Noninvasive Determination of 2-[18F]-Fluoroisonicotinic Acid Hydrazide Pharmacokinetics by Positron Emission Tomography in Mycobacterium tuberculosis-Infected Mice

Tuberculosis (TB) is a global pandemic requiring sustained therapy to facilitate curing and to prevent the emergence of drug resistance. There are few adequate tools to evaluate drug dynamics within infected tissues in vivo. In this report, we evaluated a fluorinated analog of isoniazid (INH), 2-[18F]fluoroisonicotinic acid hydrazide (2-[18F]-INH), as a probe for imaging Mycobacterium tuberculosis-infected mice by dynamic positron emission tomography (PET). We developed a tail vein catheter system to safely deliver drugs to M. tuberculosis aerosol-infected mice inside sealed biocontainment devices. Imaging was rapid and noninvasive, and it could simultaneously visualize multiple tissues. Dynamic PET imaging demonstrated that 2-[18F]-INH was extensively distributed and rapidly accumulated at the sites of infection, including necrotic pulmonary TB lesions. Compared to uninfected animals, M. tuberculosis-infected mice had a significantly higher PET signal within the lungs (P 0.85), suggesting that 2-[18F]-INH accumulated at the site of the pulmonary infection. Furthermore, our data indicated that similar to INH, 2-[18F]-INH required specific activation and accumulated within the bacterium. Pathogen-specific metabolism makes positron-emitting INH analogs attractive candidates for development into imaging probes with the potential to both detect bacteria and yield pharmacokinetic data in situ. Since PET imaging is currently used clinically, this approach could be translated from preclinical studies to use in humans.Chemistry and Chemical Biolog

Ultrafast Structural Dynamics of BlsA, a Photoreceptor from the Pathogenic Bacterium Acinetobacter baumannii

Acinetobacter baumannii is an important human pathogen that can form biofilms and persist under harsh environmental conditions. Biofilm formation and virulence are modulated by blue light, which is thought to be regulated by a BLUF protein, BlsA. To understand the molecular mechanism of light sensing, we have used steady-state and ultrafast vibrational spectroscopy to compare the photoactivation mechanism of BlsA to the BLUF photosensor AppA from Rhodobacter sphaeroides. Although similar photocycles are observed, vibrational data together with homology modeling identify significant differences in the β5 strand in BlsA caused by photoactivation, which are proposed to be directly linked to downstream signaling

One-to-one direct modeling of experiments and astrophysical scenarios: pushing the envelope on kinetic plasma simulations

There are many astrophysical and laboratory scenarios where kinetic effects play an important role. These range from astrophysical shocks and plasma shell collisions, to high intensity laser-plasma interactions, with applications to fast ignition and particle acceleration. Further understanding of these scenarios requires detailed numerical modelling, but fully relativistic kinetic codes are computationally intensive, and the goal of one-to-one direct modelling of such scenarios and direct comparison with experimental results is still difficult to achieve. In this paper we discuss the issues involved in performing kinetic plasma simulations of experiments and astrophysical scenarios, focusing on what needs to be achieved for one-to-one direct modeling, and the computational requirements involved. We focus on code efficiency and new algorithms, specifically on parallel scalability issues, namely on dynamic load balancing, and on high-order interpolation and boosted frame simulations to optimize simulation performance. We also discuss the new visualization and data mining tools required for these numerical experiments and recent simulation work illustrating these techniques is also presented.Comment: 10 pages, 5 figure

Development of parent- and teacher-reported emotional and behavioural problems in young people with intellectual disabilities: Does level of ID matter?

This study described similarities and differences in the 5-year stability and change of problem behaviour between youths attending schools for children with mild to borderline (MiID) versus moderate intellectual disabilities (MoID). A two-wave multiple-birth-cohort sample of 6 to 18-year-old was assessed twice across a 5-year interval using the Developmental Behaviour Checklist Primary Carer version (n = 718) and Teacher version (n = 313). For most types of problem behaviour youths with MiID and MoID showed similar levels of stability of individual differences, persistence and onset of psychopathology. Whenever differences were found, youths with MoID showed the highest level of stability, persistence and onset across informants. Mean levels of parent-reported, but not teacher-reported, problem behaviour, regardless of level of intellectual disability, decreased during the 5-year follow-up period. Youths with MoID and MiID are at risk for persistent psychopathology to a similar degree. Different informants showed to have a different evaluation of the level and the amount of change of problem behaviour, and should be considered complementary in the diagnostic process. © 2007 BILD Publications

Unbounded violation of tripartite Bell inequalities

We prove that there are tripartite quantum states (constructed from random unitaries) that can lead to arbitrarily large violations of Bell inequalities for dichotomic observables. As a consequence these states can withstand an arbitrary amount of white noise before they admit a description within a local hidden variable model. This is in sharp contrast with the bipartite case, where all violations are bounded by Grothendieck's constant. We will discuss the possibility of determining the Hilbert space dimension from the obtained violation and comment on implications for communication complexity theory. Moreover, we show that the violation obtained from generalized GHZ states is always bounded so that, in contrast to many other contexts, GHZ states do in this case not lead to extremal quantum correlations. The results are based on tools from the theories of operator spaces and tensor norms which we exploit to prove the existence of bounded but not completely bounded trilinear forms from commutative C*-algebras.Comment: Substantial changes in the presentation to make the paper more accessible for a non-specialized reade

Functional dynamics of a single tryptophan residue in a BLUF protein revealed by fluorescence spectroscopy

Blue Light Using Flavin (BLUF) domains are increasingly being adopted for use in optogenetic constructs. Despite this, much remains to be resolved on the mechanism of their activation. The advent of unnatural amino acid mutagenesis opens up a new toolbox for the study of protein structural dynamics. The tryptophan analogue, 7-aza-Trp (7AW) was incorporated in the BLUF domain of the Activation of Photopigment and pucA (AppA) photoreceptor in order to investigate the functional dynamics of the crucial W104 residue during photoactivation of the protein. The 7-aza modification to Trp makes selective excitation possible using 310 nm excitation and 380 nm emission, separating the signals of interest from other Trp and Tyr residues. We used Förster energy transfer (FRET) between 7AW and the flavin to estimate the distance between Trp and flavin in both the light- and dark-adapted states in solution. Nanosecond fluorescence anisotropy decay and picosecond fluorescence lifetime measurements for the flavin revealed a rather dynamic picture for the tryptophan residue. In the dark-adapted state, the major population of W104 is pointing away from the flavin and can move freely, in contrast to previous results reported in the literature. Upon blue-light excitation, the dominant tryptophan population is reorganized, moves closer to the flavin occupying a rigidly bound state participating in the hydrogen-bond network around the flavin molecule

Opportunities for process intensification technologies in nuclear effluent treatment: A review of precipitators, adsorbers and separators

This paper reviews the technologies and opportunities for process intensification (PI) in nuclear effluent treatment. PI is an area that has already created many innovations within the chemicals industry, and offers a growing field of research and development potential for nuclear operations. Technologies are considered here to be those ultimately resulting in step-change improvements to a number of operational aspects; such as smaller unit footprints, enhanced heat and mass transfer, reduction in secondary wastes, improved process safety and synergy, or direct integration with other downstream processes. Herein, we conduct a rigorous evaluation and scoping assessment of unit designs for the treatment of nuclear liquid effluents and solid-liquid waste management. Specific focus is given to precipitation, adsorption and separation operations, where over 250 articles are detailed, and prospects for technology transfer are discussed. In general, there is a trade-off in PI designs between operational simplicity (which may be more easily adopted in nuclear treatments) and more mechanically complex strategies that may, however, attain suitable scale-up requirements. Analysed options vary from those that would be radically different for industry, to those where applications are increasingly common in other process areas, with the advantages and limitations of all being discussed

BLUF Domain Function Does Not Require a Metastable Radical Intermediate State

BLUF (blue light using flavin) domain proteins are an important family of blue light-sensing proteins which control a wide variety of functions in cells. The primary light-activated step in the BLUF domain is not yet established. A number of experimental and theoretical studies points to a role for photoinduced electron transfer (PET) between a highly conserved tyrosine and the flavin chromophore to form a radical intermediate state. Here we investigate the role of PET in three different BLUF proteins, using ultrafast broadband transient infrared spectroscopy. We characterize and identify infrared active marker modes for excited and ground state species and use them to record photochemical dynamics in the proteins. We also generate mutants which unambiguously show PET and, through isotope labeling of the protein and the chromophore, are able to assign modes characteristic of both flavin and protein radical states. We find that these radical intermediates are not observed in two of the three BLUF domains studied, casting doubt on the importance of the formation of a population of radical intermediates in the BLUF photocycle. Further, unnatural amino acid mutagenesis is used to replace the conserved tyrosine with fluorotyrosines, thus modifying the driving force for the proposed electron transfer reaction; the rate changes observed are also not consistent with a PET mechanism. Thus, while intermediates of PET reactions can be observed in BLUF proteins they are not correlated with photoactivity, suggesting that radical intermediates are not central to their operation. Alternative nonradical pathways including a keto–enol tautomerization induced by electronic excitation of the flavin ring are considered

Controlling Tungiasis in an Impoverished Community: An Intervention Study

Tungiasis is a disease caused by the sand flea Tunga penetrans, a parasite prevalent in many impoverished communities in developing countries. The female sand flea penetrates into the skin of animals and humans where it grows rapidly in size, feeds on the host's blood, produces eggs which are expelled into the environment, and eventually dies in situ. The lesions become frequently superinfected and the infestation is associated with considerable morbidity. Clearly, tungiasis is a neglected disease of neglected populations. We investigated the impact of a package of intervention measures targeted against on-host and off-host stages of T. penetrans in a fishing community in Northeast Brazil. These measures decreased disease occurrence only temporarily, but had a sustained effect on the intensity of the infestation. Since infestation intensity and morbidity are correlated, presumably the intervention also lowered tungiasis-associated morbidity. Control measures similar to the ones used in this study may help to effectively control tungiasis in impoverished communities

The Ritvo Autism Asperger Diagnostic Scale-Revised (RAADS-R): A Scale to Assist the Diagnosis of Autism Spectrum Disorder in Adults: An International Validation Study

The Ritvo Autism Asperger Diagnostic Scale-Revised (RAADS-R) is a valid and reliable instrument to assist the diagnosis of adults with Autism Spectrum Disorders (ASD). The 80-question scale was administered to 779 subjects (201 ASD and 578 comparisons). All ASD subjects met inclusion criteria: DSM-IV-TR, ADI/ADOS diagnoses and standardized IQ testing. Mean scores for each of the questions and total mean ASD vs. the comparison groups’ scores were significantly different (p < .0001). Concurrent validity with Constantino Social Responsiveness Scale-Adult = 95.59%. Sensitivity = 97%, specificity = 100%, test–retest reliability r = .987. Cronbach alpha coefficients for the subscales and 4 derived factors were good. We conclude that the RAADS-R is a useful adjunct diagnostic tool for adults with ASD