Bispidines (3,7-diazabicyclo[3.3.1]nonane) and their derivatives act as bifunctional chelators (BFC), combining the advantages of multidentate macrocyclic and acyclic ligands e.g. high kinetic inertness, rapid radiolabelling under mild conditions. This bicyclic chelator system shows a great diversity in terms of its denticity and type of functional groups, yielding a wide range of multidentate ligands that can bind a variety of different metal ions. In addition, they allow a facile functionalisation of targeting molecules such as peptides, peptidomimetics, and bispeci􀄀c antibodies. Herein, examples of various bispidine complexes labelled with [64Cu]Cu2+, [111In]In3+, [ 177Lu]Lu3+ or [ 225Ac]Ac3+ will be presented which provide a picture of how different substituents in􀄁uence the coordination mode. Target-speci􀄀c radiolabelled bispidine-based conjugates (e.g. peptides, antibody fragments, antibodies) investigated in vivo by positron emission or single-photon emission computed tomography will be presented and discussed in terms of their suitability for nuclear medicine applications.

Talk 1. PET based biomarkers of treatment efficacy in temporal lobe epilepsy A critical aspect of drug development involves identifying robust biomarkers of treatment response for use as surrogate endpoints in clinical trials. However, these biomarkers also have the capacity to inform mechanisms of disease pathogenesis and therapeutic efficacy. In this webinar, Dr Bianca Jupp will report on a series of studies using the GABAA PET ligand, [18F]-Flumazenil, to establish biomarkers of treatment response to a novel therapeutic for temporal lobe epilepsy, identifying affinity at this receptor as a key predictor of treatment outcome. Dr Bianca Jupp is a Research Fellow in the Department of Neuroscience, Monash University and Lead PET/CT Scientist at the Alfred Research Alliance–Monash Biomedical Imaging facility. Her research focuses on neuroimaging and its capacity to inform the neurobiology underlying neurological and neuropsychiatric disorders. Talk 2. The development of a PET radiotracer for reparative microglia Imaging of neuroinflammation is currently hindered by the technical limitations associated with TSPO imaging. In this webinar, Dr Lucy Vivash will discuss the development of PET radiotracers that specifically image reparative microglia through targeting the receptor kinase MerTK. This includes medicinal chemistry design and testing, radiochemistry, and in vitro and in vivo testing of lead tracers. Dr Lucy Vivash is a Research Fellow in the Department of Neuroscience, Monash University. Her research focuses on the preclinical development and clinical translation of novel PET radiotracers for the imaging of neurodegenerative diseases.

The question of the origin of homochirality of living matter, or the dominance of one handedness for all molecules of life across the entire biosphere, is a long-standing puzzle in the research on the Origin of Life. In the fifties, Frank proposed a mechanism to explain homochirality based on the properties of a simple autocatalytic network containing only a few chemical species. Following this work, chemists struggled to find experimental realizations of this model, possibly due to a lack of proper methods to identify autocatalysis [1]. In any case, a model based on a few chemical species seems rather limited, because prebiotic earth is likely to have consisted of complex ‘soups’ of chemicals. To include this aspect of the problem, we recently proposed a mechanism based on certain features of large out-of-equilibrium chemical networks [2]. We showed that a phase transition towards an homochiral state is likely to occur as the number of chiral species in the system becomes large or as the amount of free energy injected into the system increases. Through an analysis of large chemical databases, we showed that there is no need for very large molecules for chiral species to dominate over achiral ones; it already happens when molecules contain about 10 heavy atoms. We also analyzed the various conventions used to measure chirality and discussed the relative chiral signs adopted by different groups of molecules [3]. We then proposed a generalization of Frank’s model for large chemical networks, which we characterized using random matrix theory. This analysis includes sparse networks, suggesting that the emergence of homochirality is a robust and generic transition. References: [1] A. Blokhuis, D. Lacoste, and P. Nghe, PNAS (2020), 117, 25230. [2] G. Laurent, D. Lacoste, and P. Gaspard, PNAS (2021) 118 (3) e2012741118. [3] G. Laurent, D. Lacoste, and P. Gaspard, Proc. R. Soc. A 478:20210590 (2022).

Chromosomes are extremely long, active polymers that are spatially organized across multiple scales to promote cellular functions, such as gene transcription and genetic inheritance. During each cell cycle, chromosomes are dramatically compacted as cells divide and dynamically reorganized into less compact, spatiotemporally patterned structures after cell division. These activities are facilitated by DNA/chromatin-binding protein motors called SMC complexes. Each of these motors can perform a unique activity known as “loop extrusion,” in which the motor binds the DNA/chromatin polymer, reels in the polymer fiber, and extrudes it as a loop. Using simulations and theory, I show how loop-extruding motors can collectively compact and spatially organize chromosomes in different scenarios. First, I show that loop-extruding complexes can generate sufficient compaction for cell division, provided that loop-extrusion satisfies stringent physical requirements. Second, while loop-extrusion alone does not uniquely spatially pattern the genome, interactions between SMC complexes and protein “boundary elements” can generate patterns that emerge in the genome after cell division. Intriguingly, these “boundary elements” are not necessarily stationary, which can generate a variety of patterns in the neighborhood of transcriptionally active genes. These predictions, along with supporting experiments, show how SMC complexes and other molecular machinery, such as RNA polymerase, can spatially organize the genome. More generally, this work demonstrates both the versatility of the loop extrusion mechanism for chromosome functional organization and how seemingly subtle microscopic effects can emerge in the spatiotemporal structure of nonequilibrium polymers.

Personalised medicine will be greatly enhanced with the introduction of new radiopharmaceuticals for the diagnosis and treatment of various cancers, as well as cardiovascular disease and brain disorders. The unprecedented interest in developing theranostic radiopharmaceuticals is mainly due to the recent clinical successes of radiometal-based products including: • 177LuDOTA-TATE (trade name Lutathera, FDA approved in 2018), a peptide-based tracer that is used for treating metastatic neuroendocrine tumours • Ga 68 PSMA-11 (FDA approved in 2020), a positron emission tomography agent for imaging prostate-specific membrane antigen positive lesions in men with prostate cancer. In this webinar, Dr Brett Paterson and PhD candidate Mr Cormac Kelderman will present their research on developing the chemistry and radiochemistry to produce new radiometal-based imaging and therapy agents. They will discuss the synthesis of new molecules, the optimisation of the radiochemistry, and results from preclinical evaluations. Dr Brett Paterson is a National Imaging Facility Fellow at Monash Biomedical Imaging and academic group leader in the School of Chemistry, Monash University. His research focuses on the development of radiochemistry and new radiopharmaceuticals. Cormac Kelderman is a PhD candidate under the supervision of Dr Brett Paterson in the School of Chemistry, Monash University. His research focuses on developing new bis(thiosemicarbazone) chelators for technetium-99m SPECT imaging.

Cells and microorganisms produce and consume all sorts of chemicals, from nutrients to signalling molecules. The same happens at the nanoscale inside cells themselves, where enzymes catalyse the production and consumption of the chemicals needed for life. In this work, we have found a generic mechanism by which such chemically-active particles, be it cells or enzymes or engineered synthetic colloids, can "sense" each other and ultimately self- organize in a multitude of ways. A peculiarity of these chemical-mediated interactions is that they break action-reaction symmetry : for example, one particle may be repelled from a second particle, which is in turn attracted to the first one, so that it ends up "chasing" it. Such chasing interactions allow for the formation of large clusters of particles that "swim" autonomously. Regarding enzymes, we find that they can spontaneously aggregate into clusters with precisely the right composition, so that the product of one enzyme is passed on, without lack or excess, to the next enzyme in the metabolic cascade.

Active particles which are self-propelled by converting energy into mechanical motion represent an expanding research realm in physics and chemistry. For micron-sized particles moving in a liquid (``microswimmers''), most of the basic features have been described by using the model of overdamped active Brownian motion [1]. However, for macroscopic particles or microparticles moving in a gas, inertial effects become relevant such that the dynamics is underdamped. Therefore, recently, active particles with inertia have been described by extending the active Brownian motion model to active Langevin dynamics which include inertia [2]. In this talk, recent developments of active particles with inertia (``microflyers'', ``hoppers'' or ``runners'') are summarized including: inertial delay effects between particle velocity and self-propulsion direction [3], tuning of the long-time self-diffusion by the moment of inertia [3], the influence of inertia on motility-induced phase separation and the cluster growth exponent [4], and the formation of active micelles (“rotelles”) by using inertial active surfactants. References [1] C. Bechinger, R. di Leonardo, H. Löwen, C. Reichhardt, G. Volpe, G. Volpe, Reviews of Modern Physics 88, 045006 (2016). [2] H. Löwen, Journal of Chemical Physics 152, 040901 (2020). [3] C. Scholz, S. Jahanshahi, A. Ldov, H. Löwen, Nature Communications 9, 5156 (2018). [4] S. Mandal, B. Liebchen, H. Löwen, Physical Review Letters 123, 228001 (2019). [5] C. Scholz, A. Ldov, T. Pöschel, M. Engel, H. Löwen, Surfactants and rotelles in active chiral fluids, will be published

Cement is the main binding agent in concrete, literally gluing together rocks and sand into the most-used synthetic material on Earth. However, cement production is responsible for significant amounts of man- made greenhouse gases—in fact if the cement industry were a country, it would be the third largest emitter in the world. Alternatives to the current, environmentally harmful cement production process are not available essentially because the gaps in fundamental understanding hamper the development of smarter and more sustainable solutions. The ultimate challenge is to link the chemical composition of cement grains to the nanoscale physics of the cohesive forces that emerge when mixing cement with water. Cement nanoscale cohesion originates from the electrostatics of ions accumulated in a water-based solution between like-charged surfaces but it is not captured by existing theories because of the nature of the ions involved and the high surface charges. Surprisingly enough, this is also the case for unexplained cohesion in a range of colloidal and biological matter. About one century after the early studies of cement hydration, we have quantitatively solved this notoriously hard problem and discovered how cement cohesion develops during hydration. I will discuss how 3D numerical simulations that feature a simple but molecular description of ions and water, together with an analytical theory that goes beyond the traditional continuum approximations, helped us demonstrate that the optimized interlocking of ion-water structures determine the net cohesive forces and their evolution. These findings open the path to scientifically grounded strategies of material design for cements and have implications for a much wider range of materials and systems where ionic water-based solutions feature both strong Coulombic and confinement effects, ranging from biological membranes to soils. Construction materials are central to our society and to our life as humans on this planet, but usually far removed from fundamental science. We can now start to understand how cement physical-chemistry determines performance, durability and sustainability.

Neural networks can learn and recognize subtle correlations in high dimensional inputs. However, neural networks are simply many-body systems with strong non-linearities and disordered interactions. Hence, many-body physical systems with similar interactions should be able to show neural network-like behavior. Here we show neural network-like behavior in the nucleation dynamics of promiscuously interacting molecules with multiple stable crystalline phases. Using a combination of theory and experiments, we show how the physics of the system dictates relationships between the difficulty of the pattern recognition task solved, time taken and accuracy. This work shows that high dimensional pattern recognition and learning are not special to software algorithms but can be achieved by the collective dynamics of sufficiently disordered molecular systems.

Colloidal dispersions of rod-like particles are widely accepted as convenient model systems to study the phase behavior of liquid-crystal forming systems, commonly found in LCDs. This is due to the fact that colloidal rods exhibit analogous phase behavior to that of elongated molecules, while they can be directly observed by optical microscopy. Recently, there has been a surge of interest in the liquid crystalline behaviour of so-called bent-core, or banana-shaped, molecules. This is due to their ability to form exotic biaxial nematic phases such as the twist-bend and splay-bend nematic phase, which may be of particular interest inherent to their fast switching response in LCDs. Here, we develop model “banana-shaped” colloidal particles with tunable dimensions and curvature, whose structure and dynamics are accessible at the particle level. 
By heating initially straight rods made of SU-8 photoresist, we induce a controllable shape deformation that causes the rods to buckle into banana-shaped particles. We elucidate the phase behavior of differently curved colloidal bananas using confocal microscopy. Although highly curved bananas only form isotropic phases, less curved bananas exhibit very rich phase behavior, including biaxial nematic phases, polar and antipolar smectic-like phases, and even the long-predicted, elusive splay-bend nematic phase.

Carnosine is a natural dipeptide widely distributed in mammalian tissues and exists at particularly high concentrations in skeletal and cardiac muscles and brain. A growing body of evidence shows that carnosine is involved in many cellular defense mechanisms against oxidative stress, including inhibition of amyloid-β (Aβ) aggregation, modulation of nitric oxide (NO) metabolism, and scavenging both reactive nitrogen and oxygen species. Different types of cells are involved in the innate immune response, with macrophage cells representing those primarily activated, especially under different diseases characterized by oxidative stress and systemic inflammation such as depression and cardiovascular disorders. Microglia, the tissue-resident macrophages of the brain, are emerging as a central player in regulating key pathways in central nervous system inflammation; with specific regard to Alzheimer’s disease (AD) these cells exert a dual role: on one hand promoting the clearance of Aβ via phagocytosis, on the other hand increasing neuroinflammation through the secretion of inflammatory mediators and free radicals. The activity of carnosine was tested in an in vitro model of macrophage activation (M1) (RAW 264.7 cells stimulated with LPS + IFN-γ) and in a well-validated model of Aβ-induced neuroinflammation (BV-2 microglia treated with Aβ oligomers). An ample set of techniques/assays including MTT assay, trypan blue exclusion test, high performance liquid chromatography, high-throughput real-time PCR, western blot, atomic force microscopy, microchip electrophoresis coupled to laser-induced fluorescence, and ELISA aimed to evaluate the antioxidant and anti-inflammatory activities of carnosine was employed. In our experimental model of macrophage activation (M1), therapeutic concentrations of carnosine exerted the following effects: 1) an increased degradation rate of NO into its non-toxic end-products nitrite and nitrate; 2) the amelioration of the macrophage energy state, by restoring nucleoside triphosphates and counterbalancing the changes in ATP/ADP, NAD+/NADH and NADP+/NADPH ratio obtained by LPS + IFN-γ induction; 3) a reduced expression of pro-oxidant enzymes (NADPH oxidase, Cyclooxygenase-2) and of the lipid peroxidation product malondialdehyde; 4) the rescue of antioxidant enzymes expression (Glutathione peroxidase 1, Superoxide dismutase 2, Catalase); 5) an increased synthesis of transforming growth factor-β1 (TGF-β1) combined with the negative modulation of interleukines 1β and 6 (IL-1β and IL-6), and 6) the induction of nuclear factor erythroid-derived 2-like 2 (Nrf2) and heme oxygenase-1 (HO-1). In our experimental model of Aβ-induced neuroinflammation, carnosine: 1) prevented cell death in BV-2 cells challenged with Aβ oligomers; 2) lowered oxidative stress by decreasing the expression of inducible nitric oxide synthase and NADPH oxidase, and the concentrations of nitric oxide and superoxide anion; 3) decreased the secretion of pro-inflammatory cytokines such as IL-1β simultaneously rescuing IL-10 levels and increasing the expression and the release of TGF-β1; 4) prevented Aβ-induced neurodegeneration in primary mixed neuronal cultures challenged with Aβ oligomers and these neuroprotective effects was completely abolished by SB431542, a selective inhibitor of type-1 TGF-β receptor. Overall, our data suggest a novel multimodal mechanism of action of carnosine underlying its protective effects in macrophages and microglia and the therapeutic potential of this dipeptide in counteracting pro-oxidant and pro-inflammatory phenomena observed in different disorders characterized by elevated levels of oxidative stress and inflammation such as depression, cardiovascular disorders, and Alzheimer’s disease.

Information is represented in the brain by the coordinated activity of populations of neurons. Recent large-scale neural recording methods in combination with machine learning algorithms are helping understand how sensory processing and cognition emerge from neural population activity. This talk will explore the most popular machine learning methods used to gather meaningful low-dimensional representations from higher-dimensional neural recordings. To illustrate the potential of these approaches, Pedro will present his research in which chemical information is decoded from the olfactory system of the mouse for technological applications. Pedro and co-researchers have successfully extracted odor identity and concentration from olfactory receptor neuron low-dimensional activity trajectories. They have further developed a novel method to identify a shared latent space that allowed decoding of odor information across animals.

This talk aims to show how new physical methods can advance biological and biomedical research. A major advance in physical chemistry in the last two decades has been the development of quantitative methods to directly observe individual molecules in solution, attached to surfaces, in the membrane of live cells or more recently inside live cells. These single-molecule fluorescence studies have now reached a stage where they can provide new insights into important biological problems. After presenting the principles of these methods, I will give some examples from our current research to probe the molecular basis of neurodegeneration. Here we have used single-molecule fluorescence to detect and analyse the low concentrations of soluble protein aggregates thought to be responsible for Alzheimer’s disease and determine the mechanisms by which they damage neurons. Lastly, I will describe how fundamental science aimed at watching single molecules incorporating nucleotides into DNA gave rise to a new rapid method to sequence DNA that is now widely used.