Biology subjects

Robles, J.

Publications and source records attributed to Robles, J..

4 recordsLinked to original sources

bioRxiv2026

Stereoselective Covalent Targeting of BTK(C481S) and Kinases with β-Lactone Electrophiles

The cysteine to serine mutation at residue 481 of Brutons tyrosine kinase (BTK) is the most common mechanism of clinical resistance against ibrutinib for the treatment of mantle cell lymphoma and chronic lymphocytic leukemia. We report small molecule ligands containing chiral {beta}-lactone electrophiles to address this challenge. The asymmetric warhead enabled stereoselective covalent modification of wild-type and ibrutinib-resistant mutant BTK(C481S) through distinct sites of reactivity. Building on these findings, we developed kinase-directed {beta}-lactone probes and demonstrated that individual enantiomers preferentially engage distinct subsets of the kinome. These studies establish {beta}-lactones as stereochemically encodable covalent warheads whose stereochemistry can serve as a selectivity filter in covalent drug discovery. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=83 SRC="FIGDIR/small/736436v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@1b407c6org.highwire.dtl.DTLVardef@6a79ddorg.highwire.dtl.DTLVardef@66a59dorg.highwire.dtl.DTLVardef@102ecc7_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2026

Nicotine-driven hyperactivation of larval locomotion

Balance between excitatory and inhibitory activity is essential for nervous system function. Neuroactive substances like nicotine can disrupt this balance and hyperactivate dopaminergic circuits, with combined effects on behavior and neural activity. We use Drosophila larvae to examine nicotine-induced, linked behavioral changes over multiple time scales by integrating high-resolution locomotor analysis with genetic and pharmacological manipulations. Acute nicotine exposure produces concentration-dependent hyperactivity. Manipulations of the dopaminergic system establish dopamine as the main mediator for motor responses, and further exploration establishes the{gamma} lobe of the mushroom body as a key site for nicotine integration. Experiments with long-term and repetitive nicotine exposure suggest sustained circuit excitability. Finally, nicotine exposure history induces nicotine preference, highlighting experience-dependent plasticity contributing to addiction-like behaviors. These results help establish Drosophila larvae as a model organism to elucidate how neuroactive substances reconfigure neural circuits and behavior.

neuroscience↗

bioRxiv2023

A kidney-hypothalamus axis promotes compensatory glucose production in response to glycosuria

The kidneys facilitate energy conservation through reabsorption of nutrients including glucose. Almost all the filtered blood glucose is reabsorbed by the kidneys. Loss of glucose in urine (glycosuria) is offset by an increase in endogenous glucose production to maintain normal energy supply in the body. How the body senses this glucose loss and consequently enhances glucose production is unclear. Using renal Glut2 knockout mice, we demonstrate that elevated glycosuria activates the hypothalamic-pituitary-adrenal axis, which in turn drives endogenous glucose production. This phenotype was attenuated by selective afferent renal denervation, indicating the involvement of the afferent nerves in promoting the compensatory increase in glucose production. In addition, through plasma proteomics analyses we observed that acute phase proteins - which are usually involved in bodys defense mechanisms against a threat - were the top candidates which were either upregulated or downregulated in renal Glut2 KO mice. Overall, afferent renal nerves contribute to promoting endogenous glucose production in response to elevated glycosuria and loss of glucose in urine is sensed as a biological threat in mice. These findings may be useful in improving efficiency of drugs like SGLT2 inhibitors that are intended to treat hyperglycemia by enhancing glycosuria but are met with a compensatory increase in endogenous glucose production.

physiology↗

bioRxiv2019

Chemical signals act as the main reproductive barrier between sister and mimetic Heliconius butterflies

Colour pattern has been long recognised as the trait that drives mate recognition between Heliconius species that are phylogenetically close. However, when this cue is compromised such as in cases of mimetic, sympatric and closely related species, alternative mating signals must evolve to ensure reproductive isolation and species integrity. The closely related species Heliconius melpomene malleti and H. timareta florencia, occur in the same geographic region and despite being co-mimics they display strong reproductive isolation. In order to test which cues differ between species, and therefore potentially contribute to reproductive isolation, we quantified differences in wing phenotype and male chemical profile. As expected, wing colour pattern was indistinguishable between the two species while the chemical profile of their male sex pheromones showed marked differences. We then conducted behavioural experiments to study the importance of these signals in mate recognition by females. In agreement with our previous results, we found that pheromones and not wing colour pattern drive the preference of females by conspecific males. In addition, experiments with hybrid males and females suggested an important genetic component for both pheromone production and preference. Altogether, these results suggest that pheromones are the major reproductive barrier opposing gene flow between these two sister and co-mimic species.

evolutionary biology↗