Automated light-induced synthesis of 89Zr-radiolabeled antibodies for immuno-positron emission tomography

Clinical production of 89Zr-radiolabeled antibodies (89Zr-mAbs) for positron emission tomography imaging relies on the pre-conjugation of desferrioxamine B (DFO) to the purified protein, followed by isolation and characterization of the functionalized intermediate, and then manual radiosynthesis. Although highly successful, this route exposes radiochemists to a potentially large radiation dose and entails several technological and economic hurdles that limit access of 89Zr-mAbs to just a specialist few Nuclear Medicine facilities worldwide. Here, we introduce a fully automated synthesis box that can produce individual doses of 89Zr-mAbs formulated in sterile solution in 99%, and chemical purity > 99%. The synthesis unit can also produce 89Zr-mAbs via the conventional radiolabeling routes from pre-functionalized DFO-mAbs that are currently used in the clinic. This automated method will improve access to state-of-the-art 89Zr-mAbs at the many Nuclear Medicine and research institutions that require automated devices for radiotracer production

Photoactivatable Fluorescent Tags for Dual-Modality Positron Emission Tomography Optical Imaging

Fluorescent protein conjugates are vital tools in a wide range of scientific disciplines from basic biochemical research to applications in clinical pathology and intraoperative surgery. We report the synthesis and characterization of photoactivatable fluorophores (PhotoTags) based on the functionalization of coumarin, fluorescein, BODIPY, rhodamine B, and cyanine dyes with a photochemically active aryl azide group. Photochemical labeling experiments using human serum albumin produced fluorescent proteins in high yields under irradiation with ultraviolet light for <15 min. We also synthesized DFO-RhodB-PEG3-ArN3─a photoactivatable compound that can be radiolabeled with 89Zr for applications in optical imaging and positron emission tomography. One-pot 89Zr-radiolabeling and light-induced protein conjugation produced [89Zr]ZrDFO-RhodB-PEG3-azepin-trastuzumab. Proof-of-concept studies in vitro and in vivo confirmed that [89Zr]ZrDFO-RhodB-PEG3-azepin-trastuzumab is a potential dual-modality agent for detecting human epidermal growth factor receptor 2 (HER2/neu) expression. Overall, the PhotoTag technology represents a rapid, synthetically versatile, and user-friendly approach for generating novel protein conjugates

A MIDI sequencer that widens access to the compositional possibilities of novel tunings

We present a new Dynamic Tonality MIDI sequencer, Hex, that aims to make sequencing music in and across a large variety of novel tunings as straightforward as sequencing in twelve-tone equal temperament. It replaces the piano roll used in conventional MIDI sequencers with a two-dimensional lattice roll in order to enable the intuitive visualization and dynamic manipulation of tuning. In conventional piano roll sequencers, a piano keyboard is displayed on the left side of the window, and white and black note lanes extend horizontally to the right, into which a user can draw a sequence of notes. Similarly, in Hex, a button lattice is displayed in its own pane on the left side of the window, and horizontal lines are drawn from the center of each note to the right. These lines function as generalized note lanes, just like in piano roll sequencers, but with the added benefit that each note lane's height is always proportional to its pitch, even if the user changes the tuning. The presence of the button lattice on the left side of the window illustrates exactly which buttons a performer would play in order to replicate the sequence when playing a physical button lattice instrument

Haptics for the development of fundamental rhythm skills, including multi-limb coordination

This chapter considers the use of haptics for learning fundamental rhythm skills, including skills that depend on multi-limb coordination. Different sensory modalities have different strengths and weaknesses for the development of skills related to rhythm. For example, vision has low temporal resolution and performs poorly for tracking rhythms in real-time, whereas hearing is highly accurate. However, in the case of multi-limbed rhythms, neither hearing nor sight are particularly well suited to communicating exactly which limb does what and when, or how the limbs coordinate. By contrast, haptics can work especially well in this area, by applying haptic signals independently to each limb. We review relevant theories, including embodied interaction and biological entrainment. We present a range of applications of the Haptic Bracelets, which are computer-controlled wireless vibrotactile devices, one attached to each wrist and ankle. Haptic pulses are used to guide users in playing rhythmic patterns that require multi-limb coordination. One immediate aim of the system is to support the development of practical rhythm skills and multi-limb coordination. A longer-term goal is to aid the development of a wider range of fundamental rhythm skills including recognising, identifying, memorising, retaining, analysing, reproducing, coordinating, modifying and creating rhythms – particularly multi-stream (i.e. polyphonic) rhythmic sequences. Empirical results are presented. We reflect on related work, and discuss design issues for using haptics to support rhythm skills. Skills of this kind are essential not just to drummers and percussionists but also to keyboards players, and more generally to all musicians who need a firm grasp of rhythm

Recycling Argon through Metamorphic Reactions: the Record in Symplectites

The 40Ar/39Ar ages of metamorphic micas that crystallized at high temperatures are commonly interpreted as cooling ages, with grains considered to have lost 40Ar via thermally-driven diffusion into the grain boundary network. Recently reported laser-ablation data suggest that the spatial distribution of Ar in metamorphic micas does not always conform to the patterns predicted by diffusion theory and that despite high metamorphic temperatures, argon was not removed efficiently from the local system during metamorphic evolution. In the Western Gneiss Region (WGR), Norway, felsic gneisses preserve microtextural evidence for the breakdown of phengite to biotite and plagioclase symplectites during near isothermal decompression from c. 20–25 to c. 8–12 kbar at ~700°C. These samples provide an ideal natural laboratory to assess whether the complete replacement of one K-bearing mineral by another at high temperatures completely ‘resets’ the Ar clock, or whether there is some inheritance of 40Ar in the neo-crystallized phase. The timing of the high-temperature portion of the WGR metamorphic cycle has been well constrained in previous studies. However, the timing of cooling following the overprint is still much debated. In-situ laser ablation spot dating in phengite, biotite-plagioclase symplectites and coarser, texturally later biotite yielded 40Ar/39Ar ages that span much of the metamorphic cycle. Together these data show that despite residence at temperatures of ~700°C, Ar is not completely removed by diffusive loss or during metamorphic recrystallization. Instead, Ar released during phengite breakdown appears to be partially reincorporated into the newly crystallizing biotite and plagioclase (or is trapped in fluid inclusions in those phases) within a close system. Our data show that the microtextural and petrographic evolution of the sample being dated provides a critical framework in which local 40Ar recycling can be tracked, thus potentially allowing 40Ar/39Ar dates to be linked more accurately to metamorphic history

Testing the 'Extreme Female Brain' Theory of Psychosis in Adults with Autism Spectrum Disorder with or without Co-Morbid Psychosis.

INTRODUCTION: Males and females in the general population differ, on average, in their drive for empathizing (higher in females) and systemizing (higher in males). People with autism spectrum disorder (ASD) show a drive for systemizing over empathizing, irrespective of sex, which led to the conceptualisation of ASD as an 'extreme of the typical male brain'. The opposite cognitive profile, an 'extreme of the typical female brain', has been proposed to be linked to conditions such as psychosis and mania/hypomania. METHODS: We compared an empathizing-over-systemizing bias (for short 'empathizing bias') in individuals with ASD, who had experienced psychotic illness (N = 64) and who had not (N = 71). RESULTS: There were overall differences in the distribution of cognitive style. Adults with ASD who had experienced psychosis were more likely to show an empathizing bias than adults with ASD who had no history of psychosis. This was modulated by IQ, and the group-difference was driven mainly by individuals with above-average IQ. In women with ASD and psychosis, the link between mania/hypomania and an empathizing bias was greater than in men with ASD. CONCLUSIONS: The bias for empathizing over systemizing may be linked to the presence of psychosis in people with ASD. Further research is needed in a variety of clinical populations, to understand the role an empathizing bias may play in the development and manifestation of mental illness.FVL was supported by the Medical Research Council (MRC) UK and the Baily Thomas Charitable Trust. M-CL was supported by the William Binks Autism Neuroscience Fellowship, the European Autism Interventions—A Multicentre Study for Developing New Medications (EU-AIMS), and Wolfson College, Cambridge. APW and AJH received support from the NIHR Collaboration for Leadership in Applied Health Research and Care East of England at the Cambridgeshire and Peterborough NHS Foundation Trust during the preparation of this manuscript. SB-C was supported by the MRC, EU-AIMS, and the Autism Research Trust.This is the final version. It was first published by PLOS at http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0128102#abstract0

Extreme value laws in dynamical systems under physical observables

Extreme value theory for chaotic dynamical systems is a rapidly expanding area of research. Given a system and a real function (observable) defined on its phase space, extreme value theory studies the limit probabilistic laws obeyed by large values attained by the observable along orbits of the system. Based on this theory, the so-called block maximum method is often used in applications for statistical prediction of large value occurrences. In this method, one performs inference for the parameters of the Generalised Extreme Value (GEV) distribution, using maxima over blocks of regularly sampled observations along an orbit of the system. The observables studied so far in the theory are expressed as functions of the distance with respect to a point, which is assumed to be a density point of the system's invariant measure. However, this is not the structure of the observables typically encountered in physical applications, such as windspeed or vorticity in atmospheric models. In this paper we consider extreme value limit laws for observables which are not functions of the distance from a density point of the dynamical system. In such cases, the limit laws are no longer determined by the functional form of the observable and the dimension of the invariant measure: they also depend on the specific geometry of the underlying attractor and of the observable's level sets. We present a collection of analytical and numerical results, starting with a toral hyperbolic automorphism as a simple template to illustrate the main ideas. We then formulate our main results for a uniformly hyperbolic system, the solenoid map. We also discuss non-uniformly hyperbolic examples of maps (H\'enon and Lozi maps) and of flows (the Lorenz63 and Lorenz84 models). Our purpose is to outline the main ideas and to highlight several serious problems found in the numerical estimation of the limit laws

Prospect relativity: how choice options influence decision under risk.

In many theories of decision under risk (e.g., expected utility theory, rank-dependent utility theory, and prospect theory), the utility of a prospect is independent of other options in the choice set. The experiments presented here show a large effect of the available options, suggesting instead that prospects are valued relative to one another. The judged certainty equivalent for a prospect is strongly influenced by the options available. Similarly, the selection of a preferred prospect is strongly influenced by the prospects available. Alternative theories of decision under risk (e.g., the stochastic difference model, multialternative decision field theory, and range frequency theory), where prospects are valued relative to one another, can provide an account of these context effects

Psychosis in autism: comparison of the features of both conditions in a dually affected cohort.

BackgroundThere is limited information on the presentation and characteristics of psychotic illness experienced by people with autism spectrum disorder (ASD).AimsTo describe autistic and psychotic phenomenology in a group of individuals with comorbid ASD and psychosis (ASD-P) and compare this group with populations affected by either, alone.MethodWe studied 116 individuals with ASD-P. We compared features of their ASD with people with ASD and no comorbid psychosis (ASD-NP), and clinical characteristics of psychosis in ASD-P with people with psychosis only.ResultsIndividuals with ASD-P had more diagnoses of atypical psychosis and fewer of schizophrenia compared with individuals with psychosis only. People with ASD-P had fewer stereotyped interests/behaviours compared with those with ASD-NP.ConclusionsOur data show there may be a specific subtype of ASD linked to comorbid psychosis. The results support findings that psychosis in people with ASD is often atypical, particularly regarding affective disturbance.Medical Research Council (PhD studentship, Autism Imaging Multicentre Study (MRC AIMS) Consortium), Baily Thomas Charitable Trust, Health Foundation, University of Cambridge (William Binks Autism Neuroscience Fellowship), Child and Youth Mental Health Collaborative at the Centre for Addiction and Mental Health and The Hospital for Sick Children, Toronto (O’Brien Scholars Program), Autism Research Trust, National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care East of England at the Cambridgeshire & Peterborough NHS Foundation TrustThis is the final version of the article. It first appeared from The Royal College of Psychiatrists via https://doi.org/10.1192/bjp.bp.116.18768

Charting the Chemical and Mechanistic Scope of Light-Triggered Protein Ligation

The creation of discrete, covalent bonds between a protein and a functional molecule like a drug, fluorophore, or radiolabeled complex is essential for making state-of-the-art tools that find applications in basic science and clinical medicine. Photochemistry offers a unique set of reactive groups that hold potential for the synthesis of protein conjugates. Previous studies have demonstrated that photoactivatable desferrioxamine B (DFO) derivatives featuring a para-substituted aryl azide ($ArN_3$) can be used to produce viable zirconium-89-radiolabeled monoclonal antibodies ($^{89}Zr-mAbs$) for applications in noninvasive diagnostic positron emission tomography (PET) imaging of cancers. Here, we report on the synthesis, $^{89}Zr$-radiochemistry, and light-triggered photoradiosynthesis of $^{89}Zr$-labeled human serum albumin (HSA) using a series of 14 different photoactivatable DFO derivatives. The photoactive groups explore a range of substituted, and isomeric $ArN_3$ reagents, as well as derivatives of benzophenone, a para-substituted trifluoromethyl phenyl diazirine, and a tetrazole species. For the compounds studied, efficient photochemical activation occurs inside the UVA-to-visible region of the electromagnetic spectrum (∼365–450 nm) and the photochemical reactions with HSA in water were complete within 15 min under ambient conditions. Under standardized experimental conditions, photoradiosynthesis with compounds 1–14 produced the corresponding $^{89}ZrDFO-PEG_{3}-HSA$ conjugates with decay-corrected isolated radiochemical yields between 18.1 ± 1.8% and 62.3 ± 3.6%. Extensive density functional theory (DFT) calculations were used to explore the reaction mechanisms and chemoselectivity of the light-induced bimolecular conjugation of compounds 1–14 to protein. The photoactivatable DFO-derivatives operate by at least five distinct mechanisms, each producing a different type of bioconjugate bond. Overall, the experimental and computational work presented here confirms that photochemistry is a viable option for making diverse, functionalized protein conjugates