Biology subjects

Ribeiro, C.

Publications and source records attributed to Ribeiro, C..

27 records · Page 2Linked to original sources

bioRxiv2022

Predicting lifespan-extending chemical compounds with machine learning and biologically interpretable features

Recently, there has been a growing interest in the development of pharmacological interventions targeting ageing, as well as on the use of machine learning for analysing ageing-related data. In this work we use machine learning methods to analyse data from DrugAge, a database of chemical compounds (including drugs) modulating lifespan in model organisms. To this end, we created four datasets for predicting whether or not a compound extends the lifespan of C. elegans (the most frequent model organism in DrugAge), using four different types of predictive biological features, based on compound-protein interactions, interactions between compounds and proteins encoded by ageing-related genes, and two types of terms annotated for proteins targeted by the compounds, namely Gene Ontology (GO) terms and physiology terms from the WormBases Phenotype Ontology. To analyse these datasets we used a combination of feature selection methods in a data pre-processing phase and the well-established random forest algorithm for learning predictive models from the selected features. The two best models were learned using GO terms and protein interactors as features, with predictive accuracies of about 82% and 80%, respectively. In addition, we interpreted the most important features in those two best models in light of the biology of ageing, and we also predicted the most promising novel compounds for extending lifespan from a list of previously unlabelled compounds.

bioinformatics↗

bioRxiv2022

Generating parallel representations of position and identity in the olfactory system

Sex pheromones are key social signals in most animals. In Drosophila a dedicated olfactory channel senses a male pheromone, cis-vaccenyl acetate (cVA) that promotes female courtship while repelling males. Here we show that flies use separate cVA processing streams to extract qualitative and positional information. cVA olfactory neurons are sensitive to concentration differences in a 5 mm range around a male. Second-order projection neurons detect inter-antennal differences in cVA concentration, encoding the angular position of a male. We identify a circuit mechanism increasing left-right contrast through an interneuron which provides contralateral inhibition. At the third layer of the circuit we identify neurons with distinct response properties and sensory integration motifs. One population is selectively tuned to an approaching male with speed-dependent responses. A second population responds tonically to a males presence and controls female mating decisions. A third population integrates a male taste cue with cVA; only a simultaneous presentation of both signals promotes female mating via this pathway. Thus the olfactory system generates a range of complex percepts in discrete populations of central neurons that allow the expression of appropriate behaviors depending on context. Such separation of olfactory features resembles the mammalian what and where visual streams. HighlightsO_LIcVA male pheromone has a 5 mm signaling range, activating two parallel central pathways C_LIO_LIPheromone-sensing neurons have spatial receptive fields sharpened by contralateral inhibition C_LIO_LIPosition (where) and identity (what) are separated at the 3rd layer of cVA processing C_LIO_LIIntegrating taste and cVA in sexually dimorphic aSP-g controls female receptivity C_LI

neuroscience↗

bioRxiv2021

Fly Cell Atlas: a single-cell transcriptomic atlas of the adult fruit fly

The ability to obtain single cell transcriptomes for stable cell types and dynamic cell states is ushering in a new era for biology. We created the Tabula Drosophilae, a single cell atlas of the adult fruit fly which includes 580k cells from 15 individually dissected sexed tissues as well as the entire head and body. Over 100 researchers from the fly community contributed annotations to >250 distinct cell types across all tissues. We provide an in-depth analysis of cell type-related gene signatures and transcription factor markers, as well as sexual dimorphism, across the whole animal. Analysis of common cell types that are shared between tissues, such as blood and muscle cells, allowed the discovery of rare cell types and tissue-specific subtypes. This atlas provides a valuable resource for the entire Drosophila community and serves as a comprehensive reference to study genetic perturbations and disease models at single cell resolution.

genomics↗

bioRxiv2021

Distinct internal states interact to shape food choice by modulating sensorimotor processing at global and local scales

When deciding what to eat, animals evaluate sensory information about food quality alongside multiple ongoing internal states. How internal states interact to alter sensorimotor processing and shape decisions such as food choice remains poorly understood. Here, we use pan-neuronal volumetric activity imaging in the Drosophila brain to investigate the neuronal basis of internal state dependent nutrient appetites. We created a functional atlas of the ventral fly brain and find that metabolic state shapes sensorimotor processing across large sections of the neuropil. Reproductive state, in contrast, acts locally to define how sensory information is translated into feeding motor output. Thereby, these two states synergistically modulate protein-specific food intake and thus food choice. Finally, using a novel computational strategy, we identify driver lines innervating state-modulated regions and show that the newly identified borboleta region is sufficient to direct food choice towards protein-rich food. We therefore identify a generalizable principle by which distinct internal states are integrated to shape decision-making and propose a strategy to uncover and functionally validate how internal states shape behavior.

neuroscience↗

bioRxiv2020

Engineering 6-phosphogluconate dehydrogenase to improve heat tolerance in maize seed development

Endosperm starch synthesis is a primary determinant of grain yield and is sensitive to high temperature stress. The maize chloroplast-localized 6-phosphogluconate dehydrogenase (6PGDH), PGD3, is critical for endosperm starch accumulation. Maize also has two cytosolic isozymes, PGD1 and PGD2 that are not required for kernel development. We found that cytosolic PGD1 and PGD2 isozymes have heat stable activity, while amyloplast-localized PGD3 activity is labile under heat stress conditions. We targeted heat-stable 6PGDH to endosperm amyloplasts by fusing the Waxy1 chloroplast targeting peptide coding sequence to the Pgd1 and Pgd2 open reading frames. These WPGD1 and WPGD2 fusion proteins import into isolated chloroplasts demonstrating a functional targeting sequence. Transgenic maize plants expressing WPGD1 and WPGD2 with an endosperm specific promoter increased 6PGDH activity with enhanced heat stability in vitro. WPGD1 and WPGD2 transgenes complement the pgd3 defective kernel phenotype indicating the fusion proteins are targeted to the amyloplast. In the field, the WPGD1 and WPGD2 transgenes can mitigate grain yield losses in high nighttime temperature conditions by increasing kernel number. These results provide insight on subcellular distribution of metabolic activities in the endosperm and suggest the amyloplast pentose phosphate pathway is a heat-sensitive step in maize kernel metabolism that contributes to yield loss during heat stress. Significance StatementHeat stress reduces yield in maize by affecting the number of kernels that develop and the accumulation of seed storage molecules during grain fill. Climate change is expected to increase frequency and duration of high temperature stress, which will lower grain yields. Here we show that one enzyme in central carbon metabolism is sensitive to high temperatures. By providing a heat-resistant form of the enzyme in the correct subcellular compartment, a larger number of kernels develop per plant during heat stress in the field. This genetic improvement could be included as part of integrated approaches to mitigate yield losses due to climate change.

plant biology↗

bioRxiv2019

Metabolic cross-feeding allows a gut microbial community to overcome detrimental diets and alter host behaviour

The impact of commensal bacteria on the host arises from complex microbial-diet-host interactions. Mapping metabolic interactions in gut microbial communities is therefore key to understand how the microbiome influences the host. Here we use an interdisciplinary approach including isotope-resolved metabolomics to show that in Drosophila melanogaster, Aceto-bacter pomorum (Ap) and Lactobacillus plantarum (Lp) establish a syntrophic relationship to overcome detrimental host diets and identify Ap as the bacterium altering the hosts feeding decisions. Specifically, we show that Lp generates lactate which is used by Ap to produce and provide amino acids that are essential to Lp allowing it to grow in imbalanced diets. Lactate is also necessary and sufficient for Ap to alter the flys protein appetite. Our data show that gut bacterial communities use metabolic interactions to become resilient to detrimental host diets and to ensure the constant flow of metabolites used by effector bacteria to alter host behaviour.

neuroscience↗

bioRxiv2019

Cellular metabolic reprogramming controls sugar appetite

Cellular metabolic reprogramming is an important mechanism by which cells rewire their metabolism to promote proliferation and cell growth. This process has been mostly studied in the context of tumorigenesis and less is known about its relevance for non-pathological processes and how it affects whole animal physiology. Here, we show that Drosophila female germline cells reprogram their carbohydrate metabolism, upregulating the pentose phosphate pathway (PPP) to produce eggs. Strikingly, this cellular reprogramming strongly impacts nutrient preferences. PPP activity in the germline specifically increases the animals appetite for sugar, the key nutrient fueling this metabolic pathway. We furthermore provide functional evidence that the germline alters sugar appetite by regulating the expression of the fat body secreted satiety factor fit. The cellular metabolic program of a small set of cells is therefore able to increase the animals preference for specific nutrients through inter-organ communication to promote specific metabolic and cellular outcomes.

physiology↗

bioRxiv2018

optoPAD: a closed-loop optogenetics system to study the circuit basis of feeding behaviors

The regulation of feeding plays a key role in determining the fitness of animals through its impact on nutrition. Elucidating the circuit basis of feeding and related behaviors is an important goal in neuroscience. We recently used a system for closed-loop optogenetic manipulation of neurons contingent on the flys feeding behavior to dissect the impact of a specific subset of taste neurons on yeast feeding (Steck et al., 2018). Here we describe the development and validation of this system, which we term the optoPAD. We use the optoPAD to induce appetitive and aversive effects on feeding by activating or inhibiting gustatory neurons in closed loop - effectively creating virtual taste realities. The use of optogenetics allowed us to vary the dynamics and probability of stimulation in single flies and assess the impact on feeding behavior quantitatively and with high throughput. These data demonstrate that the optoPAD is a powerful tool to dissect the circuit basis of feeding behavior, allowing the efficient implementation of sophisticated behavioral paradigms to study the mechanistic basis of animals adaptation to dynamic environments.

neuroscience↗

bioRxiv2017

Internal amino acid state modulates yeast taste neurons to support protein homeostasis in Drosophila

To optimize fitness, animals must dynamically match food choices to their current needs. For drosophilids, yeast fulfils most dietary protein and micronutrient requirements. While several yeast metabolites activate known gustatory receptor neurons (GRNs) in Drosophila melanogaster, the chemosensory channels mediating yeast feeding remain unknown. Here we identify a class of proboscis GRNs required for yeast intake, and show that these GRNs act redundantly to mediate yeast feeding. While nutritional and reproductive states synergistically increase yeast appetite, we find a separation of these state signals at the level of GRN responses to yeast: amino acid but not mating state enhances yeast GRN gain. The sensitivity of sweet GRNs to sugar is not increased by protein deprivation, providing a potential basis for protein-specific appetite. The emerging picture is that different internal states act at distinct levels of a dedicated gustatory circuit to elicit nutrient-specific appetites towards a complex, ecologically relevant protein source.

neuroscience↗