Obesity affects 1 in 6 adults in Europe, driving demand for therapy. Agonists of the Glucagon Like Peptide 1 Receptor (GLP1RAs) such as semaglutide (Novo Nordisk) and tirzepatide (Eli Lilly) have led to substantial weight loss in millions of patients. However, a large fraction of lost weight is attributed to loss of lean mass: muscle and bone. A reduction in lean mass increases the risk for sarcopenia and osteoporosis – loss of muscle and bone. Our analysis of 748,667 patients using GLP1RAs has shown that most are women, over the age of 50: a population already at risk for muscle and bone loss. Sarcopenia and osteoporosis cause pain, fatigue, limit the ability of patients to perform daily activities, and increase their risk for fractures. With millions of GLP1RA users and an annual direct cost of 5000USD/osteoporosis patient, loss of lean mass can cost billions to health care systems. Growth Hormone (GH) is the natural signal in adults for sustaining lean mass. Results from our ERC project identified pathways that may sustain GH signaling during and after weight loss. We propose to develop novel molecules that will lead to an increase in natural GH secretion. We will test the efficacy and safety of a library molecules we designed for their ability to maintain lean mass during GLP1RA-induced weight loss. The results will secure the intellectual property surrounding the novel molecules and their use. By addressing the underlying causes of muscle and bone loss, we aim to develop a comprehensive solution to the obesity crisis. Our innovative biochemical approach targets the aging population struggling with obesity and has the potential to prevent disease in millions of patients and alleviate a significant burden from healthcare systems.

Southern India in the fifteenth, sixteenth, and seventeenth centuries comprised a single, strongly interwoven, multilingual cultural world that generated innovative literary, musical, theatrical and visual masterpieces as well as a theoretical erudite literature that explored the aesthetic and philosophical bases of these new works. New literary genres such as the compact, self-contained prabandha narratives crossed linguistic boundaries, emerging in and rapidly coming to dominate Tamil, Telugu, Kannada, Malayalam, and the trans-local languages of Sanskrit, Persian, Marathi and Dakhni. Such texts, seen together with major genres evolving in the other expressive domains (the early varnams and kirttanas in music, the great mural paintings of the Tamil and Karnataka regions, Kudiyattam drama), were building blocks of an eco-system whose rules, themes, forms, and intertextual relations have never been studied as a whole. We propose to explore this large corpus in relation to the new grammars of language, poetics, music, drama, and painting that evolved at the same time. Among major themes common to all these traditions are the interiority and states of mind of the individual human person, the question of how such a person is created and fashioned, the problem of the fate or destiny that a person faces or generates out of himself or herself, and the autonomy of the natural world within which he or she lives and acts. All the major expressive domains, with their thematic and theoretical continuities, give voice to a historic shift in the dynamics and underlying axioms of south Indian civilization at the start of the modern age; this shift becomes fully articulate and apparent only when we see the expressive eco-system as a whole.

Rates of depression and anxiety are constantly surging, resulting in a growing global mental health crisis. These two disorders have a remarkably high prevalence of comorbidity, with anxiety generally preceding depression. However, the biological basis of these disorders and their comorbidity is poorly understood, leaving millions of patients with inadequate treatments and thus an urgent need for improved medications. Accumulating evidence suggests that both disorders involve GABAergic deficits, but the nature of these deficits is undefined and may be the holy grail for cracking the mysteries of depression and anxiety comorbidity. Here, I will apply cutting-edge technologies to focus on hippocampal GABAergic interneurons (INs) and propose a data-driven hypothesis for the cellular and molecular basis of anxiety and depression comorbidity. I suggest that INs selectively recruit microglia to reshape inhibition in the depressed brain. This hypothesis may provide the missing link between major hallmarks of depression: GABAergic deficits, synaptic loss, and neuroinflammation. I seek to unravel the molecular adaptations of INs to stress that lead to microglia recruitment and connect them with anxiety preceding depression. Finally, I will elucidate a novel model for innate anxiolysis mediated by local dendritic translation in INs. I will combine, for the first time, the robustness of two analytical methods: translating ribosome sequencing and spatial transcriptomics to identify the involved genes, the INs subtypes expressing them, and their hippocampal location. These data will be complemented by calcium imaging, behavioral tests, imaging, connectomics, and electrophysiology. ZoomINs targets an urgent public health concern by providing a novel hypothesis for a long-standing question: what causes anxiety and depression comorbidity? The results of this ambitious project will set the ground for the development of INs-targeting medications, giving hope to millions worldwide.