On the Conservation of the Slow Conformational Dynamics within the Amino Acid Kinase Family: NAGK the Paradigm

N-Acetyl-L-Glutamate Kinase (NAGK) is the structural paradigm for examining the catalytic mechanisms and dynamics of amino acid kinase family members. Given that the slow conformational dynamics of the NAGK (at the microseconds time scale or slower) may be rate-limiting, it is of importance to assess the mechanisms of the most cooperative modes of motion intrinsically accessible to this enzyme. Here, we present the results from normal mode analysis using an elastic network model representation, which shows that the conformational mechanisms for substrate binding by NAGK strongly correlate with the intrinsic dynamics of the enzyme in the unbound form. We further analyzed the potential mechanisms of allosteric signalling within NAGK using a Markov model for network communication. Comparative analysis of the dynamics of family members strongly suggests that the low-frequency modes of motion and the associated intramolecular couplings that establish signal transduction are highly conserved among family members, in support of the paradigm sequence→structure→dynamics→function.     

Serum IGF-1, IGFBP-3 and growth hormone levels in children with congenital heart disease: relationship with nutritional status, cyanosis and left ventricular functions

In this study we aimed to evaluate serum insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein-3 (IGFBP-3) and growth hormone (GH) levels in children with congenital heart disease (CHD) and to determine if these parameters have any relationship to the cyanosis, nutritional status and the left ventricular systolic function. This study is prospective-randomized study which conducted in 94 CHD patients (36 girls and 58 boys, aged between one 1-192 months, 19 cyanotic CHD and 75 acyanotic CHD) and age-sex matched 54 children (26 girls and 28 boys) with no CHD. In the study group, 37 out of the 94 CHD patients (39.4%) and 16 out of the 54 controls (29.6%) had malnutrition. The difference between the cyanotic and acyanotic patients in respect to malnutrition was significant (57.9% and 34.6%, p<0.05). Serum IGF-1 levels were lower (41.8+/-3.9 microg/L, 106.9+/-17.9 microg/L respectively, p<0.001) and GH levels were higher (6.43+/-0.9 ng/ml, 3.87+/-0.5 respectively, p<0.05) in CHD patient group than the controls. Serum IGF-1 levels were significantly lower in cyanotic CHD patients than the acyanotic patients (17.2+/-3.2 microg/L, 48.7.0+/-4.6 microg/L respectively, p<0.001) and serum IGF-1 levels were both lower in acyanotic and cyanotic CHD patients than the controls (p<0.001 for both). Serum IGF-1 and GH levels were similar between the well-nourished CHD patients and CHD patients with malnutrition (p>0.05). In total study group, the most effective factors on serum IGF-1 levels was presence of CHD (p<0.001), in CHD patients, the presence of cyanosis is the most effective factor on serum IGF-1 level, the presence of malnutrition is the most effective factor on serum IGFBP-3 levels (p<0.01). In the acyanotic, cyanotic, and the entire CHD patient groups, we find no correlations between the serum IGF-1, IGFBP-3 levels and left ventricular systolic function measurements. But serum GH levels were negatively correlated with diastolic left ventricular interseptum diameter, diastolic left ventricular mass and left ventricular end-diastolic volume measurements in CHD patients. In conclusion, we determined that the most important factor on serum IGF-1 levels is cyanosis. Reduced IGF1 levels and decreased left ventricular mass with an elevated GH levels in CHD patients and these findings are prominent in the cases with cyanosis and malnutrition. For this reason we believe that chronic hypoxia plays a significant role in the pathogenesis of malnutrition and also we believe that IGF-1 deficiency seen in CHD patients may be responsible in the etiology of the decrease in left ventricular mass independently from GH.     

Investigation on Mitochondrial tRNA<Superscript>Leu/Lys</Superscript>, NDI and ATPase 6/8 in Iranian Multiple Sclerosis Patients

As with chromosomal DNA, the mitochondrial DNA (mtDNA) can contain mutations that are highly pathogenic .In fact, many diseases of the central nervous system are known to be caused by mutations in mtDNA. Dysfunction of the mitochondrial Respiratory Chain (RC) has been shown in patients with neurological disease including Alzheimer’s disease (AD), Parkinson’s disease (PD) and Multiple sclerosis (MS). MS is a demyelinating disease of central nervous system characterized by morphological hallmarks of inflammation, demyelination and axonal loss. Considering this importance, we decided to investigate several highly mutative parts of mtDNA for point mutations as MT-LTI (tRNA^{Leucine1(UUA/G)}), MT-NDI (NADH Dehydrogenase subunit 1), MT-COII (Cytochrome c oxidase subunit II), MT-TK (tRNA^Lysine), MT-ATP8 (ATP synthase subunit F0 8) and MT-ATP6 (ATP synthase subunit F0 6) in 20 Iranian MS patients and 80 age-matched control subjects by PCR and automated DNA sequencing to evaluate any probable point mutations. Our results revealed that 15 (75%) out of 20 MS patients had point mutations. Some of point mutations were newly found in this study. This study suggested that point mutation occurred in mtDNA might be involved in pathogenesis of MS.     

Molecular species of oxidized phospholipids in brain differentiate between learning- and memory impaired and unimpaired aged rats

Amino Acids - Loss of cognitive function is a typical consequence of aging in humans and rodents. The extent of decline in spatial memory performance of rats, assessed by a hole-board test, reaches...     

Structure,Dynamics, and Allosteric Potential of Ionotropic Glutamate Receptor N-Terminal Domains

Ionotropic glutamate receptors (iGluRs) are tetrameric cation channels that mediate synaptic transmission and plasticity. They have a unique modular architecture with four domains: the intracellular C-terminal domain (CTD) that is involved in synaptic targeting, the transmembrane domain (TMD) that forms the ion channel, the membrane-proximal ligand-binding domain (LBD) that binds agonists such as L-glutamate, and the distal N-terminal domain (NTD), whose function is the least clear. The extracellular portion, comprised of the LBD and NTD, is loosely arranged, mediating complex allosteric regulation and providing a rich target for drug development. Here, we briefly review recent work on iGluR NTD structure and dynamics, and further explore the allosteric potential for the NTD in AMPA-type iGluRs using coarse-grained simulations. We also investigate mechanisms underlying the established NTD allostery in NMDA-type iGluRs, as well as the fold-related metabotropic glutamate and GABA_B receptors. We show that the clamshell motions intrinsically favored by the NTD bilobate fold are coupled to dimeric and higher-order rearrangements that impact the iGluR LBD and ultimately the TMD. Finally, we explore the dynamics of intact iGluRs and describe how it might affect receptor operation in a synaptic environment.     

Efficacy of a Cladosporium sp. fungus against Helicoverpa armigera (Lepidoptera: Noctuidae), other insect pests and beneficial insects of cotton

A strain of the fungus Cladosporium sp. (RM16) from an egg of Helicoverpa armigera Hübner (Lepidoptera: Noctuidae) was assessed as a potential biocontrol agent for this pest. Pathogenicity of the fungus was tested against H. armigera eggs and larvae, cotton aphids (Aphis gossypii Glover; Homoptera: Aphididae), and silverleaf whitefly type B (Bemisia tabaci Gennadius; Hemiptera: Aleyrodidae). The pathogenicity of the fungus to the predatory red and blue beetles (Dicranolaius bellulus Guérin-Méneville; Coleoptera: Melyridae), transverse ladybird beetles (Coccinella transversalis Fabricius; Coleoptera: Coccinellidae), green lacewings (Mallada signatus Schneider; Neuroptera: Chrysopidae) and damsel bugs (Nabis kinbergii Reuter; Hemiptera: Nabidae), was also assessed in the laboratory. Fungus treatment resulted in failure to hatch of up to 64% of H. armigera eggs (compared with 11% in the controls) and mortality of 54% of first instar H. armigera larvae (compared with 5% in the controls). In contrast, it was not pathogenic to later instar H. armigera larvae. Cladosporium RM16 was also efficacious against the sap-sucking insect pests of cotton that were tested. No significant harmful effect of the fungus was found on any of the four beneficial predatory insects assessed in this study. Cladosporium RM16 has the potential as biological control agent to support integrated pest management in cotton farming systems, although this needs intensive study.     

Genetic diversity of the common bacterial blight pathogen of bean, <Emphasis Type="Italic">Xanthomonas axonopodis</Emphasis> pv. <Emphasis Type="Italic">phaseoli</Emphasis>, in Iran revealed by rep-PCR and PCR–RFLP analyses

Xanthomonad-like bacteria that are associated with common bacterial blight of bean in Iran were identified on the basis of their colonial morphology, biochemical and serological properties, presence of a specific DNA fragment using PCR primers and pathogenicity on bean. Xanthomonas axonopodis pv. phaseoli (Xap) strains were further characterized using rep-PCR and restriction fragment length polymorphism (RFLP). RFLP profiles generated by the restriction endonucleases RsaI, TaqI, HaeIII and Sau96I and rep-PCR analysis revealed that Iranian strains were relatively genetically homogenous. The similarity coefficients among the strains ranged from 0.87 to 1. The genetic diversity coefficients among strains from three infected provinces, Isfahan, Markazi and Lorestan, were 0.019, 0.072 and 0.033, respectively. The low overall level of polymorphism within Xap isolates collected from the three Iranian infected regions could suggest that few initial inoculum introductions might have distributed among these different bean-growing areas in Iran.     

Potent antiprotozoal activity of a novel semi-synthetic berberine derivative

Treatment of diseases such as African sleeping sickness and leishmaniasis often depends on relatively expensive or toxic drugs, and resistance to current chemotherapeutics is an issue in treating these diseases and malaria. In this study, a new semi-synthetic berberine analogue, 5,6-didehydro-8,8-diethyl-13-oxodihydroberberine chloride (1), showed nanomolar level potency against in vitro models of leishmaniasis, malaria, and trypanosomiasis as well as activity in an in vivo visceral leishmaniasis model. Since the synthetic starting material, berberine hemisulfate, is inexpensive, 8,8-dialkyl-substituted analogues of berberine may lead to a new class of affordable antiprotozoal compounds.