Intrinsic Proteolytic Activities from Cancer Cells Are Sufficient to Activate Alkoxyamine Prodrugs and Induce Cell Death.

In search of better specificity and lower chances of resistance, protease-activatable alkoxyamine prodrugs to fight cancer have been proposed. These molecules are made of a peptide linked to an alkoxyamine. Proteolysis of the peptide converts the stable prodrug at 37 °C to a metastable alkoxyamine that spontaneously homolyzes into two free radicals: a stable nitroxide and a very reactive alkyl radical.

Long-term memory induced correction to Arrhenius law.

The Kramers escape problem is a paradigmatic model for the kinetics of rare events, which are usually characterized by Arrhenius law. So far, analytical approaches have failed to capture the kinetics of rare events in the important case of non-Markovian processes with long-term memory, as occurs in the context of reactions involving proteins, long polymers, or strongly viscoelastic fluids. Here, based on a minimal model of non-Markovian Gaussian process with long-term memory, we determine quantitatively the mean FPT to a rare configuration and provide its asymptotics in the limit of a large energy barrier E.

Versatile Cloning Strategy for Efficient Multigene Editing in .

CRISPR-Cas9 technology has become an essential tool for plant genome editing. Recent advancements have significantly improved the ability to target multiple genes simultaneously within the same genetic background through various strategies. Additionally, there has been significant progress in developing methods for inducible or tissue-specific editing.

Peptide-Alkoxyamine Drugs: An Innovative Approach to Fight Schistosomiasis: "Digging Their Graves with Their Forks".

The expansion of drug resistant parasites sheds a serious concern on several neglected parasitic diseases. Our recent results on cancer led us to envision the use of peptide-alkoxyamines as a highly selective and efficient new drug against schistosome adult worms, the etiological agents of schistosomiasis. Indeed, the peptide tag of the hybrid compounds can be hydrolyzed by worm's digestive enzymes to afford a highly labile alkoxyamine which homolyzes spontaneously and instantaneously into radicals-which are then used as a drug against Schistosome adult parasites.

Integrase-LEDGF/p75 complex triggers the formation of biomolecular condensates that modulate HIV-1 integration efficiency in vitro.

The pre-integration steps of the HIV-1 viral cycle are some of the most valuable targets of recent therapeutic innovations. HIV-1 integrase (IN) displays multiple functions, thanks to its considerable conformational flexibility. Recently, such flexible proteins have been characterized by their ability to form biomolecular condensates as a result of Liquid-Liquid-Phase-Separation (LLPS), allowing them to evolve in a restricted microenvironment within cells called membrane-less organelles (MLO).

Hybrid Peptide-Alkoxyamine Drugs: A Strategy for the Development of a New Family of Antiplasmodial Drugs.

The emergence and spread of drug-resistant parasites shed a serious concern on the worldwide control of malaria, the most important tropical disease in terms of mortality and morbidity. This situation has led us to consider the use of peptide-alkoxyamine derivatives as new antiplasmodial prodrugs that could potentially be efficient in the fight against resistant malaria parasites. Indeed, the peptide tag of the prodrug has been designed to be hydrolysed by parasite digestive proteases to afford highly labile alkoxyamines drugs, which spontaneously and instantaneously homolyse into two free radicals, one of which is expected to be active against .

Unclear relationships between mean survival rate and its environmental variance in vertebrates.

Current environmental changes may increase temporal variability of life history traits of species thus affecting their long-term population growth rate and extinction risk. If there is a general relationship between environmental variances (EVs) and mean annual survival rates of species, that relationship could be used as a guideline for analyses of population growth and extinction risk for populations, where data on EVs are missing. For this purpose, we present a comprehensive compilation of 252 EV estimates from 89 species belonging to five vertebrate taxa (birds, mammals, reptiles, amphibians and fish) covering mean annual survival rates from 0.

ER Membrane Lipid Composition and Metabolism: Lipidomic Analysis.

Plant ER membranes are the major site of biosynthesis of several lipid families (phospholipids, sphingolipids, neutral lipids such as sterols and triacylglycerols). The structural diversity of lipids presents considerable challenges to comprehensive lipid analysis. This chapter will briefly review the various biosynthetic pathways and will detail several aspects of the lipid analysis: lipid extraction, handling, separation, detection, identification, and data presentation.

Proteomic analysis of SARS-CoV-2 particles unveils a key role of G3BP proteins in viral assembly.

Considerable progress has been made in understanding the molecular host-virus battlefield during SARS-CoV-2 infection. Nevertheless, the assembly and egress of newly formed virions are less understood. To identify host proteins involved in viral morphogenesis, we characterize the proteome of SARS-CoV-2 virions produced from A549-ACE2 and Calu-3 cells, isolated via ultracentrifugation on sucrose cushion or by ACE-2 affinity capture.

Integration of operator-validated contours in deformable image registration for dose accumulation in radiotherapy.

Background And Purpose: Deformable image registration (DIR) is a core element of adaptive radiotherapy workflows, integrating daily contour propagation and/or dose accumulation in their design. Propagated contours are usually manually validated and may be edited, thereby locally invalidating the registration result. This means the registration cannot be used for dose accumulation.

Endoplasmic reticulum stress controls PIN-LIKES abundance and thereby growth adaptation.

Extreme environmental conditions eventually limit plant growth [J. R. Dinneny, , 1-19 (2019), N.

No sensitivity to functional forms in the Rosenzweig-MacArthur model with strong environmental stochasticity.

The classic Rosenzweig-MacArthur predator-prey model has been shown to exhibit, like other coupled nonlinear ordinary differential equations (ODEs) from ecology, worrying sensitivity to model structure. This sensitivity manifests as markedly different community dynamics arising from saturating functional responses with nearly identical shapes but different mathematical expressions. Using a stochastic differential equation (SDE) version of the Rosenzweig-MacArthur model with the three functional responses considered by Fussmann & Blasius (2005), I show that such sensitivity seems to be solely a property of ODEs or stochastic systems with weak noise.

Modulation of the functional interfaces between retroviral intasomes and the human nucleosome.

Infection by retroviruses as HIV-1 requires the stable integration of their genome into the host cells. This process needs the formation of integrase (IN)-viral DNA complexes, called intasomes, and their interaction with the target DNA wrapped around nucleosomes within cell chromatin. To provide new tools to analyze this association and select drugs, we applied the AlphaLISA technology to the complex formed between the prototype foamy virus (PFV) intasome and nucleosome reconstituted on 601 Widom sequence.

Shigella IpaA mediates actin bundling through diffusible vinculin oligomers with activation imprint.

Upon activation, vinculin reinforces cytoskeletal anchorage during cell adhesion. Activating ligands classically disrupt intramolecular interactions between the vinculin head and tail domains that bind to actin filaments. Here, we show that Shigella IpaA triggers major allosteric changes in the head domain, leading to vinculin homo-oligomerization.

Spatial beam reshaping and large-band nonlinear conversion in rectangular-core phosphate glass fibers.

Here we present the ability of Nd-doped zinc-phosphate glasses to be shaped into rectangular core fibers. At first, the physico-chemical properties of the developed PO-based materials are investigated for different concentrations of neodymium oxide and core and cladding glass compositions are selected for further fiber development. A modified stack-and-draw technique is used to produce multimode large rectangular-core optical fibers.

A subclass of archaeal U8-tRNA sulfurases requires a [4Fe-4S] cluster for catalysis.

Sulfuration of uridine 8, in bacterial and archaeal tRNAs, is catalyzed by enzymes formerly known as ThiI, but renamed here TtuI. Two different classes of TtuI proteins, which possess a PP-loop-containing pyrophosphatase domain that includes a conserved cysteine important for catalysis, have been identified. The first class, as exemplified by the prototypic Escherichia coli enzyme, possesses an additional C-terminal rhodanese domain harboring a second cysteine, which serves to form a catalytic persulfide.

Quantitation of SARS-CoV-2 neutralizing antibodies with a virus-free, authentic test.

Neutralizing antibodies (NAbs), and their concentration in sera of convalescents and vaccinees are a correlate of protection from COVID-19. The antibody concentrations in clinical samples that neutralize SARS-CoV-2 are difficult and very cumbersome to assess with conventional virus neutralization tests (cVNTs), which require work with the infectious virus and biosafety level 3 containment precautions. Alternative virus neutralization tests currently in use are mostly surrogate tests based on direct or competitive enzyme immunoassays or use viral vectors with the spike protein as the single structural component of SARS-CoV-2.

Controlling Superselectivity of Multivalent Interactions with Cofactors and Competitors.

Moieties that compete with multivalent interactions or act as cofactors are common in living systems, but their effect on multivalent binding remains poorly understood. We derive a theoretical model that shows how the superselectivity of multivalent interactions is modulated by the presence of cofactors or competitors. We find that the role of these participating moieties can be fully captured by a simple rescaling of the affinity constant of the individual ligand-receptor bonds.

Phase separation in viral infections.

Viruses rely on the reprogramming of cellular processes to enable efficient viral replication; this often requires subcompartmentalization within the host cell. Liquid-liquid phase separation (LLPS) has emerged as a fundamental principle to organize and subdivide cellular processes, and plays an important role in viral life cycles. Despite substantial advances in the field, elucidating the exact organization and function of these organelles remains a major challenge.

Impact of Chromosomal Context on Origin Selection and the Replication Program.

Eukaryotic DNA replication is regulated by conserved mechanisms that bring about a spatial and temporal organization in which distinct genomic domains are copied at characteristic times during S phase. Although this replication program has been closely linked with genome architecture, we still do not understand key aspects of how chromosomal context modulates the activity of replication origins. To address this question, we have exploited models that combine engineered genomic rearrangements with the unique replication programs of post-quiescence and pre-meiotic S phases.

Neutrophil Elastase-Activatable Prodrugs Based on an Alkoxyamine Platform to Deliver Alkyl Radicals Cytotoxic to Tumor Cells.

Current chemotherapies suffer low specificity and sometimes drug resistance. Neutrophil elastase activity in cancer is associated with poor prognosis and metastasis settlement. More generally, tumors harbor various and persistent protease activities unseen in healthy tissues.

Mutations in the 3'-PPT Lead to HIV-1 Replication without Integration.

Integration of the reverse-transcribed genome is a critical step of the retroviral life cycle. Strand-transfer inhibitors (INSTIs) used for antiretroviral therapy inhibit integration but can lead to resistance mutations in the integrase gene, the enzyme involved in this reaction. A significant proportion of INSTI treatment failures, particularly those with second-generation INSTIs, show no mutation in the integrase gene.

How Stickiness Can Speed Up Diffusion in Confined Systems.

The paradigmatic model for heterogeneous media used in diffusion studies is built from reflecting obstacles and surfaces. It is well known that the crowding effect produced by these reflecting surfaces slows the dispersion of Brownian tracers. Here, using a general adsorption desorption model with surface diffusion, we show analytically that making surfaces or obstacles attractive can accelerate dispersion.