Effects of drug-polymer dispersions on solubility and <Emphasis Type="Italic">in vitro</Emphasis> diffusion of artemisinin across a polydimethylsiloxane membrane

Artemisinin(ART) is a sesquiterpene lactone with an endo-peroxide bridge that is thought to be responsible for its antimalarial activity.It has low oral bioavailability because of aqueous insolubility,which leads to local toxicity at the site of aggregation.The present work focused on increasing its solubility and evaluating its permeation across a model membrane to mimic transdermal delivery that bypasses the hepatic metabolism.For this purpose,physical mixtures(PM),solid dispersions(SD) and lyophilized dispersions(LD) with different drug-polymer ratios(1:0.5,1:1,1:2,1:4 and 1:9) were prepared using the hydrophilic polymer polyvinylpyrrolidone(PVP).Drug-polymer dispersions were characterized using X-ray diffraction(XRD) and Fourier transform infrared spectroscopy(FTIR).Solubility was measured in three solvents:de-ionized water,phosphate buffered saline(PBS) and methanol.The toluene-water partition coefficient was evaluated and compared with the literature and calculated logP values.In vitro diffusion of ART was studied across a polydimethylsiloxane membrane from a saturated solution of drug-polymer dispersions.XRD patterns showed a gradual decrease in crystallinity of ART with increasing polymer concentration,while FTIR confirmed no interactions between ART and PVP.Solubility was increased up to 4-,5-and 8-fold for LD in water,PBS and methanol,respectively.The logP for toluene-water was 2.65 ± 0.3,which is in good agreement with literature and calculated logP values.Permeation was enhanced,which is attributed to the decrease in crystallinity and increase in wettability of the drug.The ART flux was significantly higher than that of pure ART(0.12 ± 0.01) with increasing PVP concentration for SD and LD formulations.In conclusion,drug-polymer dispersions with PVP improve the pharmaceutical properties of ART in the order LD>SD>PM.     

Bimodal processing of olfactory information in an amphibian nose: odor responses segregate into a medial and a lateral stream

In contrast to the single sensory surface present in teleost fishes, several spatially segregated subsystems with distinct molecular and functional characteristics define the mammalian olfactory system. However, the evolutionary steps of that transition remain unknown. Here we analyzed the olfactory system of an early diverging tetrapod, the amphibian Xenopus laevis, and report for the first time the existence of two odor-processing streams, sharply segregated in the main olfactory bulb and partially segregated in the olfactory epithelium of pre-metamorphic larvae. A lateral odor-processing stream is formed by microvillous receptor neurons and is characterized by amino acid responses and Gα_o/Gα_i as probable signal transducers, whereas a medial stream formed by ciliated receptor neurons is characterized by responses to alcohols, aldehydes, and ketones, and Gα_olf/cAMP as probable signal transducers. To reveal candidates for the olfactory receptors underlying these two streams, the spatial distribution of 12 genes from four olfactory receptor gene families was determined. Several class II and some class I odorant receptors (ORs) mimic the spatial distribution observed for the medial stream, whereas a trace amine-associated receptor closely parallels the spatial pattern of the lateral odor-processing stream. Other olfactory receptors (some class I odorant receptors and vomeronasal type 1 receptors) and odor responses (to bile acids, amines) were not lateralized, the latter not even in the olfactory bulb, suggesting an incomplete segregation. Thus, the olfactory system of X. laevis exhibits an intermediate stage of segregation and as such appears well suited to investigate the molecular driving forces behind olfactory regionalization.     

Arsenite transport in plants

Arsenic is a metalloid which is toxic to living organisms. Natural occurrence of arsenic and human activities have led to widespread contamination in many areas of the world, exposing a large section of the human population to potential arsenic poisoning. Arsenic intake can occur through consumption of contaminated crops and it is therefore important to understand the mechanisms of transport, metabolism and tolerance that plants display in response to arsenic. Plants are mainly exposed to the inorganic forms of arsenic, arsenate and arsenite. Recently, significant progress has been made in the identification and characterisation of proteins responsible for movement of arsenite into and within plants. Aquaporins of the NIP (nodulin26-like intrinsic protein) subfamily were shown to transport arsenite in planta and in heterologous systems. In this review, we will evaluate the implications of these new findings and assess how this may help in developing safer and more tolerant crops.     

iASPP preferentially binds p53 proline-rich region and modulates apoptotic function of codon 72-polymorphic p53

iASPP is one of the most evolutionarily conserved inhibitors of p53, whereas ASPP1 and ASPP2 are activators of p53. We show here that, in addition to the DNA-binding domain, the ASPP family members also bind to the proline-rich region of p53, which contains the most common p53 polymorphism at codon 72. Furthermore, the ASPP family members, particularly iASPP, bind to and regulate the activity of p53Pro72 more efficiently than that of p53Arg72. Hence, escape from negative regulation by iASPP is a newly identified mechanism by which p53Arg72 activates apoptosis more efficiently than p53Pro72.     

High-throughput oncogene mutation profiling in human cancer

Systematic efforts are underway to decipher the genetic changes associated with tumor initiation and progression. However, widespread clinical application of this information is hampered by an inability to identify critical genetic events across the spectrum of human tumors with adequate sensitivity and scalability. Here, we have adapted high-throughput genotyping to query 238 known oncogene mutations across 1,000 human tumor samples. This approach established robust mutation distributions spanning 17 cancer types. Of 17 oncogenes analyzed, we found 14 to be mutated at least once, and 298 (30%) samples carried at least one mutation. Moreover, we identified previously unrecognized oncogene mutations in several tumor types and observed an unexpectedly high number of co-occurring mutations. These results offer a new dimension in tumor genetics, where mutations involving multiple cancer genes may be interrogated simultaneously and in 'real time' to guide cancer classification and rational therapeutic intervention.     

Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutières syndrome and mimic congenital viral brain infection

Aicardi-Goutières syndrome (AGS) is an autosomal recessive neurological disorder, the clinical and immunological features of which parallel those of congenital viral infection. Here we define the composition of the human ribonuclease H2 enzyme complex and show that AGS can result from mutations in the genes encoding any one of its three subunits. Our findings demonstrate a role for ribonuclease H in human neurological disease and suggest an unanticipated relationship between ribonuclease H2 and the antiviral immune response that warrants further investigation.     

An analogue of the ℤ<Subscript>4</Subscript>-Goethals code in non-primitive length

This paper constructs a cyclic ?₄-code with a parity-check matrix similar to that of Goethals code but in length 2^m + 1, for all m ≥ 4. This code is a subcode of the lifted Zetterberg code for m even. Its minimum Lee weight is shown to be at least 10, in general, and exactly 12 in lengths 33, 65. The authors give an algebraic decoding algorithm which corrects five errors in these lengths for m = 5, 6 and four errors for m > 6.     

A central role for calcineurin in protein misfolding neurodegenerative diseases

Accumulation of misfolded/unfolded aggregated proteins in the brain is a hallmark of many neurodegenerative diseases affecting humans and animals. Dysregulation of calcium (Ca²⁺) and disruption of fast axonal transport (FAT) are early pathological events that lead to loss of synaptic integrity and axonal degeneration in early stages of neurodegenerative diseases. Dysregulated Ca²⁺ in the brain is triggered by accumulation of misfolded/unfolded aggregated proteins in the endoplasmic reticulum (ER), a major Ca²⁺ storing organelle, ultimately leading to neuronal dysfunction and apoptosis. Calcineurin (CaN), a Ca²⁺/calmodulin-dependent serine/threonine phosphatase, has been implicated in T cells activation through the induction of nuclear factor of activated T cells (NFAT). In addition to the involvement of several other signaling cascades, CaN has been shown to play a role in early synaptic dysfunction and neuronal death. Therefore, inhibiting hyperactivated CaN in early stages of disease might be a promising therapeutic strategy for treating patients with protein misfolding diseases. In this review, we briefly summarize the structure of CaN, inhibition mechanisms by which immunosuppressants inhibit CaN, role of CaN in maintaining neuronal and synaptic integrity and homeostasis and the role played by CaN in protein unfolding/misfolding neurodegenerative diseases.