Aluminum is an environmentally abundant potential neurotoxic agent that may result in oxidative damage to a range of cellular biomarkers. The potential sources of aluminum accumulation in body include drinking water, food, medicines, vaccines, and aluminum cookware utensils etc. The accumulation of aluminum in brain is reported to be associated with cholinergic dysfunction, oxidative stress and neuronal damage, that may ultimately cause Alzheimer's disease. Since chronic exposure of aluminum leads to its accumulation in brain, so this study was done by a long-term (24 weeks) low dose (20 mg/kg) oral exposure of aluminum chloride in rats. In this chronic model, we have evaluated the major hallmarks of Alzheimer's disease including amyloid beta (Abeta(1-42)) and phosphorylated-tau (p231-tau) protein in brain tissue. Furthermore, we evaluated the level of acetyl cholinesterase activity, inflammatory cytokines such as TNF-alpha, IL-6 and IL-1beta, and oxidative stress biomarkers in rat brain in this model. The neurobehavioral parameters were also assessed in animals by using spontaneous locomotor activity, passive avoidance, rotarod test and novel object recognition test to evaluate alteration in learning, memory and muscle co-ordination. We found that chronic oral exposure of aluminum chloride causes a significant increase in structural hallmarks such as Abeta(1-42) and p231-tau levels along with proinflammatory cytokines (TNF-alpha and IL-6), oxidative stress, and a decrease in antioxidant markers such as GSH and catalase. in the brain tissue. These biomarkers significantly affected neurobehavioral parameters in animals. This study provides a mechanistic understanding of chronic aluminum-induced neuronal toxicity in brain with relevance to Alzheimer's disease.
Strigolactones (SLs) are a relatively recent addition to the list of plant hormones that control different aspects of plant development. SL signalling is perceived by an alpha/beta hydrolase, DWARF 14 (D14). A close homolog of D14, KARRIKIN INSENSTIVE2 (KAI2), is involved in perception of an uncharacterized molecule called karrikin (KAR). Recent studies in Arabidopsis identified the SUPPRESSOR OF MAX2 1 (SMAX1) and SMAX1-LIKE 7 (SMXL7) to be potential SCF-MAX2 complex-mediated proteasome targets of KAI2 and D14, respectively. Genetic studies on SMXL7 and SMAX1 demonstrated distinct developmental roles for each, but very little is known about these repressors in terms of their sequence features. In this study, we performed an extensive comparative analysis of SMXLs and determined their phylogenetic and evolutionary history in the plant lineage. Our results show that SMXL family members can be sub-divided into four distinct phylogenetic clades/classes, with an ancient SMAX1. Further, we identified the clade-specific motifs that have evolved and that might act as determinants of SL-KAR signalling specificity. These specificities resulted from functional diversities among the clades. Our results suggest that a gradual co-evolution of SMXL members with their upstream receptors D14/KAI2 provided an increased specificity to both the SL perception and response in land plants.
The highly thermostable esterase from the hyperthermophilic archaeon Pyrobaculum calidifontis VA1 (PestE) shows high enantioselectivity (E > 100) in the kinetic resolution of racemic chiral carboxylic acids, but little selectivity towards acetates of tertiary alcohols (E = 2-4). To explain these unique properties, its crystal structure has been determined at 2.0 A resolution. The enzyme is a member of the hormone-sensitive lipase group (group H) of the esterase/lipase superfamily on the basis of the amino acid sequence identity. The PestE structure shows a canonical alpha/beta-hydrolase fold as core domain with a cap structure at the C-terminal end of the beta-sheet. A tetramer in the crystal packing is formed of two dimers; the dimeric form is observed in solution. Conserved dimers and even tetramers are found in other group H proteins. The amino acid residues Ser157, His284, and Asp254 form the catalytic triad, which is typically found in alpha/beta-hydrolases. The oxyanion hole is composed of Gly85 and Gly86 within the conserved sequence motif HGGG(M,F,W) (amino acid residues 83-87) and Ala158. With the elucidated structure, experimental results about enantioselectivity towards the two model substrate classes (as exemplified for 3-phenylbutanoic acid ethyl ester and 1,1,1-trifluoro-2-phenylbut-3-yn-2-yl acetate) could be explained by molecular modeling. For both enantiomers of the tertiary alcohol, orientations in two binding pockets were obtained without significant energy differences corresponding to the observed low enantioselectivity due to missing steric repulsions. In contrast, for the carboxylic acid ester, two different orientations with significant energy differences for each enantiomer were found matching the high E values.
Pyridostigmine relieved episodic weakness in a family with paramyotonia congenita resulting from the R1448C mutation in the sodium channel gene. The transmission was autosomal dominant and the patients had paradoxical myotonia and exercise-induced weakness. On electrophysiological studies there were myotonic potentials, and there was progressive reduction of compound muscle action potential (CMAP) amplitudes after short exercise associated with clinical weakness. Pyridostigmine in doses of 60 mg three times daily abolished the drop in the postexercise CMAP amplitude and reduced the amplitude decrement to slow rate repetitive stimulation, but there continued to be a drop in amplitude on exposure to cold. The decline of the CMAP amplitude on exposure to cold was controlled by treatment with phenytoin. The clinical and electrophysiological features are discussed in relation to therapy with pyridostigmine and phenytoin.
BACKGROUND: Aeromonas salmonicida subsp. salmonicida is a Gram-negative bacterium that is the causative agent of furunculosis, a bacterial septicaemia of salmonid fish. While other species of Aeromonas are opportunistic pathogens or are found in commensal or symbiotic relationships with animal hosts, A. salmonicida subsp. salmonicida causes disease in healthy fish. The genome sequence of A. salmonicida was determined to provide a better understanding of the virulence factors used by this pathogen to infect fish. RESULTS: The nucleotide sequences of the A. salmonicida subsp. salmonicida A449 chromosome and two large plasmids are characterized. The chromosome is 4,702,402 bp and encodes 4388 genes, while the two large plasmids are 166,749 and 155,098 bp with 178 and 164 genes, respectively. Notable features are a large inversion in the chromosome and, in one of the large plasmids, the presence of a Tn21 composite transposon containing mercury resistance genes and an In2 integron encoding genes for resistance to streptomycin/spectinomycin, quaternary ammonia compounds, sulphonamides and chloramphenicol. A large number of genes encoding potential virulence factors were identified; however, many appear to be pseudogenes since they contain insertion sequences, frameshifts or in-frame stop codons. A total of 170 pseudogenes and 88 insertion sequences (of ten different types) are found in the A. salmonicida genome. Comparison with the A. hydrophila ATCC 7966T genome reveals multiple large inversions in the chromosome as well as an approximately 9% difference in gene content indicating instances of single gene or operon loss or gain.A limited number of the pseudogenes found in A. salmonicida A449 were investigated in other Aeromonas strains and species. While nearly all the pseudogenes tested are present in A. salmonicida subsp. salmonicida strains, only about 25% were found in other A. salmonicida subspecies and none were detected in other Aeromonas species. CONCLUSION: Relative to the A. hydrophila ATCC 7966T genome, the A. salmonicida subsp. salmonicida genome has acquired multiple mobile genetic elements, undergone substantial rearrangement and developed a significant number of pseudogenes. These changes appear to be a consequence of adaptation to a specific host, salmonid fish, and provide insights into the mechanisms used by the bacterium for infection and avoidance of host defence systems.
23 different crystal forms of 19 different biological macromolecules were examined with respect to their anomalously scattering substructures using diffraction data collected at a wavelength of 2.0 A (6.2 keV). In more than 90% of the cases the substructure was found to contain more than just the protein S atoms. The data presented suggest that chloride, sulfate, phosphate or metal ions from the buffer or even from the purification protocol are frequently bound to the protein molecule and that these ions are often overlooked, especially if they are not bound at full occupancy. Thus, in order to fully describe the macromolecule under study, it seems desirable that any structure determination be complemented with a long-wavelength data set.
The genome of the crenarchaeon Sulfolobus solfataricus P2 contains 2,992,245 bp on a single chromosome and encodes 2,977 proteins and many RNAs. One-third of the encoded proteins have no detectable homologs in other sequenced genomes. Moreover, 40% appear to be archaeal-specific, and only 12% and 2.3% are shared exclusively with bacteria and eukarya, respectively. The genome shows a high level of plasticity with 200 diverse insertion sequence elements, many putative nonautonomous mobile elements, and evidence of integrase-mediated insertion events. There are also long clusters of regularly spaced tandem repeats. Different transfer systems are used for the uptake of inorganic and organic solutes, and a wealth of intracellular and extracellular proteases, sugar, and sulfur metabolizing enzymes are encoded, as well as enzymes of the central metabolic pathways and motility proteins. The major metabolic electron carrier is not NADH as in bacteria and eukarya but probably ferredoxin. The essential components required for DNA replication, DNA repair and recombination, the cell cycle, transcriptional initiation and translation, but not DNA folding, show a strong eukaryal character with many archaeal-specific features. The results illustrate major differences between crenarchaea and euryarchaea, especially for their DNA replication mechanism and cell cycle processes and their translational apparatus.
Title: Carbofuran-induced biochemical changes in Clarias batrachus Singh RK, Sharma B Ref: Pest Sci, 53:285, 1998 : PubMed
The effect of carbofuran, an organo-carbamate pesticide, upon the level of protein as well as the activity of lactate dehydrogenase (EC 1.1.1.28, LDH) was studied by exposing the teleost fish, Clarias batrachus, to different subacute con-centrations (0.01 and 0.02 mg litre-1) for 96 h and 15 days. The results showed a drastic decrease in the protein content in different body organs of the fish. The pesticide also caused a significant decrease in the level of activity of LDH in different body tissues of the fish, the effect being more pronounced in the gills, muscle, brain and liver than in kidney and heart. The decrease in protein content and the activity of LDH in fish tissues was more marked at the higher concentration of the pesticide for the longer duration of treatment. The results suggested that carbofuran has an effect at very low concentration (compared to its LC50 value) possibly at the level of protein metabolism, and also inhibits the activity of LDH, the terminal glycolytic enzyme.
