HAL Portal ESPCI (Ecole Supérieure de Physique et de Chimie Industrielles)
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Unveiling novel conserved HIV-1 open reading frames encoding T cell antigens using ribosome profiling.
No full textThe development of ribosomal profiling (Riboseq) revealed the immense coding capacity of human and viral genomes. Here, we used Riboseq to delineate the first translatome of HIV-1 in infected CD4+ T cells. In addition to canonical viral protein coding sequences (CDSs), we identify 98 alternative open reading frames (ARFs), corresponding to small Open Reading Frames (sORFs) that are distributed across the HIV genome including the UTR regions. Using a database of HIV genomes, we observed that most ARF amino-acid sequences are likely conserved among clade B and C of HIV-1, with 8 ARF-encoded amino-acid sequences being more conserved than the overlapping CDSs. Using T cell-based assays and mass spectrometry-based immunopeptidomics, we demonstrate that ARFs encode viral polypeptides. In the blood of HIV-infected individuals, ARF-derived peptides elicit potent poly-functional T cell responses mediated by both CD4+ and CD8+ T cells. Our discovery expands the list of conserved viral polypeptides that are targets for vaccination strategies and might reveal the existence of viral microproteins or pseudogenes
Quantitative guiding of developmental cell fate transitions using gene-free modelling
No full textDuring development, cells gradually assume specialized fates via changes of transcriptional dynamics in thousands of genes. Terminal cell identities are then stabilized through the convergence of gene regulatory network dynamics and the accumulation of epigenetic DNA modifications. "Gene-free" (or geometric) modeling approaches for cell fate acquisition, which abstract from the underlying gene regulatory landscape and reason in phenotypic space, have been remarkably successful in explaining terminal fate outcomes. However, their implications for cellular dynamics during fate acquisition processes have so far not been tested in vivo. To do so, here we combine gene-free mathematical modeling of cell fate acquisition during C. elegans vulval development with temporally controlled perturbations of in vivo signaling dynamics using temperature sensitive (ts) mutant alleles of the EGF/Ras/MAPK and Notch signaling pathways. We show that gene-free modeling can quantitatively predict non-intuitive fate outcomes in a variety of ts genetic backgrounds, including pathway epistasis effects. In addition, we use genefree modeling to infer how cell fate transitions can be guided towards specific outcomes through timed pulses of signaling activity and verify these model predictions quantitatively with temporally controlled signaling perturbations via temperature shifts in ts backgrounds. Our results highlight the predictive power of gene-free models beyond terminal fate outcomes and illustrate a new approach to quantitatively guide cell fate acquisition in a developmental context
Lanthanide MOF-based luminescent sensor arrays for the detection of castration-resistant prostate cancer curing drugs and biomarkers
No full textInternational audienceIn recent years, castration-resistant prostate cancer (CRPC) has profoundly impacted the lives of many men, and early diagnosis of medication and illness is crucial. Therefore, a highly efficient detection method for CRPC biomarkers and curing drugs is required. However, the complex and diverse structures of CRPC drugs pose significant challenges for their detection and differentiation. Lanthanide metal–organic frameworks (Ln-MOFs) show great potential for sensing applications due to their intense and characteristic luminescence. In this work, a series of new bimetallic Ln-MOFs (EuxTb1−x-MOF) based luminescent sensor arrays have been developed to identify CRPC drugs, including in mixtures, via principal component analysis (PCA) and hierarchical cluster analysis (HCA) methods. These Ln-MOFs are built with a highly conjugated H2L linker (H2L = 5-(4-(triazole-1-yl)phenyl)isophthalic acid) and exhibit robust strong luminescence emissions (mainly located at 543 and 614 nm) and high energy transfer efficiencies. More specifically, Eu0.096Tb0.904-MOF (MOF 3) has demonstrated good sensing performances for CRPC curing drugs in real human serum samples. Furthermore, the curing drug hydroxyflutamide has been combined with MOF 3, to construct a robust composite sensing platform MOF 3@hydroxyflutamide for highly efficient detection of CRPC biomarkers such as the androgen receptor (AR) and prostate-specific antigen (PSA). Finally, luminescence lifetime measurements, zeta potential measurements, and density functional theory (DFT) calculations were performed to gain insights into the sensing mechanism
Functional contribution of astrocytic Kir4.1 channels to spasticity after spinal cord injury
No full textInternational audienceSpasticity, a prevalent motor issue characterized by network hyperexcitability, causes pain and discomfort, with existing treatments offering limited relief. While past research has focused on neuronal factors, the role of astrocytes in spasticity has been overlooked. This study explores the potential of restoring astrocytic potassium (K + ) uptake to reduce spasticity following SCI. Astrocytes buffer extracellular K + via Kir4.1 channels, preventing neuronal hyperexcitability. Following spinal cord injury (SCI), Kir4.1 levels decrease at the injury site, though the consequences and mechanisms of this reduction within the motor output area have not been investigated. Utilizing advanced techniques, we demonstrate that lumbar astrocytes in a juvenile thoracic SCI mouse model switch to reactive phenotype, displaying morpho-functional and pro-inflammatory changes. These astrocytes also experience NBCe1-mediated intracellular acidosis, leading to Kir4.1 dysfunction and impaired K + uptake. Enhancing Kir4.1 function reduces spasticity in SCI mice, revealing new therapeutic targets for neurological diseases associated with neuronal hyperexcitability. Highlights Lumbar astrocytes adopt a reactive phenotype following a thoracic SCI NBCe1-mediated acidosis in astrocytes disrupts Kir4.1 function post-SCI. Impaired K+ uptake leads to motoneuron hyperexcitability post-SCI. Enhanced astroglial Kir4.1 function reduces spastic-like symptoms in SCI mice
Darwinian Evolution of Self-Replicating DNA in a Synthetic Protocell
No full textInternational audienceReplication, heredity, and evolution are characteristic of Life. We and others have postulated that the reconstruction of a synthetic living system in the laboratory will be contingent on the development of a genetic self-replicator capable of undergoing Darwinian evolution. Although DNA-based life dominates, the in vitro reconstitution of an evolving DNA self-replicator has remained challenging. We hereby emulate in liposome compartments the principles according to which life propagates information and evolves. Using two different experimental configurations supporting intermittent or semi-continuous evolution (i.e., with or without DNA extraction, PCR, and re-encapsulation), we demonstrate sustainable replication of a linear DNA template – encoding the DNA polymerase and terminal protein from the Phi29 bacteriophage – expressed in the ‘protein synthesis using recombinant elements’ (PURE) system. The self-replicator can survive across multiple rounds of replication-coupled transcription-translation reactions in liposomes and, within only ten evolution rounds, accumulates mutations conferring a selection advantage. Combined data from next-generation sequencing with reverse engineering of some of the enriched mutations reveal nontrivial and context-dependent effects of the introduced mutations. The present results are foundational to build up genetic complexity in an evolving synthetic cell, as well as to study evolutionary processes in a minimal cell-free system
Design principles, growth laws, and competition of minimal autocatalysts
No full textInternational audienceThe apparent difficulty of designing simple autocatalysts that grow exponentially in the absence of enzymes, external drives or ingenious internal mechanisms severely constrains scenarios for the emergence of evolution by natural selection in chemical and physical systems. Here, we systematically analyze these difficulties in the context of one of the simplest and most generic autocatalysts: a dimeric molecule that duplicates by templated ligation. We show that despite its simplicity, such an autocatalyst can achieve exponential growth autonomously. This only requires that the rate of the spontaneous dimerization, the interactions between molecules, and the concentrations of substrates and products are in appropriate ranges. We also show, however, that it is possible to design as simple sub-exponential autocatalysts that have an advantage over exponential autocatalysts when competing for a common resource. We reach these conclusions by developing a general theoretical framework based on kinetic barrier diagrams. Besides challenging commonly accepted assumptions in the field of the origin of life, our results provide a blueprint for the experimental realization of elementary autocatalysts exhibiting a form of natural selection, whether on a molecular or colloidal scale
Multiple scattering theory in one dimensional space and time dependent disorder: Average field
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Form and function of anguilliform swimming
No full textInternational audienceABSTRACT Anguilliform swimmers are long and narrow animals that propel themselves by undulating their bodies. Observations in nature and recent investigations suggest that anguilliform swimming is highly efficient. However, understanding the underlying reasons for the efficiency of this type of locomotion requires interdisciplinary studies spanning from biology to hydrodynamics. Regrettably, these different fields are rarely discussed together, which hinders our ability to understand the repeated evolution of this swimming mode in vertebrates. This review compiles the current knowledge of the anatomical features that drive anguilliform swimming, compares the resulting kinematics across a wide range of anguilliform swimmers, and describes the resulting hydrodynamic interactions using data from both in vivo experiments and computational studies
X-ray Radiotherapy Impacts Cardiac Dysfunction by Modulating the Sympathetic Nervous System and Calcium Transients
No full textInternational audienceRecent epidemiological studies have shown that patients with right-sided breast cancer (RBC) treated with X-ray irradiation (IR) are more susceptible to developing cardiovascular diseases, such as arrhythmias, atrial fibrillation, and conduction disturbances after radiotherapy (RT). Our aim was to investigate the mechanisms induced by low to moderate doses of IR and to evaluate changes in the cardiac sympathetic nervous system (CSNS), atrial remodeling, and calcium homeostasis involved in cardiac rhythm. To mimic the RT of the RBC, female C57Bl/6J mice were exposed to X-ray doses ranging from 0.25 to 2 Gy targeting 40% of the top of the heart. At 60 weeks after RI, Doppler ultrasound showed a significant reduction in myocardial strain, ejection fraction, and atrial function, with a significant accumulation of fibrosis in the epicardial layer and apoptosis at 0.5 mGy. Calcium transient protein expression levels, such as RYR2, NAK, Kir2.1, and SERCA2a, increased in the atrium only at 0.5 Gy and 2 Gy at 24 h, and persisted over time. Interestingly, 3D imaging of the cleaned hearts showed an early reduction of CSNS spines and dendrites in the ventricles and a late reorientation of nerve fibers, combined with a decrease in SEMA3a expression levels. Our results showed that local heart IR from 0.25 Gy induced late cardiac and atrial dysfunction and fibrosis development. After IR, ventricular CSNS and calcium transient protein expression levels were rearranged, which affected cardiac contractility. The results are very promising in terms of identifying pro-arrhythmic mechanisms and preventing arrhythmias during RT treatment in patients with RBC
α‐Silylated Diazoalkynes: New Tools for Bioconjugation of Proteins
No full textInternational audienceα‐Silylated diazoalkynes are stabilized diazo compounds that can selectively react with carboxylic residues in buffered aqueous media. In‐situ fluoride induced desilylation increases this reactivity, leading to a very fast reaction. Application to the selective functionalization of RNase A, followed by post‐functionalization using click chemistry, is described. These new reagents expand the toolbox for native protein modification at carboxylic residues