Scalable Coupling of Deep Learning with Logical Reasoning

In the ongoing quest for hybridizing discrete reasoning with neural nets, there is an increasing interest in neural architectures that can learn how to solve discrete reasoning or optimization problems from natural inputs. In this paper, we introduce a scalable neural architecture and loss function dedicated to learning the constraints and criteria of NP-hard reasoning problems expressed as discrete Graphical Models. Our loss function solves one of the main limitations of Besag's pseudo-loglikelihood, enabling learning of high energies. We empirically show it is able to efficiently learn how to solve NP-hard reasoning problems from natural inputs as the symbolic, visual or many-solutions Sudoku problems as well as the energy optimization formulation of the protein design problem, providing data efficiency, interpretability, and \textit{a posteriori} control over predictions.Comment: 10 pages, 2 figures, 6 tables. Published in IJCAI'2023 proceeding

The sensory space of wines: From concept to evaluation and description. a review

The concept of sensory space was first formulated over 25 years ago and has been widely adopted in oenology for around the last 15 years. It is based on both the common organoleptic characteristics of products and the mental representations built by specific groups of people. Exploring this concept involves first assessing whether it already exists for tasters, and, when this is the case, conducting perceptual evaluations to verify its effectiveness before potentially highlighting the associated sensory properties. The goal of this review, which focuses on applications linked to the field of oenology, is to study how these three steps are carried out, how the corresponding tasks and tests are performed and managed, and the type of results that can be obtained

Month of Birth, a Risk Factor for Violent Behaviour in Suicidal Patients Admitted in Emergency?

Although there are numerous publications on the existing link between month of birth and suicide, only two studies focus on suicide attempts and auto-aggressive behavior. Research data suggest that month of birth is related to a variation of 5-HIAA in the cerebrospinal fluid, which correlates with violent behavior (VB). Therefore, the aim of this study is to search, for the first time, for a possible link between month of birth and the occurrence of VB in emergency, for patients admitted for a suicide attempt with medication. This is a 10months prospective study among all the patients of the canton of Geneva, Switzerland, admitted in emergency for a suicide attempt with medication. During a 10months study period we included 493 patients, of which 77 (15.62%) presented VB. Higher incidence of VB was found in subjects where born at the end of winter and the beginning of spring, with a maximum for April and a minimum for December. In spite of a relatively small number of subjects, it seems promising to study the occurrence of VB as a function of month of birth in patients admitted in emergency for a suicide attemp

Computational protein design to accelerate the conception of fine-tuned biocatalysts

The remarkable properties of enzymes (high catalytic efficiency, regio- and stereo-selectivity) have been recognized and largely exploited in biocatalysis. Accordingly, enzyme-driven processes should play an increasing role in the next decades, potentially substituting chemical processes and contributing to the raise of bioeconomy. However, to foresee a viable future to biocatalysis, advances in R&D are required to accelerate the delivery of fine-tuned enzymes displaying high chemical specificity on non-cognate substrates, high efficiency and better stability in reaction conditions. To this end, structure-based Computational Protein Design (CPD) is a promising strategy to fully rationalize and speed-up the conception of new enzymes while reducing associated human and financial costs. By combining physico-chemical models governing relations between protein amino-acid composition and their 3D structure with optimization algorithms, CPD seeks to identify sequences that fold into a given 3D-scaffold and possess the targeted biochemical properties. Starting from a huge search space, the protein sequence-conformation space, this in silico pre-screening aims to considerably narrow down the number of mutants tested at experimental level while substantially increasing the chances of reaching the desired enzyme. While CPD is still a very young and rapidly evolving field, success stories of computationally designed proteins highlight future prospects of this field. Nonetheless, despite landmark achievements, the success rate of the current computational approaches remains low, and designed enzymes are often way less efficient than their natural counterparts. Therefore, several limitations of the CPD still need to be addressed to improve its efficiency, predictability and reliability. Herein, we present our methodological advances in the CPD field that enabled overcoming technological bottlenecks and hence propose innovative CPD methods to explore large sequence-conformation spaces while providing more accuracy and robustness than classical approaches. Our CPD methods speed-up search across vast sequence-conformation spaces by several orders of magnitude, find the minimum energy enzyme design and generate exhaustive lists of near-optimal sequences, defining small mutant libraries. These new methods, in rupture with classical approaches are based on efficient algorithms issued from recent research in artificial intelligence. The performance and accuracy of our computer-aided enzyme design methods have been evaluated and validated on various types of protein design problems. This work was partially funded by INRA/Région Midi-Pyrénées, IDEX Toulouse, Agreenskills and the French National Research Agency (PROTICAD, ANR-12-MONU-0015-03)

Production of medium chain fatty acid by Yarrowia lipolytica: Combining molecular design and TALEN to engineer the fatty acid synthase

Yarrowia lipolytica is a promising organism for the production of lipids of biotechnological interest and particularly for biofuel. In this study, we engineered lipid biosynthesis through rational engineering of the giant multifunctional Fatty Acid Synthase (FAS) enzyme to modulate fatty acid chain length and produce shorter fatty acids. Based on the hypothesis that the Ketoacyl Synthase (KS) domain, responsible for chain elongation in Yarrowia lipolytica, is directly involved in chain length specificity, a computer-based strategy was undertaken to re-design mutants of the Ketoacyl Synthase. Molecular modelling of this domain in interaction with a C16-acyl substrate enabled identification of a key residue from the fatty acid binding site. This site was then targeted by mutagenesis in order to modify KS fatty acid chain length specificity. To introduce point mutations in this essential gene, we applied, for the first time, the TALEN technology to Yarrowia lipolytica and demonstrated the efficiency of the technique to perform site-directed mutagenesis at a specific genomic locus. Some mutants led to a significant increase of C14 fatty acid. Thanks to the use of an elegant combination of genome editing technology and molecular modelling, this study provides for the first time, evidences that the KS domain of the fungal FASI system is directly involved in fatty acid chain length specificity

Cost Function Networks to Solve Large Computational Protein Design Problems

International audienc

High quality draft sequences for prokaryotic genomes using a mix of new sequencing technologies

<p>Abstract</p> <p>Background</p> <p>Massively parallel DNA sequencing instruments are enabling the decoding of whole genomes at significantly lower cost and higher throughput than classical Sanger technology. Each of these technologies have been estimated to yield assemblies with more problematic features than the standard method. These problems are of a different nature depending on the techniques used. So, an appropriate mix of technologies may help resolve most difficulties, and eventually provide assemblies of high quality without requiring any Sanger-based input.</p> <p>Results</p> <p>We compared assemblies obtained using Sanger data with those from different inputs from New Sequencing Technologies. The assemblies were systematically compared with a reference finished sequence. We found that the 454 GSFLX can efficiently produce high continuity when used at high coverage. The potential to enhance continuity by scaffolding was tested using 454 sequences from circularized genomic fragments. Finally, we explore the use of Solexa-Illumina short reads to polish the genome draft by implementing a technique to correct 454 consensus errors.</p> <p>Conclusion</p> <p>High quality drafts can be produced for small genomes without any Sanger data input. We found that 454 GSFLX and Solexa/Illumina show great complementarity in producing large contigs and supercontigs with a low error rate.</p

Comparative genomic and proteomic analyses of two Mycoplasma agalactiae strains: clues to the macro- and micro-events that are shaping mycoplasma diversity

Background: While the genomic era is accumulating a tremendous amount of data, the question of how genomics can describe a bacterial species remains to be fully addressed. The recent sequencing of the genome of the Mycoplasma agalactiae type strain has challenged our general view on mycoplasmas by suggesting that these simple bacteria are able to exchange significant amount of genetic material via horizontal gene transfer. Yet, events that are shaping mycoplasma genomes and that are underlining diversity within this species have to be fully evaluated. For this purpose, we compared two strains that are representative of the genetic spectrum encountered in this species: the type strain PG2 which genome is already available and a field strain, 5632, which was fully sequenced and annotated in this study. Results: The two genomes differ by ca. 130 kbp with that of 5632 being the largest (1006 kbp). The make up of this additional genetic material mainly corresponds (i) to mobile genetic elements and (ii) to expanded repertoire of gene families that encode putative surface proteins and display features of highly-variable systems. More specifically, three entire copies of a previously described integrative conjugative element are found in 5632 that accounts for ca. 80 kbp. Other mobile genetic elements, found in 5632 but not in PG2, are the more classical insertion sequences which are related to those found in two other ruminant pathogens, M. bovis and M. mycoides subsp. mycoides SC. In 5632, repertoires of gene families encoding surface proteins are larger due to gene duplication. Comparative proteomic analyses of the two strains indicate that the additional coding capacity of 5632 affects the overall architecture of the surface and suggests the occurrence of new phase variable systems based on single nucleotide polymorphisms. Conclusion: Overall, comparative analyses of two M. agalactiae strains revealed a very dynamic genome which structure has been shaped by gene flow among ruminant mycoplasmas and expansion-reduction of gene repertoires encoding surface proteins, the expression of which is driven by localized genetic micro-events

Being Pathogenic, Plastic, and Sexual while Living with a Nearly Minimal Bacterial Genome

Mycoplasmas are commonly described as the simplest self-replicating organisms, whose evolution was mainly characterized by genome downsizing with a proposed evolutionary scenario similar to that of obligate intracellular bacteria such as insect endosymbionts. Thus far, analysis of mycoplasma genomes indicates a low level of horizontal gene transfer (HGT) implying that DNA acquisition is strongly limited in these minimal bacteria. In this study, the genome of the ruminant pathogen Mycoplasma agalactiae was sequenced. Comparative genomic data and phylogenetic tree reconstruction revealed that ∼18% of its small genome (877,438 bp) has undergone HGT with the phylogenetically distinct mycoides cluster, which is composed of significant ruminant pathogens. HGT involves genes often found as clusters, several of which encode lipoproteins that usually play an important role in mycoplasma–host interaction. A decayed form of a conjugative element also described in a member of the mycoides cluster was found in the M. agalactiae genome, suggesting that HGT may have occurred by mobilizing a related genetic element. The possibility of HGT events among other mycoplasmas was evaluated with the available sequenced genomes. Our data indicate marginal levels of HGT among Mycoplasma species except for those described above and, to a lesser extent, for those observed in between the two bird pathogens, M. gallisepticum and M. synoviae. This first description of large-scale HGT among mycoplasmas sharing the same ecological niche challenges the generally accepted evolutionary scenario in which gene loss is the main driving force of mycoplasma evolution. The latter clearly differs from that of other bacteria with small genomes, particularly obligate intracellular bacteria that are isolated within host cells. Consequently, mycoplasmas are not only able to subvert complex hosts but presumably have retained sexual competence, a trait that may prevent them from genome stasis and contribute to adaptation to new hosts

Crystal structures of bacterial peptidoglycan amidase AmpD and an unprecedented activation mechanism

9 pags, 5 figs, 2 tabsAmpD is a cytoplasmic peptidoglycan (PG) amidase involved in bacterial cell-wall recycling and in induction of β-lactamase, a key enzyme of β-lactam antibiotic resistance. AmpD belongs to the amidase-2 family that includes zinc-dependent amidases and the peptidoglycan-recognition proteins (PGRPs), highly conserved pattern-recognition molecules of the immune system. Crystal structures of Citrobacter freundii AmpD were solved in this study for the apoenzyme, for the holoenzyme at two different pH values, and for the complex with the reaction products, providing insights into the PG recognition and the catalytic process. These structures are significantly different compared with the previously reported NMR structure for the same protein. TheNMRstructure does not possess an accessible active site and shows the protein in what is proposed herein as an inactive "closed" conformation. The transition of the protein from this inactive conformation to the active "open" conformation, as seen in the x-ray structures, was studied by targeted molecular dynamics simulations, which revealed large conformational rearrangements (as much as 17 Å ) in four specific regions representing one-third of the entire protein. It is proposed that the large conformational change that would take the inactive NMR structure to the active x-ray structure represents an unprecedented mechanism for activation of AmpD. Analysis is presented to argue that this activation mechanism might be representative of a regulatory process for other intracellular members of the bacterial amidase-2 family of enzymes. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.This work was supported, in whole or in part, by the National Institutes of Health. This work was also supported by grants from the Spanish Ministry of Science and Technology (BFU2008-01711), EU-CP223111 (CARE-PNEUMO, European Union), and the COMBACT program (S-BIO-0260/2006). We acknowledge the Spanish Ministerio de Ciencia e Innovación (PI201060E013) and Consejo Superior de Investigaciones Científicas for financial support and for provision of synchrotron radiation facilitie