Cucurbit[8]uril-derived graphene hydrogels

The scalable production of uniformly distributed graphene (GR)-based composite materials remains a sizable challenge. While GR-polymer nanocomposites can be manufactured at large scale, processing limitations result in poor control over the homogeneity of hydrophobic GR sheets in the matrices. Such processes often result in difficulties controlling stability and avoiding aggregation, therefore eliminating benefits that might have otherwise arisen from the nanoscopic dimensions of GR. Here, we report an exfoliated and stabilized GR dispersion in water. Cucurbit[8]uril (CB[8])-mediated host guest chemistry was used to obtain supramolecular hydrogels consisting of uniformly distributed GR and guest-functionalized macromolecules. The obtained GR-hydrogels show superior bioelectrical properties over identical systems produced without CB[8]. Utilizing such supramolecular interactions with biologically-derived macromolecules is a promising approach to stabilize graphene in water and avoid oxidative chemistry.Marie Sklodowska-Curie individual research grant (H2020-MSCAIF- 2017, P.ID: 797106) The Winston Churchill Foundation of the United States EPSRC Doctoral Training Grant EP/N509620/1 EPSRC Programme Grant NOtCH (EP/L027151/1

Different niches for stem cells carrying the same oncogenic driver affect pathogenesis and therapy response in myeloproliferative neoplasms

Aging facilitates the expansion of hematopoietic stem cells (HSCs) carrying clonal hematopoiesis-related somatic mutations and the development of myeloid malignancies, such as myeloproliferative neoplasms (MPNs). While cooperating mutations can cause transformation, it is unclear whether distinct bone marrow (BM) HSC-niches can influence the growth and therapy response of HSCs carrying the same oncogenic driver. Here we found different BM niches for HSCs in MPN subtypes. JAK-STAT signaling differentially regulates CDC42-dependent HSC polarity, niche interaction and mutant cell expansion. Asymmetric HSC distribution causes differential BM niche remodeling: sinusoidal dilation in polycythemia vera and endosteal niche expansion in essential thrombocythemia. MPN development accelerates in a prematurely aged BM microenvironment, suggesting that the specialized niche can modulate mutant cell expansion. Finally, dissimilar HSC-niche interactions underpin variable clinical response to JAK inhibitor. Therefore, HSC-niche interactions influence the expansion rate and therapy response of cells carrying the same clonal hematopoiesis oncogenic driver

Different niches for stem cells carrying the same oncogenic driver affect pathogenesis and therapy response in myeloproliferative neoplasms

Aging facilitates the expansion of hematopoietic stem cells (HSCs) carrying clonal hematopoiesis-related somatic mutations and the development of myeloid malignancies, such as myeloproliferative neoplasms (MPNs). While cooperating mutations can cause transformation, it is unclear whether distinct bone marrow (BM) HSC-niches can influence the growth and therapy response of HSCs carrying the same oncogenic driver. Here we found different BM niches for HSCs in MPN subtypes. JAK-STAT signaling differentially regulates CDC42-dependent HSC polarity, niche interaction and mutant cell expansion. Asymmetric HSC distribution causes differential BM niche remodeling: sinusoidal dilation in polycythemia vera and endosteal niche expansion in essential thrombocythemia. MPN development accelerates in a prematurely aged BM microenvironment, suggesting that the specialized niche can modulate mutant cell expansion. Finally, dissimilar HSC-niche interactions underpin variable clinical response to JAK inhibitor. Therefore, HSC-niche interactions influence the expansion rate and therapy response of cells carrying the same clonal hematopoiesis oncogenic driver

Cancer Metastasis: Collective Invasion in Heterogeneous Multicellular Systems

Heterogeneity within tumour cell populations is associated with an increase in malignancy and appears to play an important role during cancer metastasis. Using in silico experiments, we study the interplay between collective behaviours and cell motility heterogeneities in a model system. Working with tumour spheroids that contain two non-proliferating cell populations of different motile properties, we explore the conditions required for maximal invasion into surrounding tissues. We show emerging spatial patterns of cellular organisation and invasion which are consistent with in vitro and in vivo observations. This demonstrates that mechanical interactions at the cellular level are sufficient to account for many of the observed morphologies of invasion and that heterogeneity in cell motility can be more important than average mechanical properties in controlling the fate of large cell populations

Theory of mechano-chemical patterning in biphasic biological tissues

The formation of self-organized patterns is key to the morphogenesis of multicellular organisms, although a comprehensive theory of biological pattern formation is still lacking. Here, we propose a biologically realistic and unifying approach to emergent pattern formation. Our biphasic model of multicellular tissues incorporates turnover and transport of morphogens controlling cell differentiation and tissue mechanics in a single framework, where one tissue phase consists of a poroelastic network made of cells and the other is the extracellular fluid permeating between cells. While this model encompasses previous theories approximating tissues to inert monophasic media, such as Turing’s reaction-diffusion model, it overcomes some of their key limitations permitting pattern formation via any two-species biochemical kinetics thanks to mechanically induced cross-diffusion flows. Moreover, we unravel a qualitatively different advection-driven instability which allows for the formation of patterns with a single morphogen and which single mode pattern scales with tissue size. We discuss the potential relevance of these findings for tissue morphogenesis

Tumour heterogeneity promotes collective invasion and cancer metastatic dissemination

Heterogeneity within tumour cell populations is commonly observed in most cancers. However, its impact on metastatic dissemination, one of the primary determinants of the disease prognosis, remains poorly understood. Working with a simplified numerical model of tumour spheroids, we investigated the impact of mechanical heterogeneity on the onset of tumour invasion into surrounding tissues. Our work establishes a positive link between tumour heterogeneity and metastatic dissemination, and recapitulates a number of invasion patterns identified in vivo, such as multicellular finger-like protrusions. Two complementary mechanisms are at play in heterogeneous tumours. A small proportion of stronger cells are able to initiate and lead the escape of cells, while collective effects in the bulk of the tumour provide the coordination required to sustain the invasive process through multicellular streaming. This suggests that the multicellular dynamics observed during metastasis is a generic feature of mechanically heterogeneous cell populations and might rely on a limited and generic set of attributes

Short-Time Water Caging and Elementary Prehydration Redox Reactions in Ionic Environments

International audienceThis article deals with the direct probing of water cages that assist two well-defined prehydration electron transfers (PHETs) with the reactive metal cation Cd2+. Early electron photodetachment processes are triggered by a two-photon UV excitation of aqueous halide ion Cl- (R = [H2O]/[CdCl2] = 110). Concomitant with an ultrafast Cd2+ reduction by IR p-like excited electron (J. Phys. Chem. A 1998, 102, 7795), a subpicosecond oxidoreduction reaction occurs in caged three-body complexes {Cl··e-··Cd2+}aq. Near-IR spectroscopic measurements give a PHET frequency of 1.38 ± 0.02 10^12 s^-1. This reduction reaction is 70 times faster than a diffusion-controlled bimolecular reaction between aqueous Cd2+ ions and fully hydrated electrons (s-state). Femtosecond spectroscopic data indicate that preexisting bridging water-molecule-bonded Cl-···Cd2+ pairs (SSIP-like configurations) assist efficient prehydration electron transfer. Because the 4s-like orbital radius of nascent {Cl··e-··Cd2+}aq configurations is larger than the mean distance of Cd2+−Cl- ion pairs in a first coordination sphere of Cd2+ ions (2.6 Å), it is suggested that an overlap between a 4s electron orbital and the localized Cd2+ orbital favors an early inner-sphere electron transfer. For the first time, a nonlinear relationship is defined between the rate of Cd2+ univalent reduction and the energy level of the trapped electron (IR e-p, {Cl··e-··Cd2+}aq, e-aq). We conclude that the short-time water cagings govern the course of PHET events and influence early branchings between elementary oxidoreduction reactions in ionic environments

Real-time probing of solvent caging effects during IR electron transfers in solution

International audienceWe investigate the real-time probing of nonequilibrium electron transfers in aqueous solutions of disulfide molecules. Our attention is focused on the elementary steps of an IR electron transfer from a charged donor (chloride ion) to a biomolecular acceptor (cystamine dihydrochloride: RSSR, 2HCl, R = (CH2)2 NH2). Following a femtosecond UV excitation of the ionic donor, an ultrafast electron attachment on a SS bond takes place with a time constant of 160 ′ 20 fs at 294K. The determination of a UV signature centered around 3.0 eV and characterized by a half band width of 0.6 eV substantiates the subpicosecond formation of a nascent sulfur-centered radical anion (RS SR-) with a 2σ/1σ* bond. The ultrafast attachment of an IR prehydrated electron on a S-S bond competes with the nonadiabatic radiationless transition of IR p-like electrons. These results raise the fundamental importance of solvent caging effects during the efficient coupling between a p-like IR prehydrated electron and a S-S bond

Theory of mechano-chemical patterning in biphasic biological tissues

The formation of self-organized patterns is key to the morphogenesis of multicellular organisms, although a comprehensive theory of biological pattern formation is still lacking. Here, we propose a minimal model combining tissue mechanics to morphogen turnover and transport in order to explore new routes to patterning. Our active description couples morphogen reaction-diffusion, which impact on cell differentiation and tissue mechanics, to a two-phase poroelastic rheology, where one tissue phase consists of a poroelastic cell network and the other of a permeating extracellular fluid, which provides a feedback by actively transporting morphogens. While this model encompasses previous theories approximating tissues to inert monophasic media, such as Turing’s reaction-diffusion model, it overcomes some of their key limitations permitting pattern formation via any two- species biochemical kinetics thanks to mechanically induced cross-diffusion flows. Moreover, we describe a qualitatively different advection-driven Keller-Segel instability which allows for the formation of patterns with a single morphogen, and whose fundamental mode pattern robustly scales with tissue size. We discuss the potential relevance of these findings for tissue morphogenesis