Biology subjects

Lozano, D.

Publications and source records attributed to Lozano, D..

4 recordsLinked to original sources

bioRxiv2024

Sensory weighting reflects changing patterns of visual investment during ecological divergence in Heliconius butterflies.

Integrating information across sensory modalities enables animals to orchestrate a wide range of complex behaviours. The relative importance placed on one sensory modality over another reflects the reliability of cues in a particular environment and corresponding differences in neural investment. As populations diverge across environmental gradients, the reliability of sensory cues may shift, favouring divergence in neural investment and the weight given to different sensory modalities. During their divergence across closed-forest and forest-edge habitats, closely related butterflies Heliconius cydno and H. melpomene evolved distinct brain morphologies, with the former investing more in vision. Quantitative genetic analyses suggest selection drove these changes, but their behavioural effects remain uncertain. We hypothesised that divergent neural investment may alter sensory weighting. We trained individuals in an associative learning experiment using multimodal colour and odour cues. When positively rewarded stimuli were presented in conflict pairing positively trained colour with negatively trained odour, and vice-versa, H. cydno favoured visual cues more strongly than H. melpomene. Hence, differences in sensory weighting may evolve early during divergence and are predicted by patterns of neural investment. These findings, alongside other examples, imply that differences in sensory weighting stem from divergent investment as adaptations to local sensory environments.

evolutionary biology↗

bioRxiv2024

Aberrant subcellular localization of mismatch repair protein MLH1 dysregulates the cell cycle to create new therapeutic opportunities

Estrogen receptor positive (ER+) breast cancer is one of the most common causes of cancer-related death in women. Mortality is largely driven by recurrence of treatment-resistant disease after many years of apparent response, making the molecular events that cause recurrence a critical area of investigation. Loss of expression of MLH1, a tumor suppressor best studied in its role in mismatch repair, induces resistance of ER+ breast cancer cells to standard estrogen-targeting therapies. It does so by delinking cell cycle progression from estrogen regulation, a role distinct from its function in mismatch repair. MLH1 loss, as currently clinically diagnosed by detecting genomic instability or by immunohistochemistry for absence of protein, occurs in 12-15% of all cancers. Here, we demonstrate that sub-clonal, patient-derived mutations in MLH1, which neither impact protein abundance nor contribute sufficiently to genomic instability to be detected diagnostically, seed endocrine treatment resistance by enabling estrogen-independent growth in vitro, ex vivo in patient-derived organoids (p=0.005) and in vivo (p=0.0001). The mechanism underlying this endocrine treatment resistance is aberrant localization of MLH1 to the cytoplasm in vitro and in vivo (p=0.04), which precludes cell cycle arrest in response to endocrine therapy while simultaneously rendering cells acutely dependent on CDK4/6 activity. Consequently, administration of CDK4/6 inhibitors causes extreme regression in cells with cytoplasmic MLH1 compared to control cell populations with nuclear localization of MLH1 in vitro (p=0.00000009), ex vivo (p=0.01) and in vivo (p=0.01). As aberrant cytoplasmic localization occurs in an additional [~]12% of ER+ breast cancer patients, it constitutes a new, major contributor to MLH1 dysregulation. The potential applicability of cytoplasmic MLH1 as a predictor of responsiveness to existing targeted therapies in a hard-to-treat breast cancer subtype posits an update of current clinical diagnostic criteria and therapeutic strategies. This is particularly important in the adjuvant setting where identification of biomarkers predicting responsiveness to CDK4/6 inhibitors remains an urgent, unmet clinical need.

cancer biology↗

bioRxiv2023

Adaptive introgression of a visual preference gene

Visual preferences are important drivers of mate choice and sexual selection, but little is known of how they evolve at the genetic level. Here we take advantage of the diversity of bright warning patterns displayed by Heliconius butterflies, which are also used during mate choice. We show that two Heliconius species have evolved the same visual mating preferences for females with red patterns by exchanging genetic material through hybridization. Extensive behavioral experiments reveal that male preferences are associated with a genomic region of increased admixture between these two species. Variation in neural expression of regucalcin1, located within this introgressed region, correlates with visual preference across populations, and disruption of regucalcin1 with CRISPR/Cas9 impairs courtship towards conspecific females, proving a direct link between gene and behavior. Our results support a role for hybridization during behavioral evolution, and show how visually-guided behaviors contributing to adaptation and speciation are encoded within the genome.

evolutionary biology↗

bioRxiv2022

Adenosine A1R/A3R Agonist AST-004 Reduces Brain Infarction in Mouse and Rat Models of Acute Ischemic Stroke

Acute ischemic stroke (AIS) is the second leading cause of death globally. No Food and Drug Administration (FDA) approved therapies exist targeting cerebroprotection following stroke. Our group recently reported significant cerebroprotection with the adenosine A1/A3 receptor agonist, AST-004, in a transient stroke model in non-human primates (NHP) and in a preclinical mouse model of traumatic brain injury (TBI). However, the specific receptor pathway activated was only inferred based on in vitro binding studies. The current study investigated the underlying mechanism of AST-004 cerebroprotection in two independent models of AIS: permanent photothrombotic stroke in mice and transient middle cerebral artery occlusion (MCAO) in rats. AST-004 treatments across a range of doses were cerebroprotective and efficacy could be blocked by A3R antagonism, indicating a mechanism of action that does not require A1R agonism. The high affinity A3R agonist MRS5698 was also cerebroprotective following stroke, but not the A3R agonist Cl-IB-MECA under our experimental conditions. AST-004 efficacy was blocked by the astrocyte specific mitochondrial toxin fluoroacetate, confirming an underlying mechanism of cerebroprotection dependent on astrocyte mitochondrial metabolism. An increase in A3R mRNA levels following stroke suggested an intrinsic cerebroprotective response that was mediated by A3R signaling. Together, these studies confirm certain A3R agonists, such as AST-004, are promising new therapeutics for the treatment of AIS.

neuroscience↗