Synthesis of new pryridyl alcohols and their use as catalysts in the asymmetric addition of diethylzinc to aldehydes.

Optically active new pyridyl alcohols 1-4, which can be easily synthesized by the reaction of (+)-camphor or (-)-menthone with lithiated pyridine derivatives, were applied as chiral ligands in the asymmetric addition of diethylzinc to aldehydes. Good yields with up to 94.0% enantiomeric excesses were observed in these reactions.     

Synthesis of a new chiral ligand, 6, 6'-dihydroxy-5, 5'-biquinoline (BIQOL) and its applications in the asymmetric addition of diethylzinc to aldehydes

A new chiral ligand 6, 6'-dihydroxy-5, 5'-biquinoline (BIQOL, 2) was prepared via Cu2+ mediated coupling. The resolution was carried out by separating the corresponding ditrifluomethanesulfonate on chiral column. When applied to the enantioselective addition of diethylzinc to aromatic aldehydes, this ligand induced the reaction with enantioselectivity equivalent to that induced by BINOL. The effects of solvent and reaction temperature on enantioselectivity were also studied.     

On the role of the axial ligand in heme-based catalysis of the peroxidase and P450 type

 The present commentary focusses on the role of the axial ligand in peroxidase- and P450-type catalysis. Based on molecular orbital calculations and the experimental evidence available, it is argued that the ligand of a heme-containing enzyme may be a factor in setting the relative chance, although not the intrinsic capability, of the enzyme to catalyse a specific type of heme-based reaction chemistry. The ligand can do so by influencing the electrophilicity, i.e. the redox potential of the high-valency iron-oxo complex, and also by influencing the energy barrier for a reaction pathway through delocalization of valence electrons along the axial ligands, thereby, in the case of a cysteinate but not a histidine axial ligand, stabilizing oxygen transfer pathways. Received and accepted: 7 May 1996     

On the role of the axial ligand in heme proteins: a theoretical study

We present a systematic investigation of how the axial ligand in heme proteins influences the geometry, electronic structure, and spin states of the active site, and the energies of the reaction cycles. Using the density functional B3LYP method and medium-sized basis sets, we have compared models with His, His+Asp, Cys, Tyr, and Tyr+Arg as found in myoglobin and hemoglobin, peroxidases, cytochrome P450, and heme catalases, respectively. We have studied 12 reactants and intermediates of the reaction cycles of these enzymes, including complexes with H(2)O, OH(-), O(2-), CH(3)OH, O(2), H(2)O(2), and HO(2)(-) in various formal oxidation states of the iron ion (II to V). The results show that His gives ~0.6 V higher reduction potentials than the other ligands. In particular, it is harder to reduce and protonate the O(2) complex with His than with the other ligands, in accordance with the O(2) carrier function of globins and the oxidative chemistry of the other proteins. For most properties, the trend Cys相似文献   

Amphibian larvae and zinc sulphate: a suitable model to study the role of brain-derived neurotrophic factor (BDNF) in the neuronal turnover of the olfactory epithelium

The vertebrate olfactory system has fascinated neurobiologists over the last six decades because of its ability to replace its neurons and synaptic connections continuously throughout adult life, under both physiological and pathological conditions. Among the factors that are proposed to be involved in this regenerative potential, brain-derived neurotrophic factor (BDNF) is a candidate for having an important role in the neuronal turnover in the olfactory epithelium (OE) because of its well-documented neurogenic and trophic effects throughout the nervous system. The aim of the present study was to generate a suitable model to study the participation of BDNF in the recovery of the OE after injury in vivo. We developed an experimental design in which the OE of Rhinella arenarum tadpoles could be easily and selectively damaged by immersing the animals in ZnSO₄ solutions of various concentrations for differing time periods. Image analysis of histological sections showed that different combinations of each of these conditions produced statistically different degrees of injury to the olfactory tissue. We also observed that the morphology of the OE was restored within a few days of recovery after ZnSO₄ treatment. Immunohistochemical analysis of BDNF was performed with an antiserum whose specificity was confirmed by Western blotting, and which showed drastic changes in the abundance and distribution pattern of this neurotrophin in the damaged olfactory system. Our results thus suggest that BDNF is involved in the regeneration of the OE of amphibian larvae, and that our approach is suitable for further investigations of this topic. This work was supported by grants from CONICET (PIP 5842), Universidad de Buenos Aires (UBACYT X131) and ANPCYT (PICT 32219).     

The role of screening and treatment in the transmission dynamics of HIV/AIDS and tuberculosis co-infection: a mathematical study

In this paper, we present a deterministic non-linear mathematical model for the transmission dynamics of HIV and TB co-infection and analyze it in the presence of screening and treatment. The equilibria of the model are computed and stability of these equilibria is discussed. The basic reproduction numbers corresponding to both HIV and TB are found and we show that the disease-free equilibrium is stable only when the basic reproduction numbers for both the diseases are less than one. When both the reproduction numbers are greater than one, the co-infection equilibrium point may exist. The co-infection equilibrium is found to be locally stable whenever it exists. The TB-only and HIV-only equilibria are locally asymptotically stable under some restriction on parameters. We present numerical simulation results to support the analytical findings. We observe that screening with proper counseling of HIV infectives results in a significant reduction of the number of individuals progressing to HIV. Additionally, the screening of TB reduces the infection prevalence of TB disease. The results reported in this paper clearly indicate that proper screening and counseling can check the spread of HIV and TB diseases and effective control strategies can be formulated around ‘screening with proper counseling’.     

The role of natural regeneration to ecosystem services provision and habitat availability: a case study in the Brazilian Atlantic Forest

Natural regeneration provides multiple benefits to nature and human societies, and can play a major role in global and national restoration targets. However, these benefits are context specific and impacted by both biophysical and socioeconomic heterogeneity across landscapes. Here, we investigate the benefits of natural regeneration for climate change mitigation, sediment retention and biodiversity conservation in a spatially explicit way at very high resolution for a region within the global biodiversity hotspot of the Atlantic Forest. We classified current land‐use cover in the region and simulated a natural regeneration scenario in abandoned pasturelands, areas where potential conflicts with agricultural production would be minimized and where some early stage regeneration is already occurring. We then modeled changes in biophysical functions for climate change mitigation and sediment retention, and performed an economic valuation of both ecosystem services. We also modeled how land‐use changes affect habitat availability for species. We found that natural regeneration can provide significant ecological and social benefits. Economic values of climate change mitigation and sediment retention alone could completely compensate for the opportunity costs of agricultural production over 20 yr. Habitat availability is improved for three species with different dispersal abilities, although by different magnitudes. Improving the understanding of how costs and benefits of natural regeneration are distributed can be useful to design incentive structures that bring farmers’ decision making more in line with societal benefits. This alignment is crucial for natural regeneration to fulfill its potential as a large‐scale solution for pressing local and global environmental challenges.     

Inversion of the roles of the nucleophile and acid/base catalysts in the covalent binding of epoxyalkyl xyloside inhibitor to the catalytic glutamates of endo-1,4-beta-xylanase (XYNII): a molecular dynamics study

X-Ray crystal structures have revealed that 2, 3-epoxypropyl-beta-D-xyloside reacts with endo-1,4-beta-xylanase (XYNII) by forming a covalent bond with Glu86. In contrast, 3, 4-epoxybutyl-beta-D-xyloside forms a covalent bond with Glu177. In the normal enzyme reaction Glu86 acts as the catalytic nucleophile and Glu177 as the acid/base catalyst. To rationalize the observed reactivity of the two mechanism-based inhibitors, we carried out eight 300 ps molecular dynamics simulations for different enzyme-inhibitor complexes. Simulations were done for both stereo isomers (R and S) of the inhibitors and for enzyme in which the protonation state of the nucleophile and acid/base catalyst was normal (Glu86 charged, Glu177 neutral) and in which the roles of the catalytic residues were reversed (Glu86 neutral, Glu177 charged). The number of reactive conformations found in each simulation was used to predict the reactivity of epoxy inhibitors. The conformation was considered to be a reactive one when at the same time (i) the proton of the catalytic acid was close (<2.9/3.4/3.9 A) to the oxirane oxygen of the inhibitor, (ii) the nucleophile was close to the terminal carbon of the oxirane group (<3.4/3.9/4.4 A) and (iii) the nucleophile approached the terminal carbon from a reactive angle (<30/45/60 degrees from an ideal attack angle). On the basis of the number of reactive conformations, 2,3-epoxypropyl-beta-D-xyloside was predicted to form a covalent bond with Glu86 and 3, 4-epoxybutyl-beta-D-xyloside with Glu177, both in agreement with the experiment. Thus, the MD simulations and the X-ray structures indicate that in the covalent binding of 3, 4-epoxybutyl-beta-D-xyloside the roles of the catalytic glutamates of XYNII are reversed from that of the normal enzyme reaction.     

A new model to account for the order in which enantiomers of alkylarylcarbinols elute from a Pirkle chiral HPLC column: preparation, absolute stereochemistry, and chromatographic properties of (+)-1,2-benzocyclononen-3-ol and (+)-1,2-benzocyclodecen-3-ol

Samples enriched in (-)- and (+)-1,2-benzocyclononen-3-ol were prepared by microbially mediated reactions. An enriched sample of (+)-1,2-benzocyclodecen-3-ol was prepared by fractional crystallization of the diastereoisomeric camphanates, followed by hydrolysis. The absolute stereochemistry of both alcohols was established by chemical transformations. The elution order of their enantiomers from a chiral Pirkle HPLC column [(R)-N-(3,5-dinitrobenzoyl)phenyl glycine ionically bound to gamma-aminopropyl silanized silica] was determined. The information in conjunction with other data was used to formulate a rule to predict the configuration of an enantiomer of an alkylarylcarbinol from its elution order from this column.     

Down syndrome as a genetic model to evaluate the role of oxidative stress and transsulfuration abnormalities in autism spectrum disorder: A 10‐year longitudinal cohort study

Autism spectrum disorder (ASD) is a neurodevelopmental disorder in which evidence reveals oxidative stress and transsulfuration pathway abnormalities. Down syndrome (DS) is a genetic disorder characterized by similar oxidative stress and transsulfuration pathway abnormalities. This hypothesis‐testing longitudinal cohort study determined whether transsulfuration abnormalities and oxidative stress are important susceptibility factors in ASD etiology by evaluating the rate of ASD diagnoses in DS as compared to the general population. The Independent Healthcare Research Database was analyzed for healthcare records prospectively generated in Florida Medicaid. A cohort of 101,736 persons (born: 1990–1999) with ≥10 outpatient office visits and continuously followed for 120 months after birth was examined. There were 942 children in the DS cohort (ICD‐9 code: 758.0) and 100,749 children in the undiagnosed cohort (no DS diagnosis). ASD diagnoses were defined as autistic disorder (ICD‐9 code: 299.00) or Asperger's disorder/pervasive developmental disorder—not otherwise specified (ICD‐9 code: 299.80). ASDs were diagnosed in 5.31% of the DS cohort and 1.34% of the undiagnosed cohort. The risk ratio of being diagnosed with an ASD in the DS cohort as compared to the undiagnosed cohort was 3.97‐fold significantly increased with a risk difference of 3.97%. Among children diagnosed with DS, less than 6% were also diagnosed with an ASD. Among children diagnosed with an ASD, less than 5% were also diagnosed with DS. Children diagnosed with DS are apparently more susceptible to ASD diagnosis relative to the general population suggesting oxidative stress and transsulfuration pathway abnormalities are important susceptibility factors in ASD.