Dual-Space Optimization: Improved Molecule Sequence Design by Latent Prompt Transformer

Designing molecules with desirable properties, such as drug-likeliness and high binding affinities towards protein targets, is a challenging problem. In this paper, we propose the Dual-Space Optimization (DSO) method that integrates latent space sampling and data space selection to solve this problem. DSO iteratively updates a latent space generative model and a synthetic dataset in an optimization process that gradually shifts the generative model and the synthetic data towards regions of desired property values. Our generative model takes the form of a Latent Prompt Transformer (LPT) where the latent vector serves as the prompt of a causal transformer. Our extensive experiments demonstrate effectiveness of the proposed method, which sets new performance benchmarks across single-objective, multi-objective and constrained molecule design tasks

Genome-wide Analysis of the Interplay Between Chromatin-associated Rna and 3d Genome Organization in Human Cells

The interphase genome is dynamically organized in the nucleus and decorated with chromatin-associated RNA (caRNA). It remains unclear whether the genome architecture modulates the spatial distribution of caRNA and vice versa. Here, we generate a resource of genome-wide RNA-DNA and DNA-DNA contact maps in human cells. These maps reveal the chromosomal domains demarcated by locally transcribed RNA, hereafter termed RNA-defined chromosomal domains. Further, the spreading of caRNA is constrained by the boundaries of topologically associating domains (TADs), demonstrating the role of the 3D genome structure in modulating the spatial distribution of RNA. Conversely, stopping transcription or acute depletion of RNA induces thousands of chromatin loops genome-wide. Activation or suppression of the transcription of specific genes suppresses or creates chromatin loops straddling these genes. Deletion of a specific caRNA-producing genomic sequence promotes chromatin loops that straddle the interchromosomal target sequences of this caRNA. These data suggest a feedback loop where the 3D genome modulates the spatial distribution of RNA, which in turn affects the dynamic 3D genome organization

Le rôle d'une voie de signalisation bactérienne (Dif) dans l'environnement externe, l'exopolysaccharide (EPS) et la multicellularité dans la bactérie sociale Myxococcus xanthus

Les EPS sont les principaux composants de la matrice extracellulaire et jouent un rôle dans de nombreuses fonctions. Les EPS sont cruciaux pour la motilité médiée par T4P. L'EPS sert d'ancrage pour la liaison de T4P qui déclenche la rétraction de T4P pour tirer les cellules vers l'avant.La synthèse d'EPS est régulée par Dif, par WzxX/WzyX, qui est régulée par Dif. Cependant, la façon dont Dif transduit les signaux vers WzxX/WzyX est encore insaisissable.Dans la première partie, j'ai analysé la localisation subcellulaire de Dif et WzxX/WzyX pour corréler leurs localisations avec des fonctions. J'ai effectué BACTH pour tester les interactions entre EpsW et WzxX/WzyX. Les analyses ont montré que Dif et WzxX/WzyX forment des amas périphériques occupant des positions différentes. BACTH n'a pas révélé d'interactions, indiquant que EpsW pourrait être un facteur intermédiaire.Dans la deuxième partie, j'ai utilisé un criblage génétique pour rechercher des cibles EpsW. L'écran a révélé un nouveau type de motilité. D'autres caractérisations ont révélé que la motilité est médiée par PilY1s participant à l'assemblage de T4P et à l'adhésion à des substrats alternatifs. Les PilY1s sont régulées par HsfAB, confirmé par EMSA, qRT-PCR et RNA-seq.Dans l'ensemble, dans la première partie, j'ai caractérisé le positionnement cellulaire d'une voie de biosynthèse de l'EPS et de son régulateur. Cela pourrait contribuer à mieux comprendre comment les signaux sont convertis en production EPS. Au cours de la deuxième partie, j'ai mis en lumière les mécanismes de motilité où deux PilY1 sont importants pour l'assemblage de T4P et la liaison à des substrats alternatifs pour le mouvement cellulaire.EPS are the major components of the extracellular matrix and play important roles in many biological functions. In M. xanthus, EPS are crucial for T4P-mediated motility. EPS deposited on cell surface or on the substrate, serve as the anchor for T4P binding which triggers T4P retraction to pull cells forward.The EPS synthesis in M. xanthus is regulated by a chemotaxis-like system Dif. The synthesis of EPS is via a WzxX/WzyX pathway, which is regulated by Dif. However, how Dif transduces signals to WzxX/WzyX is still elusive. In the first part, I analyzed the subcellular localization of Dif and WzxX/WzyX to correlate their localizations with functions. I also performed BACTH assays to test interactions between EpsW and WzxX/WzyX. Localization analyses showed that Dif and WzxX/WzyX form peripheral clusters occupied different positions. BACTH did not reveal interactions, indicating that EpsW could be an intermediate factor.In the second part, I used a genetic screen to search for EpsW targets. The screen revealed a novel type of motility. Further characterizations revealed that motility is mediated by PilY1s participating in T4P assembly and adhesion to alternative substrates. In addition, PilY1s are regulated by the HsfAB two-component system, confirmed by EMSA, qRT-PCR and RNA-seq.Taken together, in the first part I characterized the cellular positioning of an EPS biosynthetic pathway and its regulator. This might contribute to better understand how signals are transduced into EPS production. During the second part, I put light on mechanisms of motility where two PilY1s are important for T4P assembly and binding to alternative substrates for cell movement

Coordination of symbiosis and cell cycle functions in Sinorhizobium meliloti

International audienceThe symbiotic nitrogen fixing species Sinorhizobium meliloti represents a remarkable model system for the class Alphaproteobacteria, which includes genera such as Caulobacter, Agrobacterium and Brucella. It is capable of living free in the soil, and is also able to establish a complex symbiosis with leguminous plants, during which its cell cycle program is completely rewired presumably due, at least in part, to the action of peptides secreted by the plant. Here we will discuss how the cell cycle regulation works in S. meliloti and the kinds of molecular mechanisms that take place during the infection. We will focus on the complex regulation of the master regulator of the S. meliloti cell cycle, the response regulator CtrA, discussing its implication in symbiosis

The differential expression of PilY1 proteins by the HsfBA phosphorelay allows twitching motility in the absence of exopolysaccharides

International audienceType Four Pili (T4P) are extracellular appendages mediating several bacterial functions such as motility, biofilm formation and infection. The ability to adhere to substrates is essential for all these functions. In Myxococcus xanthus , during twitching motility, the binding of polar T4P to exopolysaccharides (EPS), induces pilus retraction and the forward cell movement. EPS are produced, secreted and weakly associated to the M . xanthus cell surface or deposited on the substrate. In this study, a genetic screen allowed us to identify two factors involved in EPS-independent T4P-dependent twitching motility: the PilY1.1 protein and the HsfBA phosphorelay. Transcriptomic analyses show that HsfBA differentially regulates the expression of PilY1 proteins and that the down-regulation of pilY1 . 1 together with the accumulation of its homologue pilY1 . 3 , allows twitching motility in the absence of EPS. The genetic and bioinformatic dissection of the PilY1.1 domains shows that PilY1.1 might be a bi-functional protein with a role in priming T4P extension mediated by its conserved N-terminal domain and roles in EPS-dependent motility mediated by an N-terminal DUF4114 domain activated upon binding to Ca 2+ . We speculate that the differential transcriptional regulation of PilY1 homologs by HsfBA in response to unknown signals, might allow accessorizing T4P tips with different modules allowing twitching motility in the presence of alternative substrates and environmental conditions

Vitamin E Can Ameliorate Oxidative Damage of Ovine Hepatocytes In Vitro by Regulating Genes Expression Associated with Apoptosis and Pyroptosis, but Not Ferroptosis

(1) Background: the current research was conducted to investigate the potential non-antioxidant roles of vitamin E in the protection of hepatocysts from oxidative damage. (2) Methods: primary sheep hepatocytes were cultured and exposed to 200, 400, 600, or 800 μmol/L hydrogen peroxide, while their viability was assessed using a CCK-8 kit. Then, cells were treated with 400 μmol/L hydrogen peroxide following a pretreatment with 50, 100, 200, 400, and 800 μmol/L vitamin E and their intracellular ROS levels were determined by means of the DCF-DA assay. RNA-seq, verified by qRT-PCR, was conducted thereafter: non-treated control (C1); cells treated with 400 μmol/L hydrogen peroxide (C2); and C2 plus a pretreatment with 100 μmol/L vitamin E (T1). (3) Results: the 200–800 μmol/L hydrogen peroxide caused significant cell death, while 50, 100, and 200 μmol/L vitamin E pretreatment significantly improved the survival rate of hepatocytes. ROS content in the cells pretreated with vitamin E was significantly lower than that in the control group and hydrogen-peroxide-treated group, especially in those pretreated with 100 μmol/L vitamin E. The differentially expressed genes (DEGs) concerning cell death involved in apoptosis (RIPK1, TLR7, CASP8, and CASP8AP2), pyroptosis (NLRP3, IL-1β, and IRAK2), and ferroptosis (TFRC and PTGS2). The abundances of IL-1β, IRAK2, NLRP3, CASP8, CASP8AP2, RIPK1, and TLR7 were significantly increased in the C1 group and decreased in T1 group, while TFRC and PTGS2 were increased in T1 group. (4) Conclusions: oxidative stress induced by hydrogen peroxide caused cellular damage and death in sheep hepatocytes. Pretreatment with vitamin E effectively reduced intracellular ROS levels and protected the hepatocytes from cell death by regulating gene expression associated with apoptosis (RIPK1, TLR7, CASP8, and CASP8AP2) and pyroptosis (NLRP3, IL-1β, and IRAK2), but not ferroptosis (TFRC and PTGS2)

Sinorhizobium meliloti FcrX coordinates cell cycle and division during free-living growth and symbiosis

ABSTRACT Sinorhizobium meliloti is a soil bacterium that establishes a symbiosis within root nodules of legumes ( Medicago sativa , for example) where it fixes atmospheric nitrogen into ammonia and obtains in return carbon sources and other nutrients. In this symbiosis, S. meliloti undergoes a drastic cellular change leading to a terminal differentiated form (called bacteroid) characterized by genome endoreduplication, increase of cell size and high membrane permeability. The bacterial cell cycle (mis)regulation is at the heart of this differentiation process. In free-living cells, the master regulator CtrA ensures the progression of cell cycle by activating cell division (controlled by the tubulin-like protein FtsZ) and simultaneously inhibiting supernumerary DNA replication, while on the other hand the downregulation of CtrA and FtsZ is essential for bacteroid differentiation during symbiosis, preventing endosymbiont division and permitting genome endoreduplication. Little is known in S. meliloti about regulators of CtrA and FtsZ, as well as the processes that control bacteroid development. Here, we combine cell biology, biochemistry and bacterial genetics approaches to understand the function(s) of FcrX, a new factor that controls both CtrA and FtsZ, in free-living growth and in symbiosis. Depletion of the essential gene fcrX led to abnormally high levels of FtsZ and CtrA and minicell formation. Using multiple complementary techniques, we showed that FcrX is able to interact physically with FtsZ and CtrA. Moreover, its transcription is controlled by CtrA itself and displays an oscillatory pattern in the cell cycle. We further showed that, despite a weak homology with FliJ-like proteins, only FcrX proteins from closely-related species are able to complement S. meliloti fcrX function. Finally, deregulation of FcrX showed abnormal symbiotic behaviors in plants suggesting a putative role of this factor during bacteroid differentiation. In conclusion, FcrX is the first known cell cycle regulator that acts directly on both, CtrA and FtsZ, thereby controlling cell cycle, division and symbiotic differentiation

Genome-wide analysis of the interplay between chromatin-associated RNA and 3D genome organization in human cells.

The interphase genome is dynamically organized in the nucleus and decorated with chromatin-associated RNA (caRNA). It remains unclear whether the genome architecture modulates the spatial distribution of caRNA and vice versa. Here, we generate a resource of genome-wide RNA-DNA and DNA-DNA contact maps in human cells. These maps reveal the chromosomal domains demarcated by locally transcribed RNA, hereafter termed RNA-defined chromosomal domains. Further, the spreading of caRNA is constrained by the boundaries of topologically associating domains (TADs), demonstrating the role of the 3D genome structure in modulating the spatial distribution of RNA. Conversely, stopping transcription or acute depletion of RNA induces thousands of chromatin loops genome-wide. Activation or suppression of the transcription of specific genes suppresses or creates chromatin loops straddling these genes. Deletion of a specific caRNA-producing genomic sequence promotes chromatin loops that straddle the interchromosomal target sequences of this caRNA. These data suggest a feedback loop where the 3D genome modulates the spatial distribution of RNA, which in turn affects the dynamic 3D genome organization