Sustaining attention in affective contexts during adolescence: age-related differences and association with elevated symptoms of depression and anxiety.

Sustained attention, a key cognitive skill that improves during childhood and adolescence, tends to be worse in some emotional and behavioural disorders. Sustained attention is typically studied in non-affective task contexts; here, we used a novel task to index performance in affective versus neutral contexts across adolescence (N = 465; ages 11-18). We asked whether: (i) performance would be worse in negative versus neutral task contexts; (ii) performance would improve with age; (iii) affective interference would be greater in younger adolescents; (iv) adolescents at risk for depression and higher in anxiety would show overall worse performance; and (v) would show differential performance in negative contexts. Results indicated that participants performed more poorly in negative contexts and showed age-related performance improvements. Those at risk of depression performed more poorly than those at lower risk. However, there was no difference between groups as a result of affective context. For anxiety there was no difference in performance as a function of severity. However, those with higher anxiety showed less variance in their reaction times to negative stimuli than those with lower anxiety. One interpretation is that moderate levels of emotional arousal associated with anxiety make individuals less susceptible to the distracting effects of negative stimuli.

Case Series: Hepatic and Splenic Titanium Dioxide Deposition in Association With Intravenous Drug Use.

ABSTRACT: Titanium dioxide is a versatile compound that is found in a variety of consumer products, medical hardware, and pharmaceuticals. Although oral and topical ingestion of this compound is common, intravenous introduction is much less common. We present three cases where significant titanium dioxide deposits were identified in liver and splenic tissue of three decedents, all of whom died of illicit drug overdose in the same geographic area and had fentanyl and its metabolites in blood on postmortem toxicologic testing. At autopsy, liver sections had a granular texture with fine white stippling grossly, and histologic examination of hepatic and splenic tissues showed scattered patches of black granular material with pink birefringence. Energy-dispersive x-ray spectroscopy performed on these tissues revealed the presences of clusters of titanium dioxide. Immunohistochemical staining of both the liver and spleen with CD68 confirmed the titanium dioxide clusters were within macrophages. Intravenous titanium dioxide nanoparticle elimination studies in rats suggest a time sensitive period for this elimination, with a transient period of pigment deposition between 1-58 days following injection. If a time-dependent link between titanium dioxide pigment deposition within tissues and intravenous drug use can be shown, this could be a valuable tool for Pathologists.

First Evidence of Axial Shape Asymmetry and Configuration Coexistence in

The excited states of N=44 ^{74}Zn were investigated via γ-ray spectroscopy following ^{74}Cu ß decay. By exploiting γ-γ angular correlation analysis, the 2_{2}^{+}, 3_{1}^{+}, 0_{2}^{+}, and 2_{3}^{+} states in ^{74}Zn were firmly established. The γ-ray branching and E2/M1 mixing ratios for transitions deexciting the 2_{2}^{+}, 3_{1}^{+}, and 2_{3}^{+} states were measured, allowing for the extraction of relative B(E2) values. In particular, the 2_{3}^{+}→0_{2}^{+} and 2_{3}^{+}→4_{1}^{+} transitions were observed for the first time. The results show excellent agreement with new microscopic large-scale shell-model calculations, and are discussed in terms of underlying shapes, as well as the role of neutron excitations across the N=40 gap. Enhanced axial shape asymmetry (triaxiality) is suggested to characterize ^{74}Zn in its ground state. Furthermore, an excited K=0 band with a significantly larger softness in its shape is identified. A shore of the N=40 "island of inversion" appears to manifest above Z=26, previously thought as its northern limit in the chart of the nuclides.

ß-Delayed One and Two Neutron Emission Probabilities Southeast of

The ß-delayed one- and two-neutron emission probabilities (P_{1n} and P_{2n}) of 20 neutron-rich nuclei with N≥82 have been measured at the RIBF facility of the RIKEN Nishina Center. P_{1n} of ^{130,131}Ag, ^{133,134}Cd, ^{135,136}In, and ^{138,139}Sn were determined for the first time, and stringent upper limits were placed on P_{2n} for nearly all cases. ß-delayed two-neutron emission (ß2n) was unambiguously identified in ^{133}Cd and ^{135,136}In, and their P_{2n} were measured. Weak ß2n was also detected from ^{137,138}Sn. Our results highlight the effect of the N=82 and Z=50 shell closures on ß-delayed neutron emission probability and provide stringent benchmarks for newly developed macroscopic-microscopic and self-consistent global models with the inclusion of a statistical treatment of neutron and γ emission. The impact of our measurements on r-process nucleosynthesis was studied in a neutron star merger scenario. Our P_{1n} and P_{2n} have a direct impact on the odd-even staggering of the final abundance, improving the agreement between calculated and observed Solar System abundances. The odd isotope fraction of Ba in r-process-enhanced (r-II) stars is also better reproduced using our new data.

Effect of bovine feeding system (pasture or concentrate) on the oxidative and sensory shelf life of whole milk powder.

Correlating volatile compounds with the sensory attributes of whole milk powder (WMP) is fundamental for appreciating the effect of lipid oxidation (LO) on sensory perception. LO compounds can adversely affect the sensory perception of WMP by imparting rancid, metallic, and painty notes. Whole milk powders derived from milk produced by cows maintained on a pasture diet (grass and grass-clover mix) versus a nonpasture diet [total mixed ration (TMR); concentrates and silage] were stored at room temperature 21°C (ambient storage) and 37°C (accelerated storage) and analyzed for volatile compounds and sensory attributes every 2 mo for a total of 6 mo. Thirteen volatile compounds originating from LO were chosen to track the volatile profile of the WMP during storage. Color, composition, total fatty acid, and free fatty acid profiling were also carried out. Significant variations in the concentrations of 14 fatty acids were observed in WMP based on diet. Concentrations of free fatty acids increased in all sample types during storage. Similar trends in sensory attributes were observed with an increase in painty attributes, corresponding to an increase in hexanal. Buttery/toffee attributes were found to be more closely correlated with TMR WMP. Those WMP derived from pasture diets were found to be more susceptible to LO from a volatile perspective, particularly in relation to aldehyde development, which is likely due to increased concentrations of conjugated linoleic acid and α-linolenic acid found in these samples.

Susceptibility to prosocial and antisocial influence in adolescence.

INTRODUCTION: Adolescents are particularly susceptible to social influence and previous studies have shown that this susceptibility decreases with age. The current study used a cross-sectional experimental paradigm to investigate the effect of age and puberty on susceptibility to both prosocial and antisocial influence. METHODS: Participants (N = 520) aged 11-18 from London and Cambridge (United Kingdom) rated how likely they would be to engage in a prosocial (e.g. "help a classmate with their work") or antisocial (e.g. "make fun of a classmate") act. They were then shown the average rating (in fact fictitious) that other adolescents had given to the same question, and were then asked to rate the same behaviour again. RESULTS: Both prosocial and antisocial influence decreased linearly with age, with younger adolescents being more socially influenced when other adolescents' ratings were more prosocial and less antisocial than their own initial rating. Both antisocial and prosocial influence significantly decreased across puberty for boys but not girls (independent of age). CONCLUSIONS: These findings suggest that social influence declines with increasing maturity across adolescence. However, the exact relationship between social influence and maturity is dependent on the nature of the social influence and gender. Understanding when adolescents are most susceptible to different types of social influence, and how this might influence their social behaviour, has important implications for understanding adolescent social development.

Developmental patterns and variation among early theropods.

Understanding ontogenetic patterns is important in vertebrate paleontology because the assessed skeletal maturity of an individual often has implications for paleobiogeography, species synonymy, paleobiology, and body size evolution of major clades. Further, for many groups the only means of confidently determining ontogenetic status of an organism is through the destructive process of histological sampling. Although the ontogenetic patterns of Late Jurassic and Cretaceous dinosaurs are better understood, knowledge of the ontogeny of the earliest dinosaurs is relatively poor because most species-level growth series known from these groups are small (usually, maximum of n ~ 5) and incomplete. To investigate the morphological changes that occur during ontogeny in early dinosaurs, I used ontogenetic sequence analysis (OSA) to reconstruct developmental sequences of morphological changes in the postcranial ontogeny of the early theropods Coelophysis bauri and Megapnosaurus rhodesiensis, both of which are known from large sample sizes (n = 174 and 182, respectively). I found a large amount of sequence polymorphism (i.e. intraspecific variation in developmental patterns) in both taxa, and especially in C. bauri, which possesses this variation in every element analyzed. Megapnosaurus rhodesiensis is similar, but it possesses no variation in the sequence of development of ontogenetic characters in the tibia and tarsus. Despite the large amount of variation in development, many characters occur consistently earlier or later in ontogeny and could therefore be important morphological features for assessing the relative maturity of other early theropods. Additionally, there is a phylogenetic signal to the order in which homologous characters appear in ontogeny, with homologous characters appearing earlier or later in developmental sequences of early theropods and the close relatives of dinosaurs, silesaurids. Many of these morphological features are important characters for the reconstruction of archosaurian phylogeny (e.g. trochanteric shelf). Because these features vary in presence or appearance with ontogeny, these characters should be used with caution when undertaking phylogenetic analyses in these groups, since a specimen may possess certain character states owing to ontogenetic stage, not evolutionary relationships.

Using species traits to predict detectability of animals on aerial surveys.

In animal surveys, detectability can vary widely across species. We hypothesized that detectability of animals should be a function of species traits such as mass, color, and mean herd size. We also hypothesized that models of detectability based on species traits can be used to predict detectability for new species not in the original data set, leading to substantial benefits for ecology and conservation. We tested these hypotheses with double-observer aerial surveys of 10 mammal species in northern Botswana. We combined all 10 species and modeled their detectability with species traits (mass, mean herd size, color) as predictors while controlling for observer effects, vegetation, and herd size. We found support for effects of mass and an interaction between herd size and mean herd size on detectability. This model accurately predicted the ratio of herds detected by two observers vs. one observer for 8 of 10 species. To test whether a model based on species traits could be applied to a new species, we serially deleted each species from the data set, fit a trait-based model to the remaining nine species, and used this model to predict detectability for the deleted species. The model was able to reproduce the species-trait model for seven species and accurately predicted the ratio of detections by one or two observers for a different set of seven species; the model was successful by both measures for five species. To our knowledge, this represents the first time that a mechanistic model for detectability of animals has been used to predict detectability for new species. Prediction failed for species with extreme values of traits, suggesting that predicting detectability is not possible near or beyond the boundaries of one's data set. The approach taken in this paper can potentially be used with a variety of taxa and may provide new opportunities to apply detectability corrections where they have not been possible before.

Can acoustic radiation force imaging of the liver and spleen predict the presence of gastroesophageal varices?

AIM: To determine whether acoustic radiation force imaging (ARFI) of the liver/spleen could be used in patients with cirrhosis to predict the presence of gastroesophageal varices (GOVs). MATERIALS AND METHODS: Fifty-eight patients with cirrhosis who were undergoing 6-monthly ultrasound examinations for hepatoma surveillance and who were due to have oesophagogastroduodenoscopy (OGD) within 6 months of their ultrasound were recruited. During routine ultrasound, the patient's liver and spleen were also assessed using ARFI. Other clinical parameters (platelet count, spleen size, and transient elastography measurements) were also collected. Logistic regression was used to determine which variables were significantly associated with presence or absence of varices univariably and multivariably RESULTS: Fourteen patients (24%) had GOVs. Patients with GOVs had higher ARFI measurements in the liver and spleen than patients without GOVs (liver: 2.39 versus 2.13, spleen: 2.89 versus 2.82), but these results were not statistically significant (odds ratio=1.75, 95% confidence interval [CI]=0.82, 3.91 and odds ratio=1.12, 95% CI=0.33, 3.97, respectively). The platelet/splenic ratio, in comparison, was associated with the presence or absence of GOVs in multivariate analysis (odds ratio=0.32, 95% CI=0.008, 0.91). CONCLUSION: Although patients with GOVs had overall higher ARFI liver and spleen results, this was not statistically significant. As such, ARFI cannot yet replace OGD in predicting GOVs in this patient group.

A Multibacteriocin Cheese Starter System, Comprising Nisin and Lacticin 3147 in Lactococcus lactis, in Combination with Plantaricin from Lactobacillus plantarum.

Functional starter cultures demonstrating superior technological and food safety properties are advantageous to the food fermentation industry. We evaluated the efficacies of single- and double-bacteriocin-producing starters of Lactococcus lactis capable of producing the class I bacteriocins nisin A and/or lacticin 3147 in terms of starter performance. Single producers were generated by mobilizing the conjugative bacteriophage resistance plasmid pMRC01, carrying lacticin genetic determinants, or the conjugative transposon Tn5276, carrying nisin genetic determinants, to the commercial starter L. lactis CSK2775. The effect of bacteriocin coproduction was examined by superimposing pMRC01 into the newly constructed nisin transconjugant. Transconjugants were improved with regard to antimicrobial activity and bacteriophage insensitivity compared to the recipient strain, and the double producer was immune to both bacteriocins. Bacteriocin production in the starter was stable, although the recipient strain proved to be a more efficient acidifier than transconjugant derivatives. Overall, combinations of class I bacteriocins (the double producer or a combination of single producers) proved to be as effective as individual bacteriocins for controlling Listeria innocua growth in laboratory-scale cheeses. However, using the double producer in combination with the class II bacteriocin producer Lactobacillus plantarum or using the lacticin producer with the class II producer proved to be most effective for reducing bacterial load. As emergence of bacteriocin tolerance was reduced 10-fold in the presence of nisin and lacticin, we suggest that the double producer in conjunction with the class II producer could serve as a protective culture providing a food-grade, multihurdle approach to control pathogenic growth in a variety of industrial applications.IMPORTANCE We generated a suite of single- and double-bacteriocin-producing starter cultures capable of generating the class I bacteriocin lacticin 3147 or nisin or both bacteriocins simultaneously via conjugation. The transconjugants exhibited improved bacteriophage resistance and antimicrobial activity. The single producers proved to be as effective as the double-bacteriocin producer at reducing Listeria numbers in laboratory-scale cheese. However, combining the double producer or the lacticin-producing starter with a class II bacteriocin producer, Lactobacillus plantarum LMG P-26358, proved to be most effective at reducing Listeria numbers and was significantly better than a combination of the three bacteriocin-producing strains, as the double producer is not inhibited by either of the class I bacteriocins. Since the simultaneous use of lacticin and nisin should reduce the emergence of bacteriocin-tolerant derivatives, this study suggests that a protective starter system produced by bacteriocin stacking is a worthwhile multihurdle approach for food safety applications.

94 ß-Decay Half-Lives of Neutron-Rich _{55}Cs to _{67}Ho: Experimental Feedback and Evaluation of the r-Process Rare-Earth Peak Formation.

The ß-decay half-lives of 94 neutron-rich nuclei ^{144-151}Cs, ^{146-154}Ba, ^{148-156}La, ^{150-158}Ce, ^{153-160}Pr, ^{156-162}Nd, ^{159-163}Pm, ^{160-166}Sm, ^{161-168}Eu, ^{165-170}Gd, ^{166-172}Tb, ^{169-173}Dy, ^{172-175}Ho, and two isomeric states ^{174m}Er, ^{172m}Dy were measured at the Radioactive Isotope Beam Factory, providing a new experimental basis to test theoretical models. Strikingly large drops of ß-decay half-lives are observed at neutron-number N=97 for _{58}Ce, _{59}Pr, _{60}Nd, and _{62}Sm, and N=105 for _{63}Eu, _{64}Gd, _{65}Tb, and _{66}Dy. Features in the data mirror the interplay between pairing effects and microscopic structure. r-process network calculations performed for a range of mass models and astrophysical conditions show that the 57 half-lives measured for the first time play an important role in shaping the abundance pattern of rare-earth elements in the solar system.

Sexually dimorphic myeloid inflammatory and metabolic responses to diet-induced obesity.

It is well known in clinical and animal studies that women and men have different disease risk as well as different disease physiology. Women of reproductive age are protected from metabolic and cardiovascular disease compared with postmenopausal women and men. Most murine studies are skewed toward the use of male mice to study obesity-induced metabolic dysfunction because of similar protection in female mice. We have investigated dietary obesity in a mouse model and have directly compared inflammatory responses in males and females. In this review we will summarize what is known about sex differences in diet-induced inflammation and will summarize our data on this topic. It is clear that sex differences in high-fat diet-induced inflammatory activation are due to cell intrinsic differences in hematopoietic responses to obesogenic cues, but further research is needed to understand what leads to sexually dimorphic responses.

Higher relatedness mitigates mortality in a nematode with lethal male fighting.

According to kin selection theory, individuals show less aggression towards their relatives. Limited dispersal promotes interactions among relatives but also increases competition among them. The evolution of cooperation in viscous populations has been subject of mainly theoretical exploration. We investigated the influence of relatedness on aggression in males of entomopathogenic nematode Steinernema longicaudum that engage in lethal fighting. In a series of in vitro experiments, we found that both competitor male group size and relatedness influence male mortality rates. Higher relatedness led to progressively lower rates of male mortality. In experimentally infected insects, wherein large numbers of males and females interact, the proportion of dead and paralysed (= terminally injured) males was higher when infection was established by infective juveniles originating from a mixture of three lines than in those infected by a single line. The results collectively show that Steinernema longicaudum males recognize their kin and consequently male mortality rates are lower in groups consisting of more related males. Furthermore, this monotonic negative relationship between aggression and relatedness suggests that kin selection benefits are still substantial even under extreme competition. Our experiments also suggest that kin recognition in entomopathogenic nematodes has a genetic basis rather than being strictly based on environmental cues. We discuss our findings within the theoretical context of the evolution of altruistic/cooperative behaviour in structured populations.

Repeat duplex ultrasound scanning in suspected Deep Vein Thrombosis (DVT): putting the onus back on the referring clinician.

Duplex scanning is utilised by many departments in the investigation of suspected DVT. NICE Guideline CG144 recommended repeat scanning for patients in whom the initial Wells score was 'likely' in the presence of a raised D-Dimer, following a normal first scan. Following implementation of this recommendation in our department there was a dramatic rise in the number of repeat scans being undertaken, all of which were negative for DVT. Introduction of an electronic message to the report, placing the onus back on the referring clinician to arrange repeat scan if deemed appropriate resulted in a fall in the number of scans being undertaken without impacting on patient outcome.

Learning from the QUEST multicentre feasibility randomization trials in breast reconstruction after mastectomy.

BACKGROUND: Breast reconstruction aims to improve health-related quality of life after mastectomy. However, evidence guiding patients and surgeons in shared decision-making concerning the optimal type or timing of surgery is lacking. METHODS: QUEST comprised two parallel feasibility phase III randomized multicentre trials to assess the impact of the type and timing of latissimus dorsi breast reconstruction on health-related quality of life when postmastectomy radiotherapy is unlikely (QUEST A) or highly probable (QUEST B). The primary endpoint for the feasibility phase was the proportion of women who accepted randomization, and it would be considered feasible if patient acceptability rates exceeded 25 per cent of women approached. A companion QUEST Perspectives Study (QPS) of patients (both accepting and declining trial participation) and healthcare professionals assessed trial acceptability. RESULTS: The QUEST trials opened in 15 UK centres. After 18 months of recruitment, 17 patients were randomized to QUEST A and eight to QUEST B, with overall acceptance rates of 19 per cent (17 of 88) and 22 per cent (8 of 36) respectively. The QPS recruited 56 patients and 51 healthcare professionals. Patient preference was the predominant reason for declining trial entry, given by 47 (53 per cent) of the 88 patients approached for QUEST A and 22 (61 per cent) of the 36 approached for QUEST B. Both trials closed to recruitment in December 2012, acknowledging the challenges of achieving satisfactory patient accrual. CONCLUSION: Despite extensive efforts to overcome recruitment barriers, it was not feasible to reach timely recruitment targets within a feasibility study. Patient preferences for breast reconstruction types and timings were common, rendering patients unwilling to enter the trial.

Characterization of placentome vascular perfusion in relation to pregnancy associated glycoproteins throughout gestation in pregnant beef heifers.

During pregnancy, blood flow to the uterus changes to support fetal demand. Placentomes serve as vascular attachment sites on the placenta for exchange of gases, nutrients, and metabolic products. Non-invasive methods of ultrasonography and biomarkers have been described to assess placental health and fetal viability. Pregnancy associated glycoproteins (PAGs) are produced by the ruminant placenta and are detected in maternal circulation. In cattle, changes in circulating PAG concentrations are associated with embryonic and fetal outcomes. The objective of this study was to determine the association between placentome blood perfusion and circulating PAG concentrations as they relate to the health of the developing fetus. We hypothesized that placentome perfusion and PAG concentration will be positively correlated and associated with neonatal outcome. A prospective, observational study was designed using 26 pregnant, nulliparous, Angus heifers in which PAG concentration and placentome blood perfusion were assessed throughout gestation, with assessment of calving characteristics following parturition. Placentome blood perfusion was visualized at 30-day intervals via transrectal Doppler ultrasonography with power flow function. Ultrasound images were analyzed using ImageJ software to determine the percent area of perfusion and integrated pixel densities. Venous blood was collected and PAG concentrations were determined via serum PAG enzyme-linked immunoassay. Mean placentome blood perfusion increased as gestation advanced. PAG concentrations demonstrated the expected temporal trend, increasing with gestation length, and were positively linearly correlated with placentome perfusion (P < 0.0001). The relationship identified between circulating PAG concentration and placentome blood perfusion suggests the use of transrectal power flow Doppler ultrasonography as a noninvasive technique to determine placental blood flow morphometrics to assess conceptus wellbeing throughout pregnancy.

Chronic inflammation decreases arcuate kisspeptin expression in male sheep.

Lipopolysaccharide (LPS) from Gram-negative bacteria induces an immune response and impairs reproduction through suppression of gonadotropin releasing hormone (GnRH), subsequently luteinizing hormone (LH) secretion. While there is evidence that acute inflammation inhibits kisspeptin, little is known about the impact of chronic inflammation on this key reproductive neuropeptide in livestock species. Thus, we sought to examine a central mechanism whereby LPS suppresses LH secretion in sheep. Twenty wethers were randomly assigned to one of five treatment groups: control (CON; n=4), single acute IV LPS dose (SAD; n=4), daily acute IV LPS dose (DAD; n=4), daily increasing IV LPS dose (DID; n=4), and chronic subcutaneous LPS dose (CSD; n=4). On Days 1 and 7, blood samples were collected every 12 minutes for 360 minutes using jugular venipuncture. Following blood collection on Day 7, all animals were euthanized, brain tissue was perfused with 4% paraformaldehyde, and hypothalamic blocks were removed and processed for immunohistochemistry. On Day 1, LH pulse frequency was significantly lower (p=0.02) in SAD (0.25 ± 0.1 pulses/hour), DAD (0.25 ± 0.1 pulses/hour), DID (0.35 ± 0.1 pulses/hour), and CSD (0.40 ± 0.1 pulses/hour) compared to CON (0.70 ±0.1 pulses/hour). On Day 7, only DID animals (0.35 ± 0.1 pulses/hour) had significantly lower (p=0.049) LH pulse frequency compared to controls (0.85 ± 0.1 pulse/hour). Furthermore, only DID animals (33.3 ± 10.9 cells/section/animal) had significantly fewer (p=0.001) kisspeptin-immunopositive cells compared to controls (82.6 ± 13.6 cells/section/animal). Taken together, we suggest that daily increasing doses of LPS is a powerful inhibitor of kisspeptin neurons in young male sheep and a physiologically relevant model to examine the impact of chronic inflammation on the reproductive axis in livestock.

Size-Tunable Band Structure and Optical Properties of Colloidal Silicon Nanocrystals Synthesized via Thermal Disproportionation of Hydrogen Silsesquioxane Polymers.

Dodecane-capped silicon nanocrystals (NCs) were synthesized by using a low-temperature (800-1100 °C) polymer variant of traditional hydrogen silsesquioxane thermal disproportionation. Highly crystalline Si NCs having tunable diameters (3.0-6.7 nm) and thus photoluminescence (PL) peaks (1.68-1.29 eV) were attained via changes in the maximum annealing temperature. Modifications in the NC band structure with diameter were explored by comparison of emission with absorption spectra obtained from diffuse reflectance spectroscopy. Large apparent energy shifts between onsets and PL were noted, being significant for smaller NCs (≤∼4.0 nm). This, along with comparatively "softer" onsets, is commensurate with density of states elongation around PL peaks associated with increasing confinement predicted for indirect semiconductor nanostructures. Tauc analyses of absorption additionally revealed three distinguishable optical transitions in all NCs: attributed to indirect Γ25'-Δ1 in lower energy ranges (likely the emission progenitor), indirect Γ25'-L1 overtaken by quasi-direct Γ-X wave function mixing for NC diameters ≤∼4.0 nm within the midenergy regime, and direct Γ25'-Γ15 transitions at energies nearing and above ∼3 eV.

Self-Assembling Peptide-Based High-Relaxivity Targeted MRI Contrast Agents.

Concentration-dependent increases in relaxivity (r1) were found to be induced by self-assembly when Fmoc is adjacent to tryptophan in peptide-based MRI contrast agents featuring Gd-DOTA.  A series of di- and tri-peptides were synthesized to test the effect of ionic strength, N-terminal substituent, peptide length, net charge, and relative location of Fmoc and tryptophan on r1 and critical aggregation concentration (CAC) at 1.0 Tesla. Compared to nominal r1 values of 3.5-7.4 mM-1s-1 per Gd(III), r1 values increased dramatically to 13.2-16.9 mM-1s-1 per Gd(III) upon self-assembly, with CACs between 0.22 and 2.59 mM when tested in H2O or PBS. When tested in fetal bovine serum (FBS), the compounds maintained high r1 values of 11.2-13.0 mM-1s-1, but had dramatically lower CAC values below 25 µM. These findings guided the synthesis of two targeted, high-relaxivity MRI contrast agents that contained PSMA-binding ligand, DCL. Their r1 values in H2O or PBS increased from 5.9-7.4 mM-1s-1 to 13.5-14.8 mM-1s-1 with CAC values of 1.65-2.70 mM. In FBS, their r1 values were found to be 11.2-11.9 mM-1s-1, with CAC values below 25 µM. By the conjugation of targeting agents in the last step of synthesis, a broadly applicable route to targeted, high-relaxivity MRI contrast agents is offered.