of them showed moderate inhibition of α-L-fucosidase and β-glucosidase.

Two different lithiated alkoxyallenes and the enantiopure L-erythrose-derived cyclic nitrone (+)-3 were used as precursors for the preparation of novel bicyclic 2H-1,2-oxazine derivatives, which were formed as single diastereomers. A highly stereoselective hydroboration/oxidation sequence provided key substrates that were suitable for the synthesis of a series of polyhydroxylated bicyclic N-heterocycles, including unique 5-oxaindolizidines such as 8 and 12. Depending on the protecting groups installed, a straightforward ring-opening/recyclization protocol allowed the preparation of the corresponding pyrrolizidines bearing two, three or four free hydroxy groups. By inversion of the order of reaction steps, the synthesis of novel isomeric azabicyclo[3.2.0]heptane derivatives that are the lower homologues of pyrrolizidines and indolizidines were achieved. The prepared novel polyhydroxylated compounds were examined for their property as glycosidase inhibitors, but none of the compounds showed noteworthy activity.

To probe the utility of a multivalent approach for fucosidase inhibition, a series of di- and tri-valent imino sugars based on L-fuco-configured 1,4-imino- and 1,4-bis(imino)-cyclitol epitopes has been synthesized and analyzed for fucosidase inhibition with the best trivalent species yielding a modest improvement in binding constant. Structural analysis of a representative pair of mono- and tri-valent imino sugars has been performed on a bacterial fucosidase, BtFuc2970. The 3D structures show binding of the imino-cyclitol in the 3E conformation, consistent with the known pathway for fucosidase action.

Objective The aim of this study was to determine whether treated, weight-stabilized adolescents with anorexia nervosa (AN) present brain volume differences in comparison with healthy controls. Method Thirty-five adolescents with weight-recovered AN and 17 healthy controls were assessed by means of psychopathology scales and magnetic resonance imaging. Axial three-dimensional T1-weighted images were obtained in a 1.5 Tesla scanner and analyzed using optimized voxel-based morphometry (VBM). Results There were no significant differences between controls and weight-stabilized AN patients with regard to global volumes of either gray or white brain matter, or in the regional VBM study. Differences were not significant between patients with psychopharmacological treatment and without, between those with amenorrhea and without, as well as between patients with restrictive versus purgative AN. Discussion The present findings reveal no global or regional gray or white matter abnormalities in this sample of adolescents following weight restoration. © 2013 Wiley Periodicals, Inc. (Int J Eat Disord 2013; 46:841–848)

The synthesis of three tetrahydroxyindolizidines and one tetrahydroxypyrrolizidine related to natural hyacinthacines B and their biological evaluation as glycosidase inhibitors is reported. The target molecules were obtained through highly stereoselective cycloadditions between sugriched allylic and homoallylic alcohols. This allowed the installation of a methyl group at C5 – a common feature of many natural hyacinthacines – with high control over the stereoselectivity. The new compounds inhibit amyloglucosidase from Aspergillus niger and β-glucosidase from almonds. Compound 1 is a competitive inhibitor of amyloglucosidase and shows a fair selectivity towards this enzyme. The presence of C5-Me substitution in indolizidines 2 and 3 slightly diminishes the inhibitory activity towards amyloglucosidase whereas it improves the inhibitory properties towards β-glucosidase.

The 1,3 dipolar cycloaddition reactions of three pentose-derived pyrroline N-oxides with mono- and disubstituted alkenes are reported. A strong dependence of the diastereoselectivity of the cycloadditions on the relative configuration of the nitrone stereocentres was observed. Further transformation of the reaction products allowed the synthesis of four new tetrahydroxylated indolizidines. Their activity as glycosidase inhibitors was evaluated against a panel of commercially available glycosidases. The specificity of inhibitory activity against amyloglucosidase and α-mannosidases depends on the configuration at C-2 of the indolizidine moiety.

Enantiopure 3,6-dihydro-2H-1,2-oxazines were prepared by [3+3] cyclisations starting from lithiated methoxyallene and the L-erythrose-derived nitrones 1′ and 3. The role of the side-chain protective group, which steers the highly selective formation of either anti- or syn-configured products, was demonstrated. A hydroboration/oxidation protocol smoothly converted 1,2-oxazine derivative syn-5 into secondary alcohol 6. After deprotection, polyhydroxylated tetrahydro-2H-1,2-oxazine 11, which can be regarded as an azasugar, was isolated. Analogous treatment of 1,2-oxazine anti-5 with the borane not only provided the expected secondary alcohol 7, but it also induced reduction of the C=C bond and ring opening. Treatment of syn-5 and anti-2 with hydrochloric acid in methanol induced deprotections and cyclisations leading to bicyclic tetrahydro-2H-1,2-oxazine derivatives. The second ring can be either a furan or a pyran ring. In the syn series, furan derivative 12 was formed exclusively, and its hydrogenolysis led to enantiopure aminofuran derivative 14. Acid-promoted rearrangement of unprotected anti-2 led to a mixture of bicyclic compounds with furan or pyran rings fused to the 1,2-oxazine core. However, when TBDPS-protected compound 20 was used it cleanly led to 1,2-oxazine 21 with a fused furan ring and then to aminofuran 22. Alternatively, the N–O bond in unprotected anti-2 was chemoselectively reduced with samarium diiodide, efficiently generating highly functionalized allylic alcohol 23. Acid-promoted cyclisation and deprotection furnished furan derivative 24. Mechanistic suggestions to explain the different outcomes of the acid-induced transformations are provided. Overall, it is demonstrated that the stereodivergent addition of lithiated alkoxyallenes to L-erythrose-derived nitrones allow flexible access to a series of enantiopure amino polyols, including aminofuran derivatives.

The total synthesis of natural (+)-hyacinthacine A1 (6), (+)-7a-epi-hyacinthacine A1 (7) and their 6-hydroxy analogues 21 and 16 was achieved using a nitrone cycloaddition strategy with D-ribose-derived cyclic nitrone 8 as the dipole and tert-butyl acrylate as the dipolarophile. After separation of the adducts, reductive cleavage of the N–O bond followed by lactam reduction and deprotection afforded the two non-natural hydroxy analogues in excellent yields. The synthesis of (+)-hyacinthacine A1 (6) and of (+)-7a-epi-hyacinthacine A1 (7), which required deoxygenation at C(6), was accomplished by DIBAL-H reduction of mesylate derivatives of the pyrrolizidinols 20 and 15, respectively. Evaluation of the synthesized compounds against a panel of 12 commercially available glycosidases showed that hyacinthacine A1 (6) and its (6R)-hydroxy analogue 21 are good inhibitors of amyloglucosidase; the non-natural compound 21 is also a strong inhibitor of β-glucosidase, while 6 showed only moderate inhibition. The non-natural (+)-7a-epi-hyacinthacine A1 (7) is a moderate inhibitor of amyloglucosidase and α-L-fucosidase; the presence of the (6S)-hydroxy group in 16 led to diminished activity.

We studied 127 samples of bivalve mollusks (Mediterranean mussel, Mytilus galloprovincialis; smooth clam, Callista chione; grooved carpet-shell clam, Tapes decussatus; and striped venus clam, Chamelea gallina) obtained in the winter and spring of 2009 from retail fish and shellfish vendors in Granada, Spain. Samples were analyzed (raw and after steaming) to determine the prevalence of Escherichia coli, mesophilic aerobes, Staphylococcus aureus and the disease-causing microorganisms Salmonella spp., Listeria monocytogenes and Vibrio parahaemolyticus. E. coli was found in 25% of raw samples and 4% of cooked samples. Aerobes were found in 89% of raw samples (more than 1,000 cfu/g), and S. aureus was found in 37.0%. Only one raw sample was positive for V. parahaemolyticus. The percentage of positive findings was fourfold as high in the spring sample as in the winter sample. Contamination was most frequent in the smooth clam, and samples obtained on Mondays were more frequently contaminated than those obtained on other days of the week. PRACTICAL APPLICATIONS Current Spanish legislation establishes that all bivalve mollusks intended for commercial sale and human consumption must be treated at a detoxification center. The application of detoxification is of fundamental importance because it constitutes a barrier against the transmission of bacterial and viral diseases of aquatic origin. We analyzed possible differences in contamination parameters in this type of shellfish, indicated characteristics that may be affected by alterations in quality, and discussed the potential effects of these alterations on human health.

A new furyl amino acid derivative was trimerized to give a linear peptide and finally was cyclized. The newly generated cyclopeptide was subjected to a conformational study in order to be considered as a C 3 -symmetric platform for the rational design of complex receptors. Moreover, the recognition properties towards cyanide, acetate and chloride anions were studied.

The synthesis of two new furyl amino acids as rigid isosteres of the dipeptides (D)-H-Ser-(D,L)-Thr-OH and (L)-H-Ser-(D,L)-Thr-OH is presented. The developed synthetic methodology starts from D-xylose and D-arabinose and makes use of trihydroxypropylfurans as intermediates. The key step of the strategy is the introduction of an amino function at the α-position of the adequate trihydroxypropylfuran derivative. This methodology was also applied to the synthesis of two new (2R,3R)-3-furylisoserines as analogues of the C-13 Taxol/Taxotere side chain.

Summary Nitrogen balances were done on children affected with chronic severe malnutrition while on a diet of corn-meal and beans with and without lysine and tryptophane supplements. Calculated as per cent of intake both absorption and retention of nitrogen were greater when the supplement was added to the basal diet. Du metabolisme protoique dans la sous-alimentation chronique grave (Kwashiorkor). 2. Influence des supplements amino-acides sur l'absorption et la retention d'azotes dans le regime dietetique au mais et aux legumineuses. Chez des enfants souffrant de sous-alimentation chronique grave, des balances ont eteetablies pendant un regime dietetique de farine de mais et des legumineuses, avec et sans supplements de lysine et de tryptophane. Calculees en pourcentages de matiere ingeree, l'absorption aussi bien que la retention d'azotes ont ete plus grandes lorsque le suppleement etait ajouto au regime fondamental. Eiweisstoffwechsel in schwerer chronischer Unterernahrung (Kwashiorkor). 2. Einfluss erganzender Aminosauren auf die Absorption und Retention von Stickstoff bei einer Mais-und Bohnendiat. Stickstoffbilanzuntersuchungen wurden bei Kindern mit schwerer chronischer Unternahrung, die an einer Maismehl-und Bohnendiat mit und ohne Zusatz von Lysin und Tryptophan gehalten waren, durchgefuhrt. Es zeigte sich, dass sowohl die Absorption als auch die Retention von Stickstoff, ausgedruckt in Prozenten der Einnahme, grosser war, wenn die zugrundeliegende Diat die zusatzlichen Aminosauren enthielt. Metabolismo proteico en la desnutricion cronica grave (Kwashiorkor) 2. Influencia de los suplementos aminoacidos en la absorcion y retencion nitrogenicas bajo un regimen dietetico de maiz y legurninosas. Establecieronse balanzas nitrogenicas de ninos afectos de desnutricion cronica grave, mientras quedaban sometidos a un regimen dietetico de harina de maiz y leguminosas, con y sin suplementos de lisinas y triptofano. Calculadas en porcentajes de materia ingerida, tanto la absorcion como la retencion del nitrogeno, fueron mayores al ser anadido el suplemento a la dieta fundamental.

The primary goals for most ground water capture systems (i.e., pump-and-treat systems) are that (1) all contaminants within zones of interest will eventually be captured and (2) the extraction and reinjection wells are best located and operated at optimal flow rates, creating hydraulically efficient flow systems. A new tool, MODular ALLocation (MODALL), is presented to aid in the design and assessment of capture systems. MODALL uses the MODFLOW-calculated cell-by-cell flow terms to evaluate internodal flow balances to determine the percentage of flow in each cell which has either originated from a given source(s) or flows to a specified sink(s). Output from MODALL can be easily displayed in isopleths of "capture fraction" (CF) to indicate the certainty or strength of capture in various areas. MODALL results are compared to the results from an analytical solution, a pathline analysis using MODPATH, and solute transport simulation with MT3DMS. A brief case study is also presented where MODALL is used to optimize an existing pump-and-treat system to more effectively and more efficiently contain a 5000-m long plume.

Partitioning interwell tracer tests (PITTs) have been proposed as a tool to characterize source zones of waste sites with chemicals entrapped in the form of nonaqueous-phase liquids (NAPLs). This technique has the potential to be applied to NAPL source characterization of both the vadose and saturated zones, but the recent applications have been primarily focused on dense NAPLs (DNAPLs) entrapped below the water table. This study presents an intermediate-scale experiment to investigate the applicability of the technique to heterogeneous sites with complex NAPL entrapment architecture. Tracer experiments were conducted in an intermediate-scale test tank (4.87 by 1.21 by 0.05 m) with heterogeneity defined using the geostatistical parameters of a spatially correlated random field. Tetrachloroethene (PCE), a DNAPL, was spilled into the heterogeneous packing and was allowed to distribute naturally, creating zones of both residual and pooled entrapment. The saturation distribution of the DNAPL was determined in situ using a gamma attenuation system. Once the saturation distribution was characterized, a set of tracer tests was conducted. Results of this study demonstrate how the inversion of the tracer breakthrough concentrations provided valuable information to establish the validity of the use of equilibrium partition coefficients in situations where tracer partitioning might be controlled by nonequilibrium behavior. While our previous work quantified the estimation error introduced by the assumption of equilibrium partitioning in tracer data analysis, this study demonstrated that more accurate NAPL estimates can be obtained using effective partition coefficients in combination with inverse modeling methods upscaled for more realistic heterogeneous settings.

Straightforward strategies for the synthesis of diversely functionalized polyhydroxy and polyhydroxyamino piperidines are presented, starting from aldehydes (I) or (V).

The initiatory reaction between nitrone (I) and alkoxyallenes yields novel bicyclic 2H-1,2-oxazine derivatives (III), which are obtained as single diastereomers.

The ring strain of (7-hetero)norbornene and (7-hetero)norbornane systems is exploited in the opening of (7-hetero)bicyclic skeletons containing a β-ketosulfone/ester functionality through a retro-Dieckmann type reaction.

Objective The current article describes the case of a 13-year-old girl with body dysplasia, anorexia nervosa, and obsessive-compulsive disorder (OCD). Method She was given cognitive-behavioral therapy and pharmacologic treatment for the obsessive-compulsive symptomatology and exogenous growth hormone to increase her height. Results She experienced an adequate weight and height increase and remission of obsessive-compulsive symptomatology, and reestablished adequate social and academic functioning. Conclusion After a follow-up of almost 2 years, she had had her menarche, continued her positive eating habits, and had not relapsed into OCD. © 2005 by Wiley Periodicals, Inc.

A stereocontrolled synthesis of norphenyl hyperolactone C together with its utility as a direct precursor to the anti-HIV agent hyperolactone C and analogues by addition of organolithiums, are described. Preliminary studies to access this key building block in a catalytic enantioselective manner are also reported.

The method can be extended to the preparation of di- and tripeptides without epimerization.

We present herein a selection of ingenious methods that have been developed to convert inexpensive furan, pyrrole and unsaturated hydrocarbons into enantiomerically enriched monosaccharides and analogues of biological interest.

Since the discovery of the 'formose reaction' by Butlerow, total synthesis of carbohydrates has undergone rapid development. The most important methods for the asymmetric synthesis of monosaccharides and analogues of biological importance are presented. Nowadays any natural and non-natural monosaccharide can be prepared pure in both enantiomeric forms starting from inexpensive starting materials. Metal-based asymmetric catalysis and organocatalysis have been successfully applied, alone or in combination with chemoenzymatic methods. Alternative methods rely upon substrate- or reagent-controlled diastereo- and enantioselective reactions. Suitably protected carbohydrates have been prepared by total synthesis, thus allowing their direct use in the preparation of oligosaccharides and analogues.

A review dealing with 1,4-iminoalditol (hydroxylated pyrrolidine) derivatives as inhibitors of alpha-L-fucosidases including the different synthetic approaches for their preparation as well as their inhibitory properties is presented.

Efficient methodologies for the synthesis of regioisomeric 3-pyrrolines by reaction of electron-deficient imines and sulfur-containing allenyl derivatives are presented. Lithiated thioallenes give ...

Fluorescence in situ hybridization (FISH) has advantages over molecular techniques for the detection of minimal residual disease (MRD) during follow up of patients with haematological malignancies undergoing treatment. FISH is a fully quantitative technique and enables identification of the cell morphology, when it is performed on routine smears. However, one of its main disadvantages is its low sensitivity compared with that of other molecular approaches. MRD quantification by FISH can give false negative results due to the limited sensitivity of standard approaches (1–3%) in patients with low percentages of persistent ⁄ reappearing recipient cells after sex-mismatched allogeneic stem cell transplantation (SCT). In such cases, sequential FISH can be used to increase the sensitivity of MRD studies by specifically targeting recipient cells on routine smears previously used for chimaerism analysis. For this purpose, slides hybridized with sex-chromosome specific probes (CEP XY, Vysis Inc.) were washed in 0AE1% non-idet P-40 (NP-40) ⁄2x saline-sodium citrate (SSC) at room temperature for 1 min, dehydrated in an ethanol series (70-85-100%), denatured in 70% formamide ⁄2x SSC at 72 C for 20 s and hybridized again with the appropriate probe. In the example shown here, sequential FISH was used for the follow up of chimaerism (left) and MRD (right) in a Philadelphia (Ph) chromosome-positive chronic myeloid leukaemia (CML) patient in relapse after sexmismatched allogeneic SCT. Chimaerism was analysed using sex-chromosome specific probes (labelled red for the X chromosome and green for the Y chromosome) and MRD was subsequently analysed upon the same cells using probes for the BCR (red) and ABL (green) to detect the BCR–ABL fusion (D-FISH, Oncor Inc.). Donor cells (XX, left) showed the characteristic pattern of normal cells after FISH to detect the BCR–ABL fusion (right), while reappearing recipient cells (XY; left, arrow) showed the typical pattern of Ph-positive cells (right, arrow).