Depletion of CXCR2 inhibits γ-secretase activity and amyloid-β production in a murine model of Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disorder that leads to progressive cognitive decline. Recent studies from our group and others have suggested that certain G-protein coupled receptors (GPCRs) can influence the processing of the amyloid precursor protein (APP). Earlier, we demonstrated that stimulation of a chemokine receptor, CXCR2, results in enhanced γ-secretase activity and in increased amyloid-beta (Aβ) production. Taken together, results obtained from in vitro studies indicate that therapeutic targeting of CXCR2 might aid in lowering Aβ levels in the AD brain. To better understand the precise function and to predict the consequences of CXCR2 depletion in the AD brain, we have crossed CXCR2 knockout mice with mice expressing presenilin (PS1 M146L) and APPsw mutations (PSAPP). Our present study confirms that CXCR2 depletion results in reduction of Aβ with concurrent increases of γ-secretase substrates. At the mechanistic level, the effect of CXCR2 on γ-secretase was not found to occur via their direct interaction. Furthermore, we provide evidence that Aβ promotes endocytosis of CXCR2 via increasing levels of CXCR2 ligands. In conclusion, our current study confirms the regulatory role of CXCR2 in APP processing, and poses it as a potential target for developing novel therapeutics for intervention in AD.     

Life Cycle of Titanium Dioxide Nanoparticle Production

Life cycle impact of emissions, energy requirements, and exergetic losses are calculated for a novel process for producing titanium dioxide nanoparticles from an ilmenite feedstock. The Altairnano hydrochloride process analyzed is tailored for the production of nanoscale particles, unlike established commercial processes. The life cycle energy requirements for the production of these particles is compared with that of traditional building materials on a per unit mass basis. The environmental impact assessment and energy analysis results both emphasize the use of nonrenewable fossil fuels in the upstream life cycle. Exergy analysis shows fuel losses to be secondary to material losses, particularly in the mining of ilmenite ore. These analyses are based on the same inventory data. The main contributions of this work are to provide life cycle inventory of a nanomanufacturing process and reveal potential insights from exergy analysis that are not available from other methods.     

Molecular docking analysis of stevioside with Akt and PPARγ

Stevioside is a diterpenoid glycoside consisting of an aglycone (steviol) and three glucose molecules. It is commonly used as an anti-hyperglycemic food because of its non-caloric property. Therefore, it is of interest to document the interactions of stevioside with AKT & PPAR-γ proteins using Autodock Vina PyRx docking techniques. Results of the docking studies indicate that stevioside had more than two hydrogen bond interactions with the AKT and PPAR γ protein for further consideration.     

Concordant phylogeography and cryptic speciation in two Western Palaearctic oak gall parasitoid species complexes

Little is known about the evolutionary history of most complex multi‐trophic insect communities. Widespread species from different trophic levels might evolve in parallel, showing similar spatial patterns and either congruent temporal patterns (Contemporary Host‐tracking) or later divergence in higher trophic levels (Delayed Host‐tracking). Alternatively, host shifts by natural enemies among communities centred on different host resources could disrupt any common community phylogeographic pattern. We examined these alternative models using two Megastigmus parasitoid morphospecies associated with oak cynipid galls sampled throughout their Western Palaearctic distributions. Based on existing host cynipid data, a parallel evolution model predicts that eastern regions of the Western Palaearctic should contain ancestral populations with range expansions across Europe about 1.6 million years ago and deeper species‐level divergence at both 8–9 and 4–5 million years ago. Sequence data from mitochondrial cytochrome b and multiple nuclear genes showed similar phylogenetic patterns and revealed cryptic genetic species within both morphospecies, indicating greater diversity in these communities than previously thought. Phylogeographic divergence was apparent in most cryptic species between relatively stable, diverse, putatively ancestral populations in Asia Minor and the Middle East, and genetically depauperate, rapidly expanding populations in Europe, paralleling patterns in host gallwasp species. Mitochondrial and nuclear data also suggested that Europe may have been colonized multiple times from eastern source populations since the late Miocene. Temporal patterns of lineage divergence were congruent within and across trophic levels, supporting the Contemporary Host‐tracking Hypothesis for community evolution.     

Identification of a novel Francisella tularensis factor required for intramacrophage survival and subversion of innate immune response

Francisella tularensis, the causative agent of tularemia, is one of the deadliest agents of biological warfare and bioterrorism. Extremely high virulence of this bacterium is associated with its ability to dampen or subvert host innate immune response. The objectives of this study were to identify factors and understand the mechanisms of host innate immune evasion by F. tularensis. We identified and explored the pathogenic role of a mutant interrupted at gene locus FTL_0325, which encodes an OmpA-like protein. Our results establish a pathogenic role of FTL_0325 and its ortholog FTT0831c in the virulent F. tularensis SchuS4 strain in intramacrophage survival and suppression of proinflammatory cytokine responses. This study provides mechanistic evidence that the suppressive effects on innate immune responses are due specifically to these proteins and that FTL_0325 and FTT0831c mediate immune subversion by interfering with NF-κB signaling. Furthermore, FTT0831c inhibits NF-κB activity primarily by preventing the nuclear translocation of p65 subunit. Collectively, this study reports a novel F. tularensis factor that is required for innate immune subversion caused by this deadly bacterium.     

Seedling preconditioning in thidiazuron enhances axillary shoot proliferation and recovery of transgenic cowpea plants

Lack of competence of seedling explants for efficient shoot proliferation in recalcitrant grain legume cowpea restricts its genetic manipulation for crop improvement. This study aimed at establishing a protocol to increase the shoot proliferation efficiency during the regeneration of transgenic cowpea plants. Here, we describe how seedling preconditioning in thidiazuron (TDZ) could stimulate the transformation process (by 3.5-fold), shoot proliferation potential of cotyledonary node (by a factor of fourfold) and accelerate the transgenic shoot regeneration. We investigated the effect of TDZ and 6-benzyladenine (BA) at high dose (5?C20???M) in the induction phase of regeneration by preconditioning seedlings for different durations (2?C6?days) with the aim of improving shoot proliferation competence from cultured explants. Cotyledonary node explants from preconditioned seedlings were cultured on MSB₅ medium supplemented with 5???M BA and 0.5???M kinetin for 4?weeks. Best response in terms of maximum shoot proliferation (7.1 shoots per explants), and greatest shoot length (2.6?cm) were obtained with explants derived from seedlings preconditioned in 10???M TDZ for 4?days. This enhanced shoot proliferation ability was maintained through three subsequent 4-week long regeneration passages. On comparison of the transformation rate in absence and presence of seedling preconditioning (in 10???M TDZ for 4?days), a significant enhancement from 0.6 to 2.1% was observed. The promotive effect of seedling preconditioning had a direct beneficial effect on transgenic plant recovery time leading to a reduction of more than 2?weeks. The protocol was found applicable to seven cowpea genotypes.     

Cadmium exerts its toxic effects on photosynthesis via a cascade mechanism in the cyanobacterium,Synechocystis PCC 6803

Despite intense research, the mechanism of Cd²⁺ toxicity on photosynthesis is still elusive because of the multiplicity of the inhibitory effects and different barriers in plants. The quick Cd²⁺ uptake in Synechocystis PCC 6803 permits the direct interaction of cadmium with the photosynthetic machinery and allows the distinction between primary and secondary effects. We show that the CO₂‐dependent electron transport is rapidly inhibited upon exposing the cells to 40 µm Cd²⁺ (50% inhibition in ～15 min). However, during this time we observe only symptoms of photosystem I acceptor side limitation and a build of an excitation pressure on the reaction centres, as indicated by light‐induced P700 redox transients, O₂ polarography and changes in chlorophyll a fluorescence parameters. Inhibitory effects on photosystem II electron transport and the degradation of the reaction centre protein D1 can only be observed after several hours, and only in the light, as revealed by chlorophyll a fluorescence transients, thermoluminescence and immunoblotting. Despite the marked differences in the manifestations of these short‐ and long‐term effects, they exhibit virtually the same Cd²⁺ concentration dependence. These data strongly suggest a cascade mechanism of the toxic effect, with a primary effect in the dark reactions.     

Decreased GABA receptor in the cerebral cortex of epileptic rats: effect of Bacopa monnieri and Bacoside-A

Abstact

Background

Gamma amino butyric acid (GABA), the principal inhibitory neurotransmitter in the cerebral cortex, maintains the inhibitory tones that counter balances neuronal excitation. When this balance is perturbed, seizures may ensue.

Methods

In the present study, alterations of the general GABA, GABA_A and GABA_B receptors in the cerebral cortex of the epileptic rat and the therapeutic application of Bacopa monnieri were investigated.

Results

Scatchard analysis of [³H]GABA, [³H]bicuculline and [³H]baclofen in the cerebral cortex of the epileptic rat showed significant decrease in B_max (P < 0.001) compared to control. Real Time PCR amplification of GABA receptor subunits such as GABA_Aά1, GABA_Aγ, GABA_Aδ, GABA_B and GAD where down regulated (P < 0.001) in epileptic rats. GABA_Aά5 subunit and Cyclic AMP responsible element binding protein were up regulated. Confocal imaging study confirmed the decreased GABA receptors in epileptic rats. Epileptic rats have deficit in radial arm and Y maze performance.

Conclusions

Bacopa monnieri and Bacoside-A treatment reverses epilepsy associated changes to near control suggesting that decreased GABA receptors in the cerebral cortex have an important role in epileptic occurrence; Bacopa monnieri and Bacoside-A have therapeutic application in epilepsy management.     

Identification of a Live Attenuated Vaccine Candidate for Tularemia Prophylaxis

Francisella tularensis is the causative agent of a fatal human disease, tularemia. F. tularensis was used in bioweapon programs in the past and is now classified as a category A select agent owing to its possible use in bioterror attacks. Despite over a century since its discovery, an effective vaccine is yet to be developed. In this study four transposon insertion mutants of F. tularensis live vaccine strain (LVS) in Na/H antiporter (FTL_0304), aromatic amino acid transporter (FTL_0291), outer membrane protein A (OmpA)-like family protein (FTL_0325) and a conserved hypothetical membrane protein gene (FTL_0057) were evaluated for their attenuation and protective efficacy against F. tularensis SchuS4 strain. All four mutants were 100–1000 fold attenuated for virulence in mice than parental F. tularensis. Except for the FTL_0304, single intranasal immunization with the other three mutants provided 100% protection in BALB/c mice against intranasal challenge with virulent F. tularensis SchuS4. Differences in the protective ability of the FTL_0325 and FTL_0304 mutant which failed to provide protection against SchuS4 were investigated further. The results indicated that an early pro-inflammatory response and persistence in host tissues established a protective immunity against F. tularensis SchuS4 in the FTL_0325 immunized mice. No differences were observed in the levels of serum IgG antibodies amongst the two vaccinated groups. Recall response studies demonstrated that splenocytes from the FTL_0325 mutant immunized mice induced significantly higher levels of IFN-γ and IL-17 cytokines than the FTL_0304 immunized counterparts indicating development of an effective memory response. Collectively, this study demonstrates that persistence of the vaccine strain together with its ability to induce an early pro-inflammatory innate immune response and strong memory responses can discriminate between successful and failed vaccinations against tularemia. This study describes a live attenuated vaccine which may prove to be an ideal vaccine candidate for prevention of respiratory tularemia.     

Enhanced biodecolorization of synthetic textile dye effluent by Phanerochaete chrysosporium under improved culture conditions

Biodecolorization of a synthetic commercial textile dye effluent (0.1 gl^–1) by Phanerochaete chrysosporium was enhanced by improving the original Kirk's medium with respect to buffer, C:N ratio, Mg²⁺ and Zn²⁺ ions, inoculum, temperature shifts, agitation and sunflower oil additon. An increase of 6.7-fold in lignin peroxidase (LIP) level, 4-fold in biomass and 45.5% enhanced decolorization of effluent was achieved. Degradation was both enzymatic (47.2%) and by biosorption (61.67%).