Biology subjects

Soler, N.

Publications and source records attributed to Soler, N..

4 recordsLinked to original sources

bioRxiv2024

Integration of diverse bioactivity data into the Chemical Checker compound universe

Chemical signatures encode the physicochemical and structural properties of small molecules into numerical descriptors, forming the basis for chemical comparisons and search algorithms. The increasing availability of bioactivity data has improved compound representations to include biological effects, although bioactivity descriptors are often limited to a few well-documented molecules. To address this issue, we implemented a collection of deep neural networks able to leverage the experimentally determined bioactivity data associated to small molecules and infer the missing bioactivity signatures for any compound of interest. However, unlike static chemical descriptors, these bioactivity signatures dynamically evolve with new data and processing strategies. Here, we present a computational protocol to modify or generate novel bioactivity spaces and signatures, describing the main steps needed to leverage diverse bioactivity data with the current knowledge, as catalogued in the Chemical Checker (CC), using the predefined data curation pipeline. We illustrate the functioning of the protocol through four specific examples, including the incorporation of new compounds to an already existing bioactivity space, a change in the data pre-processing without altering the underlying experimental data, and the creation of two novel bioactivity spaces from scratch, which are completed in under 9 hours using GPU computing. Overall, this protocol offers a guideline for installing, testing and running the CC data integration approach on user-provided data, with the aim of extending the annotation presented for a limited number of small molecules to a larger chemical landscape. Key pointsO_LIThe Chemical Checker is a large collection of processed, harmonized and integrated bioactivity signatures for over 1 million small molecules. Data are organized into 5 levels of increasing biological complexity and curation degrees: from chemical properties to clinical outcomes and from raw data representing explicit knowledge to embedded signatures inferred from observed bioactivity patterns. C_LIO_LIThe Chemical Checker package provides a predefined and versatile framework to integrate user-provided data to the Chemical Checker universe of small molecules and generate novel customized bioactivity signatures. C_LI Key referencesDuran-Frigola et al. "Extending the small-molecule similarity principle to all levels of biology with the Chemical Checker." Nature Biotechnology 38.9 (2020): 1087-1096. Bertoni et al. "Bioactivity descriptors for uncharacterized chemical compounds." Nature Communications 12.1 (2021): 3932.

bioinformatics↗

bioRxiv2023

Only three principal components account for inter-embryo variability of the spindle length over time.

How to quantify inter-individual variability? When measuring many features per experiment/individual, this question becomes non-trivial. One challenge lies in choosing features to recapitulate high-dimensional data. This paper focuses on spindle elongation phenotypes to highlight how a data-driven approach can help tackle this challenge. We showed that only three typical elongation patterns describe spindle elongation in C. elegans one-cell embryo. We called them archetypes. These archetypes were automatically extracted from the experimental data using principal component analysis (PCA) rather than defined a priori. They accounted for more than 95% of inter-individual variability in a dataset of more than 1600 experiments across more than 100 different experimental conditions (RNAi, mutants, changes in temperature, etc.). The two first archetypes were consistent with standard measures in the field, namely the average spindle length and the spindle elongation rate in late metaphase and anaphase. However, our archetypes were not strictly corresponding to these classic, manually-set, features. The third archetype, accounting for 6% of the variability, was novel and corresponded to a transient spindle shortening in late metaphase. We revealed that it is part of spindle elongation dynamics in all conditions. It is reminiscent of the spindle elongation pattern observed upon kinetochore function defects. Interestingly, because these archetypes were all three present from metaphase on, it implied that spindle elongation around the anaphase onset is sufficient to predict its late anaphase length. We validated this idea using a machine-learning approach. The inter-individual differences between embryos depleted from cell division-related proteins have the same underlying nature as inter-individual differences naturally arising between wild-type embryos. The same conclusion holds also when analysing embryos dividing at various temperatures. We thus propose that beyond the apparent complexity of the spindle and variability in the phenotypes of various gene depletions, only three independent mechanisms account for spindle elongation, weighted differently in the various conditions; meanwhile, no mechanism is specific to any condition. As such, given amounts of these three archetypes could represent a quantitative phenotype.

bioinformatics↗

bioRxiv2022

Kinetochore microtubules flux poleward along fixed centrosome-anchored microtubules during the metaphase of C. elegans one-cell embryo.

The mitotic spindle, a key structure to partition chromosomes during cell division, connects its poles to the chromosomes through microtubules. Their plus-ends, oriented towards the chromosomes, exhibit dynamic instability crucial for kinetochore correct attachments. Involved in this process, the poleward flux implicates the displacement of microtubules towards the spindle poles, coordinated with polymerisation at the plus ends. The mechanisms behind this are diverse. It includes treadmilling powered by microtubule depolymerisation at the spindle poles, sliding of spindle microtubules by molecular motors like Kinesin-5, and pushing microtubules away from the chromosomes by chromokinesins. Interestingly, no such flux was reported in the Caenorhabditis elegans zygote, although all proteins contributing to flux in mammals have homologs in the nematode. To explore this, we fluorescently labelled microtubules and conducted photobleaching. We found no global poleward flux; the bleached zones edges moved inward. The centrosome-side front motion was caused by dynamic instability, while the chromosome-side front exhibited faster recovery, suggesting an additional mechanism. This larger slope was detected only near the chromosomes, indicating that only kinetochore microtubules undergo flux. Consistently, this flux depended on proteins ensuring the chromosome attachment and growth of the kinetochore microtubules, notably NDC-80, CLS-2CLASP, and ZYG-9XMAP215. Furthermore, this flux decreased as metaphase progressed and attachments transitioned from side-to end-on; it was reduced by SKA-1 recruitment. Treadmilling was unlikely to account for these observations, as most kinetochore microtubules do not reach spindle poles in the zygote spindle. Conversely, the depletion of kinesin-12 KLP-18KIF15, which cross-links and focuses microtubules at meiosis, reduced the front rate. Ultimately, we propose that the sole kinetochore microtubules slide along spindle microtubules, likely powered by KLP-18, contrasting with solid displacement in other systems. It aligns with observations in human cells of decreasing flux with increasing chromosome distance.

cell biology↗

bioRxiv2019

Two dynamical behaviours of the microtubules at cell cortex reveal pulling and pushing forces that position the spindle in C. elegans embryo.

In the Caenorhabditis elegans zygote, astral microtubules generate forces, pushing against and pulling from the cell periphery. They are essential to position the mitotic spindle. By measuring the dynamics of astral microtubules at the cortex, we revealed the presence of two populations, residing there for 0.4 s and 1.8 s, which correspond to the pulling and pushing events, respectively. Such an experiment offers a unique opportunity to monitor both forces that position the spindle under physiological conditions and study their variations along the anteroposterior axis (space) and the mitotic progression (time). By investigating pulling-force-generating events at the microscopic level, we showed that an anteroposterior asymmetry in dynein on-rate - encoding pulling-force imbalance - is sufficient to cause posterior spindle displacement. The regulation by spindle position - reflecting the number of microtubule contacts in the posterior-most region - reinforces this imbalance only in late-anaphase. Furthermore, we exhibited the first direct proof that the force-generator increasing persistence to pull (processivity) accounts for the temporal control of pulling force throughout mitosis. We thus propose a three-fold control of pulling force, by the polarity, spindle position and mitotic progression. Focusing on pushing force, we discovered a correlation between its density and the stability of the spindle position during metaphase, which strongly suggests that the pushing force contributes to maintaining the spindle at the cell centre. This force remains constant and symmetric along the anteroposterior axis during the division. The pulling one increases in intensity and becomes dominant at anaphase. In conclusion, the two-population study enabled us to decipher the complex regulation of the spindle positioning during cell division.

biophysics↗