Biology subjects

Marchand, B.

Publications and source records attributed to Marchand, B..

6 recordsLinked to original sources

bioRxiv2025

On the Comparison of LGT networks and Tree-based Networks

Phylogenetic networks are widespread representations of evolutionary histories for taxa that undergo hybridization or Lateral-Gene Transfer (LGT) events. There are now many tools to reconstruct such networks, but no clearly established metric to compare them. Such metrics are needed, for example, to evaluate predictions against a simulated ground truth. Despite years of effort in developing metrics, known dissimilarity measures either do not distinguish all pairs of different networks, or are extremely difficult to compute. Since it appears challenging, if not impossible, to create the ideal metric for all classes of networks, it may be relevant to design them for specialized applications. In this article, we introduce a metric on LGT networks, which consist of trees with additional arcs that represent lateral gene transfer events. Our metric is based on edit operations, namely the addition/removal of transfer arcs, and the contraction/expansion of arcs of the base tree, allowing it to connect the space of all LGT networks. We show that it is linear-time computable if the order of transfers along a branch is unconstrained but NP-hard otherwise, in which case we provide a fixed-parameter tractable (FPT) algorithm in the level. We implemented our algorithms and demonstrate their applicability on three numerical experiments. Full online versionhttps://www.biorxiv.org/content/10.1101/2025.11.20.689557

bioinformatics↗

bioRxiv2024

A Proximity MAP of RAB GTPases

RAB GTPases are the most abundant family of small GTPases and regulate multiple aspects of membrane trafficking events, from cargo sorting to vesicle budding, transport, docking, and fusion. To regulate these processes, RABs are tightly regulated by guanine exchange factors (GEFs) and GTPase-activating proteins (GAPs). Activated RABs recruit effector proteins that regulate trafficking. Identifying RAB-associated proteins has proven to be difficult because their association with interacting proteins is often transient. Recent advances in proximity labeling approaches that allow for the covalent labeling of neighbors of proteins of interest now permit the cataloging of proteins in the vicinity of RAB GTPases. Here, we report APEX2 proximity labeling of 23 human RABs and their neighboring proteomes. We have used bioinformatic analyses to map specific proximal proteins for an extensive array of RAB GTPases, and RAB localization can be inferred from their adjacent proteins. Focusing on specific examples, we identified a physical interaction between RAB25 and DENND6A, which affects cell migration. We also show functional relationships between RAB14 and the EARP complex, or between RAB14 and SHIP164 and its close ortholog UHRF1BP1. Our dataset provides an extensive resource to the community and helps define novel functional connections between RAB GTPases and their neighboring proteins.

cell biology↗

bioRxiv2024

Discovery and Synthesis of GS-7682, a Novel Prodrug of a 4'-CN-4-Aza-7,9-Dideazaadenosine C-Nucleoside with Broad-Spectrum Potency Against Pneumo- and Picornaviruses and Efficacy in RSV-Infected African Green Monkeys.

Acute respiratory viral infections (ARVI), such as pneumovirus and respiratory picornavirus infections, exacerbate disease in COPD and asthma patients. A research program targeting respiratory syncytial virus (RSV) led to the discovery of GS-7682 (1) a novel phosphoramidate prodrug of a 4'-CN-4-aza-7,9-dideazaadenosine C-nucleoside GS-646089 (2) with broad antiviral activity against RSV EC50 = 3-46 nM, human metapneumovirus (hMPV) EC50 = 210 {+/-} 50 nM, human rhinovirus (RV) EC50 = 54-61 nM, and enterovirus (EV) EC50 = 83-90 nM. Prodrug optimization for cellular potency and lung cell metabolism identified the 5-methyl((S)-hydroxy(phenoxy)phosphoryl)-L-alaninate in combination with 2,3-diisobutyrate promoieties as optimal for high intracellular triphosphate formation in vitro and in vivo. 1 demonstrated significant reductions of viral loads in the lower respiratory tract of RSV-infected African green monkeys when administered once daily via intratracheal nebulized aerosol. Together these finding support additional evaluation of 1 and its analogs as a potential therapeutic for pneumo- and picornaviruses.

biochemistry↗

bioRxiv2023

Designing molecular RNA switches with Restricted Boltzmann machines

Riboswitches are structured allosteric RNA molecules that change conformation upon metabolite binding, triggering a regulatory response. Here we focus on the de novo design of riboswitch-like aptamers, the core part of the riboswitch undergoing structural changes. We use Restricted Boltzmann machines (RBM) to learn generative models from homologous sequence data. We first verify, on four different riboswitch families, that RBM-generated sequences correctly capture the conservation, covariation and diversity of natural aptamers. The RBM model is then used to design new SAM-I riboswitch aptamers. To experimentally validate the properties of the structural switch in designed molecules, we resort to chemical probing (SHAPE and DMS), and develop a tailored analysis pipeline adequate for high-throughput tests of diverse sequences. We probe a total of 476 RBM-designed and 201 natural sequences. Designed molecules with high RBM scores, with 20% to 40% divergence from any natural sequence, display{approx} 30% success rate of responding to SAM with a structural switch similar to their natural counterparts. We show how the capability of the designed molecules to switch conformation is connected to fine energetic features of their structural components.

bioinformatics↗

bioRxiv2021

Tree Diet: Reducing the Treewidth to Unlock FPT Algorithms in RNA Bioinformatics

Hard graph problems are ubiquitous in Bioinformatics, inspiring the design of specialized Fixed-Parameter Tractable algorithms, many of which rely on a combination of tree-decomposition and dynamic programming. The time/space complexities of such approaches hinge critically on low values for the treewidth tw of the input graph. In order to extend their scope of applicability, we introduce the TO_SCPLOWREEC_SCPLOW-DO_SCPLOWIETC_SCPLOW problem, i.e. the removal of a minimal set of edges such that a given tree-decomposition can be slimmed down to a prescribed treewidth tw'. Our rationale is that the time gained thanks to a smaller treewidth in a parameterized algorithm compensates the extra post-processing needed to take deleted edges into account. Our core result is an FPT dynamic programming algorithm for TO_SCPLOWREEC_SCPLOW-DO_SCPLOWIETC_SCPLOW, using 2O(tw)n time and space. We complement this result with parameterized complexity lower-bounds for stronger variants (e.g., NP-hardness when tw' or tw - tw' is constant). We propose a prototype implementation for our approach which we apply on difficult instances of selected RNA-based problems: RNA design, sequence-structure alignment, and search of pseudoknotted RNAs in genomes, revealing very encouraging results. This work paves the way for a wider adoption of tree-decomposition-based algorithms in Bioinformatics.

bioinformatics↗

bioRxiv2021

Structural modeling of the SARS-CoV-2 Spike/human ACE2 complex interface can identify high-affinity variants associated with increased transmissibility

The COVID-19 pandemic has triggered concerns about the emergence of more infectious and pathogenic viral strains. As a public health measure, efficient screening methods are needed to determine the functional effects of new sequence variants. Here we show that structural modeling of SARS-CoV-2 Spike protein binding to the human ACE2 receptor, the first step in host-cell entry, predicts many novel variant combinations with enhanced binding affinities. By focusing on natural variants at the Spike-hACE2 interface and assessing over 700 mutant complexes, our analysis reveals that high-affinity Spike mutations (including N440K, S443A, G476S, E484R, G502P) tend to cluster near known human ACE2 recognition sites (K31 and K353). These Spike regions are conformationally flexible, allowing certain mutations to optimize interface interaction energies. Although most human ACE2 variants tend to weaken binding affinity, they can interact with Spike mutations to generate high-affinity double mutant complexes, suggesting variation in individual susceptibility to infection. Applying structural analysis to highly transmissible variants, we find that circulating point mutations S447N, E484K and N501Y form high-affinity complexes (~40% more than wild-type). By combining predicted affinities and available antibody escape data, we show that fast-spreading viral variants exploit combinatorial mutations possessing both enhanced affinity and antibody resistance, including S447N/E484K, E484K/N501Y and K417T/E484K/N501Y. Thus, three-dimensional modeling of the Spike/hACE2 complex predicts changes in structure and binding affinity that correlate with transmissibility and therefore can help inform future intervention strategies.

molecular biology↗