New 64Cu PET imaging agents for personalised medicine and drug development using the hexa-aza cage, SarAr

The success of positron emission tomography (PET) in personalised medicine and drug development requires radioisotopes that provide high quality images and flexible chemistry for a broad application. 64Cu is arguably one of the most suitable PET isotopes for imaging with the evolving target agents, but there are not many appropriate chelating agents for 64Cu and this has limited its wider application. The bi-functional chelator, SarAr is known to bind 64Cu2+ quantitatively (i.e. one metal per ligand present) and rapidly (<2 min) at 10(-6) M over a range of pH (4-9). In this paper the conjugation of SarAr to the whole and fragmented antibody is described. Conjugation of the SarAr to the protein does not impair its coordination of the 64Cu. It complexes the 64Cu2+ rapidly, quantitatively and essentially irreversibly at pH 5. Animal studies show that the 64Cu-SarAr-immunoconjugates maintain their specificity for the target and are stable in vivo. Also, SarAr is a platform technology, is easy to use in a kit formulation and is readily adaptable for the wider application in 64Cu PET imaging.     

Oxidative reactions of 6-pentyl indolo[3,2-b]carbazole: formation of novel C-C and C-N coupled dimers

The oxidative coupling reactions of 6-pentyl-5,11-dihydroindolo[3,2-b]carbazole have been studied and as a result, a number of novel dimers of the indolo[3,2-b]carbazole derivative have been prepared, forming C-C coupled compound when treated with FeCl(3) x 6H(2)O or C-N coupled compounds and when oxidized with air or Pd(OAc)(2), respectively.     

Lyapunov functions for SIR and SIRS epidemic models

In this paper, we construct a new Lyapunov function for a variety of SIR and SIRS models in epidemiology. Global stability of the endemic equilibrium states of these systems is established.     

Stable isotope analysis of white-tailed deer teeth as a paleoenvironmental proxy at the Maya site of La Joyanca,northwestern Petén,Guatemala*

ABSTRACT

Carbon and oxygen isotopes ratios from herbivore teeth have previously been used as paleo-environmental proxies in temperate zones. However, their utility in tropical zones remains uncertain. In this study, sequential sub-samples from white-tailed deer (Odocoileus virginianus) teeth (second and third molars) from the Maya archaeological site of La Joyanca, located in northwestern Petén, Guatemala, show that δ¹⁸O of enamel carbonate corresponds broadly to modern observed precipitation δ¹⁸O over the 10-month period of tooth formation, capturing rainfall seasonality. The analyses also detect significant diachronic differences in the δ¹⁸O between the periods 1100–1000 BP (850–950 A.D.) and 1000–900 BP (950–1050 A.D.) at La Joyanca. The δ¹³C in both periods are indicative of a C₃-plant based diet, which suggests cultivation of maize did not differentially affect deer diet during this period.     

Antisense-mediated isoform switching of steroid receptor coactivator-1 in the central nucleus of the amygdala of the mouse brain

Background

Antisense oligonucleotide (AON)-mediated exon skipping is a powerful tool to manipulate gene expression. In the present study we investigated the potential of exon skipping by local injection in the central nucleus of the amygdala (CeA) of the mouse brain. As proof of principle we targeted the splicing of steroid receptor coactivator-1 (SRC-1), a protein involved in nuclear receptor function. This nuclear receptor coregulator exists in two splice variants (SRC-1a and SRC-1e) which display differential distribution and opposing activities in the brain, and whose mRNAs differ in a single SRC-1e specific exon.

Methods

For proof of principle of feasibility, we used immunofluorescent stainings to study uptake by different cell types, translocation to the nucleus and potential immunostimulatory effects at different time points after a local injection in the CeA of the mouse brain of a control AON targeting human dystrophin with no targets in the murine brain. To evaluate efficacy we designed an AON targeting the SRC-1e-specific exon and with qPCR analysis we measured the expression ratio of the two splice variants.

Results

We found that AONs were taken up by corticotropin releasing hormone expressing neurons and other cells in the CeA, and translocated into the cell nucleus. Immune responses after AON injection were comparable to those after sterile saline injection. A successful shift of the naturally occurring SRC-1a:SRC-1e expression ratio in favor of SRC-1a was observed, without changes in total SRC-1 expression.

Conclusions

We provide a proof of concept for local neuropharmacological use of exon skipping by manipulating the expression ratio of the two splice variants of SRC-1, which may be used to study nuclear receptor function in specific brain circuits. We established that exon skipping after local injection in the brain is a versatile and useful tool for the manipulation of splice variants for numerous genes that are relevant for brain function.     

Fluorescent Microcrystals Obtained from Coumarin 6 Using the Reprecipitation Method

The reprecipitation method was applied to Coumarin 6. A concentrated solution of the dye in acetone was mixed at room temperature with a large volume of water, and microcrystals rapidly appeared in the medium. Their size and shape were visualized by fluorescence microscopy, as well as by transmission electron microscopy. The absorption and fluorescence properties were studied on the suspensions and compared with those of the dissolved dye. This study is aimed at clarifying the influence of the reprecipitation process upon the fluorescence properties of the dye in the solid state.     

A magnetic resonance imaging-based articulatory and acoustic study of "retroflex" and "bunched" American English /r/

Speakers of rhotic dialects of North American English show a range of different tongue configurations for /r/. These variants produce acoustic profiles that are indistinguishable for the first three formants [Delattre, P., and Freeman, D. C., (1968). "A dialect study of American English r's by x-ray motion picture," Linguistics 44, 28-69; Westbury, J. R. et al. (1998), "Differences among speakers in lingual articulation for American English /r/," Speech Commun. 26, 203-206]. It is puzzling why this should be so, given the very different vocal tract configurations involved. In this paper, two subjects whose productions of "retroflex" /r/ and "bunched" /r/ show similar patterns of F1-F3 but very different spacing between F4 and F5 are contrasted. Using finite element analysis and area functions based on magnetic resonance images of the vocal tract for sustained productions, the results of computer vocal tract models are compared to actual speech recordings. In particular, formant-cavity affiliations are explored using formant sensitivity functions and vocal tract simple-tube models. The difference in F4/F5 patterns between the subjects is confirmed for several additional subjects with retroflex and bunched vocal tract configurations. The results suggest that the F4/F5 differences between the variants can be largely explained by differences in whether the long cavity behind the palatal constriction acts as a half- or a quarter-wavelength resonator.     

Components of the ubiquitin-proteasome pathway compete for surfaces on Rad23 family proteins

Background  

The delivery of ubiquitinated proteins to the proteasome for degradation is a key step in the regulation of the ubiquitin-proteasome pathway, yet the mechanisms underlying this step are not understood in detail. The Rad23 family of proteins is known to bind ubiquitinated proteins through its two ubiquitin-associated (UBA) domains, and may participate in the delivery of ubiquitinated proteins to the proteasome through docking via the Rad23 ubiquitin-like (UBL) domain.     

Facile synthesis of novel indolo[3,2-b]carbazole derivatives and a chromogenic-sensing 5,12-dihydroindolo[3,2-b]carbazole

Novel indolo[3,2-b]carbazole derivatives and a chromogenic-sensing 5,12-dihydroindolo[3,2-b]carbazole have been synthesized starting from tetra-tert-butylated 6,12-diaryl-5,11-dihydroindolo[3,2-b]carbazoles, which were prepared via an efficient tert-butylation of 6,12-diaryl-5,11-dihydroindolo[3,2-b]carbazoles.     

Mechanical and frictional properties of nanoparticle monolayers grafted on functionalized mica substrates

Normal and lateral forces between two opposing monolayers of grafted polymer nanoparticles (NPs) were measured using the Surface Forces Apparatus in a humid atmosphere. The NPs made of N, N-diethylacrylamide and 2-hydroxyethyl methacrylate have a hydrodynamic diameter of ca. 660 nm at 25 degrees C. The effect of surface roughness was studied by creating surface asperities using different NP grafting densities ranging from 0.41 to 2.63 NPs/mum (2). An increase in the NPs grafting density gave rise to an increase in surface roughness and to a deformation of the nanoparticles caused by the lateral pressure between neighboring particles. An elastoplastic behavior of the nanoparticles was observed for large grafting densities, while a purely elastic behavior was observed for small grafting densities. The lateral forces measured between two opposing NP monolayers sliding past each other followed Amontons' law for all grafting densities. The friction coefficient between the surfaces appeared to increase significantly with an increase in surface roughness, which was inherent to an increase in the elastoplastic behavior of the NP monolayers.