The Regulation of Reactive Neuroblastosis, Neuroplasticity, and Nutraceuticals for Effective Management of Autism Spectrum Disorder.

Autism spectrum disorder (ASD) encompasses a cluster of neurodevelopmental and genetic disorders that has been characterized mainly by social withdrawal, repetitive behavior, restricted interests, and deficits in language processing mainly in children. ASD has been known to severely impair behavioral patterns and cognitive functions including learning and memory due to defects in neuroplasticity. The biology of the ASD appears to be highly complex and heterogeneous, and thus, finding a therapeutic target for autism remains obscure. There has been no complete prevention or disease-modifying cure for this disorder. Recently, individuals with autism have been characterized by reactive neurogenesis, obstructions in axonal growth, heterotopia, resulting from dysplasia of neuroblasts in different brain regions. Therefore, it can be assumed that the aforementioned neuropathological correlates seen in the autistic individuals might originate from the defects mainly in the regulation of neuroblasts in the developing as well as adult brain. Nutrient deficiencies during early brain development and intake of certain allergic foods have been proposed as main reasons for the development of ASD. However, the integrated understanding of neurodevelopment and functional aspects of neuroplasticity working through neurogenesis in ASD is highly limited. Moreover, neurogenesis at the level of neuroblasts can be regulated by nutrition. Hence, defects in neuroblastosis underlying the severity of autism potentially could be rectified by appropriate implementation of nutraceuticals.

Identifying dual leucine zipper kinase (DLK) inhibitors using e-pharamacophore screening and molecular docking.

Alzheimer's is a neural disorder causing gradual loss in structure and function of nerve cell. To treat such disorders, c-Jun N-terminal Kinase (JNK) Pathway inhibitors were developed by representing chemical compounds that were used to inhibit the JNK signaling pathways. DLK is the stress sensor and implicating as regulatory factor in JNK pathway. Therefore, in the present investigation, pharmacophore screening was tried to identify the chemical compounds that involving inhibition of DLK proteins. To explore the pharmacophore region and mode of binding with DLK protein, N- (I H-pyrazol-3-y l) pyridin-2-aminer inhibitors were docked with DLK. Results reveal the information on the interaction mechanism of protein and ligand with chemical characteristics required to inhibit DLK protein. Such predicted information (AAAARH) was used as query to find out potential novel lead compounds sourced from public database. As an outcome of 65 compounds were listed based on the fitness score (2≥), and were subjected to glide HTVS.SP and XP. Best performing 5 lead compounds were shortlisted for dynamic simulations. This exhibited a constant RMSD over 20 ns of timescale.

Genetic reprogramming of somatic cells into neuroblasts through a co-induction of the doublecortin gene along the Yamanaka factors: A promising approach to model neuroregenerative disorders.

Neural stem cell (NSC) mediated adult neurogenesis represents the regenerative plasticity of the brain. The functionality of the neurogenic process appears to be operated by neuroblasts, the multipotent immature neuronal population of the adult brain. While neuroblasts have been realized to play a major role in synaptic remodeling and immunogenicity, neurodegenerative disorders have been characterized by failure in the terminal differentiation, maturation, integration and survival of newborn neuroblasts. Advancement in understanding the impaired neuroregenerative process along the neuropathological conditions has currently been limited by lack of an appropriate experimental model of neuroblasts. The genetic reprogramming of somatic cells into pluripotent state offers a potential strategy for the experimental modeling of brain disorders. Thus, the induced pluripotent stem cell (iPSC) based direct reprogramming of somatic cells into neuroblasts would represent a potential tool to understand the regenerative biology of the adult brain. Therefore, this concise article discusses the significance of iPSCs, the functional roles of neuroblasts in the adult brain and provides a research hypothesis for the direct reprogramming of somatic cells into neuroblasts through the co-induction of a potential proneurogenic marker, the doublecortin (DCX) gene along with the Yamanaka factors. The proposed cellular model of adult neurogenesis may provide us with further insights into neuropathogenesis of many neurodegenerative disorders and will provide a potential experimental platform for diagnostic, drug discovery and regenerative therapeutic strategies.

Identification of potential inhibitors for Penicillinbinding protein (PBP) from Staphylococcus aureus.

Staphylococcus aureus is an infectious agent that causes severe skin and soft tissue infection in hospitalized patients. Therefore, it is of interest to develop potent inhibitors for S. aureus. Penicillin Binding protein (PBP) is a known drug target for inhibition of cell wall biosynthesis in S. aureus. Hence, PBP was screened with compounds from six databases using virtual screening approaches. Results shows that the screened lead compound produced higher docking score (-9.87 kcal/mol) compared to resistant drugs. Antimicrobial activity using screened lead compounds and resistant drugs showed maximum activity in potential screened compounds compared to resistant compounds.

Role of morphological growth state and gene expression in Desulfovibrio africanus strain Walvis Bay mercury methylation.

The biogeochemical transformations of mercury are a complex process, with the production of methylmercury, a potent human neurotoxin, repeatedly demonstrated in sulfate- and Fe(III)-reducing as well as methanogenic bacteria. However, little is known regarding the morphology, genes, or proteins involved in methylmercury generation. Desulfovibrio africanus strain Walvis Bay is a Hg-methylating δ-proteobacterium with a sequenced genome and has unusual pleomorphic forms. In this study, a relationship between the pleomorphism and Hg methylation was investigated. Proportional increases in the sigmoidal (regular) cell form corresponded with increased net MeHg production but decreased when the pinched cocci (persister) form became the major morphotype. D. africanus microarrays indicated that the ferrous iron transport genes (feoAB), as well as ribosomal genes and several genes whose products are predicted to have metal binding domains (CxxC), were up-regulated during exposure to Hg in the exponential phase. Whereas no specific methylation pathways were identified, the finding that Hg may interfere with iron transport and the correlation of growth-phase-dependent morphology with MeHg production are notable. The identification of these relationships between differential gene expression, morphology, and the growth-phase dependence of Hg transformations suggests that actively growing cells are primarily responsible for methylation, and so areas with ample carbon and electron-acceptor concentrations may also generate a higher proportion of methylmercury than more oligotrophic environments. The observation of increased iron transporter expression also suggests that Hg methylation may interfere with iron biogeochemical cycles.

Bacterial growth phase influences methylmercury production by the sulfate-reducing bacterium Desulfovibrio desulfuricans ND132.

The effect of bacterial growth phase is an aspect of mercury (Hg) methylation that previous studies have not investigated in detail. Here we consider the effect of growth phase (mid-log, late-log and late stationary phase) on Hg methylation by the known methylator Desulfovibrio desulfuricans ND132. We tested the addition of Hg alone (chloride-complex), Hg with Suwannee River natural organic matter (SRNOM) (unequilibrated), and Hg equilibrated with SRNOM on monomethylmercury (MMHg) production by ND132 over a growth curve in pyruvate-fumarate media. This NOM did not affect MMHg production even under very low Hg:SRNOM ratios, where Hg binding is predicted to be dominated by high energy sites. Adding Hg or Hg-NOM to growing cultures 24 h before sampling (late addition) resulted in ~2× greater net fraction of Hg methylated than for comparably aged cultures exposed to Hg from the initial culture inoculation (early addition). Mid- and late-log phase cultures produced similar amounts of MMHg, but late stationary phase cultures (both under early and late Hg addition conditions) produced up to ~3× more MMHg, indicating the potential importance of growth phase in studies of MMHg production.

Natural mercury isotope variation in coal deposits and organic soils.

There is a need to distinguish among sources of Hg to the atmosphere in order to more fully understand global Hg pollution. In this study we investigate whether coal deposits within the United States, China, and Russia-Kazakhstan, which are three of the five greatest coal-producing regions, have diagnostic Hg isotopic fingerprints that can be used to discriminate among Hg sources. We also investigate the Hg isotopic composition of modern organic soil horizons developed in areas distant from point sources of Hg in North America. Mercury stored in coal deposits displays a wide range of both mass dependent fractionation (MDF, delta202Hg) and mass independent fractionation (MIF, delta201Hg). delta202Hg varies in coals by 3 per thousand and delta201Hg varies by 0.9 per thousand. Combining these two Hg isotope signals results in what may be a unique isotopic "fingerprint" for many coal deposits. Mass independent fractionation of mercury has been demonstrated to occur during photochemical reactions of mercury. This suggests that Hg found in most coal deposits was subjected to photochemical reduction near the Earth's surface prior to deposition. The similarity in MDF and MIF of modern organic soils and coals from North America suggests that Hg deposition from coal may have imprinted an isotopic signature on soils. This research offers a new tool for characterizing mercury inputs from natural and anthropogenic sources to the atmosphere and provides new insights into the geochemistry of mercury in coal and soils.

Mercury storage in surface soils in a central Washington forest and estimated release during the 2001 Rex Creek Fire.

Recent investigations indicate that wildfires provide a significant flux of mercury (Hg) from terrestrial ecosystems to the atmosphere. However, little is known about how geographic location, climate, stand age, and tree species affect Hg accumulation prior to burning and loss during burning. Soil cores collected in sites burned during the summer 2001 Rex Creek Fire in the eastern Cascade Mountains (Washington State, USA) and in adjacent unburned control sites indicate that Hg loss from soils during the Rex Creek Fire averaged 6.7 (+/-2.5) g Hg ha(-1). This soil profile-based estimate of Hg release is higher than a previous estimate for the same fire based on airborne measurements of Hg and CO concentrations in smoke. This study has implications for global estimates of Hg storage in forests and release to the atmosphere during wildfires.

Influence of snow and ice crystal formation and accumulation on mercury deposition to the Arctic.

Mercury is deposited to the Polar Regions during springtime atmospheric mercury depletion events (AMDEs) but the relationship between snow and ice crystal formation and mercury deposition is not well understood. The objective of this investigation was to determine if mercury concentrations were related to the type and formation of snow and ice crystals. On the basis of almost three hundred analyses of samples collected in the Alaskan Arctic, we suggestthat kinetic crystals growing from the vapor phase, including surface hoar, frost flowers, and diamond dust, yield mercury concentrations that are typically 2-10 times higher than that reported for snow deposited during AMDEs (approximately 80 ng/L). Our results show that the crystal type and formation affect the mercury concentration in any given snow sample far more than the AMDE activity prior to snow collection. We present a conceptual model of how snow grain processes including deposition, condensation, reemission, sublimation, and turbulent diffusive uptake influence mercury concentrations in snow and ice. These processes are time dependent and operate collectively to affect the retention and fate of mercury in the cryosphere. The model highlights the importance of the formation and postdeposition crystallographic history of snow or ice crystals in determining the fate and concentration of mercury in the cryosphere.