Biology subjects

Monti, A.

Publications and source records attributed to Monti, A..

5 recordsLinked to original sources

bioRxiv2026

DCN1 inhibitor induces fetal hemoglobin through self-limited regulation of CUL3 neddylation

Few genetic loci are as well-characterized as the globin gene locus, and the substitution of healthy {gamma}-globin (HbF) for missing or mutated {beta}-globin (HbB) is an established therapeutic strategy for {beta}-hemoglobinopathies including sickle cell disease (SCD) and {beta}-thalassemia. Although substantial progress has been made in understanding HbF derepression and globin switching, many current therapeutic strategies involving small molecules increase HbF through broad epigenetic perturbations or cytotoxic stress, raising concerns about dose-limiting cytopenias and off-target effects. By coupling single-cell transcriptomics, genetic perturbations, and functional genomics, we identified an unknown role of neddylation in the regulation of fetal hemoglobin (HbF). Partial impairment of neddylation of cullin ubiquitin ligase 3 (CUL3) through defective in cullin neddylation 1 (DCN1) inhibition leads to highly selective chromatin changes, histone demethylation, and globin locus binding of known activators of HbF transcription. Further, DCN1 inhibition drives globin switching and HbF increases in vitro and in vivo with minimal off-target transcriptional effects and no evidence of cytotoxicity or stress erythropoiesis. To therapeutically target this axis, we report the discovery and characterization of CLY-124, a first-in-class, covalent DCN1 inhibitor with favorable pharmacology properties. In a humanized mouse model, CLY-124 showed a dose-dependent increase in HbF as monotherapy and in synergy with hydroxyurea (HU), a current standard of care. Collectively, these findings highlight the power of single-cell transcriptomics to elucidate undiscovered biologic insights with therapeutic potential, and the promise of DCN-1 inhibitors like CLY-124 to address {beta}-hemoglobinopathies. With an appropriate nonclinical safety profile, a first-in human study of safety, pharmacokinetics and HbF assessments in healthy volunteers and participants with SCD is ongoing for CLY-124. One-sentence SummaryDCN1 is a promising target for {beta}-hemoglobinopathies

molecular biology↗

bioRxiv2023

Chemotactic interactions drive migration ofmembraneless active droplets

In nature, chemotactic interactions are ubiquitous and play a critical role in driving the collective behaviour of living organisms. Reproducing these interactions in vitrois still a paramount challenge due to the complexity of mimicking and controlling cellular features, such as metabolic density, cytosolic macromolecular crowding and cellular migration, on a microorganism size scale. Here we generate enzymatically-active cell-size droplets able to move freely and, by following a chemical gradient, able to interact with the surrounding droplets in a collective manner. The enzyme within the droplets generates a pH gradient that extends outside the edge of the droplets. We discovered that the external pH gradient triggers droplet migration and controls its directionality, which is selectively towards the neighbouring droplets. Hence, by changing the enzyme activity inside the droplet we tuned the droplet migration speed. Further, we showed that these cellular-like features can facilitate the reconstitution of a simple and linear protometabolic pathway with improved overall activity. Our work suggests that simple and stable membraneless droplets can be applied to reproduce complex biological phenomena opening new perspectives as bioinspired materials and synthetic biology tools.

biochemistry↗

bioRxiv2023

Deep-body feelings: ingestible pills reveal gastric correlates of emotions

Although it is generally held that gastro-intestinal (GI) signals are related to emotions, direct evidence for such a link is currently lacking. One of the reasons why the internal milieu of the GI system is poorly investigated is because visceral organs are difficult to access and monitor. To directly measure the influence of endoluminal markers of GI activity on the emotional experience, we asked a group of healthy male participants to ingest a pill that measured pH, pressure, and temperature of their GI tract while they watched video-clips that consistently induced disgust, fear, happiness, sadness, or a control neutral state. In addition to the objective physiological markers of GI activity, subjective ratings of perceived emotions and visceral (i.e. gastric, respiratory and cardiac) sensations were recorded. We found that when participants observed fearful and disgusting video-clips, they reported to perceive not only cardiac and respiratory sensations but also gastric sensations, such as nausea. Moreover, we found that there was a clear relation between the physiology of the stomach and the perceived emotions. Specifically, when disgusting video-clips were displayed, the more acidic the pH, the more participants reported feelings of disgust and fear; the less acidic the pH, the more they reported happiness. Our findings suggest that gastric signals contribute to unique emotional states and that ingestible pills may open new avenues for exploring the deep-body physiology of emotions.

neuroscience↗

bioRxiv2021

Gut markers of bodily self-consciousness

Bodily self-consciousness, the state of mind that allows humans to be aware of their own body, forms the backdrop for almost every human experience, yet its underpinnings remain elusive. Here we combine an ingestible, minimally invasive capsule with surface electrogastrography to probe if gut physiology correlates with bodily self-consciousness during a virtual bodily illusion. We discover that specific patterns of stomach and bowel activity (temperature, pressure, pH, and gastric peak frequency) covary with specific facets of bodily self-consciousness (feelings of body agency, location, and disembodiment). These results uncover the hitherto untapped potential of minimally invasive probes to study the link between mental and gut states, and reveal a deep visceral pathway to the self-conscious perception of ourselves as embodied beings.

physiology↗

bioRxiv2021

Untargeted metabolomic analyses reveal the diversity and plasticity of the specialized metabolome in seeds of different Camelina sativa varieties

Despite the essential role of Specialized Metabolites (SMs) in the interaction of plants with the environment, studying the ability of crop seeds to produce these protective compounds has been neglected. Furthermore, seeds produce a myriad of SMs providing an interesting model to investigate their diversity and plasticity. Camelina sativa gained a lot of interest in the past few years as rustic oil seed crop. A characterization of seed SM landscapes in six camelina genotypes grown in the field and harvested during five growing seasons has been undertaken in this work. This allowed a comprehensive annotation of seed SMs combining analyses that cluster SMs based on their chemical structures and co-accumulation patterns. These data showed broad effects of the environment on the stimulation of the seed-specialized metabolome. Among well annotated compounds, flavonols were identified as the metabolic class characterised by high plasticity, revealing significant variable accumulation according to the year and/or the genotype. Lastly, a deeper characterisation of primary metabolites and lipids in two selected genotypes has been performed. We showed that, in addition to flavonols, alkaloids and glucosinolates displayed a higher phenotypic plasticity with respect to most of the primary metabolites, including some sugars and major storage compounds such as fatty acids, proteins and most lipid classes (e.g. DAG, TAG), but similar plasticity compared to free aminoacids and carboxylic acids. This work highlighted major and unexplored effects of the environment on the seed specialized metabolome demonstrating that seeds exhibit a dynamic and plastic metabolism, with an impact on seed quality. Significance statementSeeds produce a myriad of Specialized Metabolites (SMs) with an essential role in the interaction of plants with the environment. We characterized SM landscapes, primary metabolites and lipid composition in the seeds of camelina genotypes grown in the open field in five consecutive growing seasons. Our results showed the predominant effect of the environment on the regulation of the seed - specialized metabolome, with a potential impact on seed quality of camelina that may also occur in other oilseed crops.

plant biology↗