During a first-order phase transition, an interfacial layer is formed between the coexisting phases and kinetically limits homogeneous nucleation of the new phase in the original phase. This inhibition is commonly alleviated by presence of impurities, often of unknown origin, that serve as heterogeneous nucleation sites for the transition.
Living systems present theoretical opportunity: The regulated structure of living systems allows modeling of the impurities, enabling quantitative analysis and comparison between homogeneous and heterogeneous nucleation mechanisms, usually a difficult task. Here, we formulate an analytical model of heterogeneous nucleation of holes in the nuclear lamina, a phenomenon with implications in cancer metastasis, aging and additional diseases. Then, we present measurements of hole nucleation in the lamina of nuclei migrating through controlled constrictions and fit the experimental data to our heterogeneous nucleation model as well as a homogeneous model.
Surprisingly, we find that different mechanisms dominate depending on the density of filaments that comprise the nuclear lamina. Intrinsically disordered proteins differ from globular proteins in their high dynamic secondary and tertiary structure and their ability to undergo liquid-liquid phase separation LLPS 1. For these reasons, conventional structure-based drug discovery cannot be applied to IDPs and other strategies need to be sought 2. Androgen Receptor AR is a hormone-activated transcription factor. AR over-activation leads to prostate cancer and, eventually, castration-resistant prostate cancer CRPC for which there is currently no treatment 3.
Our results help understand the mode of action of this experimental drug and exploit the LLPS process as a new avenue for targeting proteins rich in intrinsic disorder such as transcription factors. Cancer Cell. ACS Chem.
During embryonic development sexually reproducing species rely on the segregation of germ granules as one characteristic to specify their germ line. The underlying biochemical control of the segregation has been described as an mRNA competition mechanism. Furthermore, it has been suggested that this drives segregation via spatially defined changes in the phase separation behavior of the condensates. We replace biochemical control with a localized temperature gradient that mimics its physical mechanism. Furthermore, with this approach, we are able to invert the endogenous spatial distribution of P granules in zygotes.
In this study we conclude, that P granule segregation is a spatially tuned, diffusive-flux dependent, dissolution-condensation phenomenon. Phosphorylated CPEB4 is in a monomeric state and active for cytoplasmic polyadenylation, while unphosphorylated CPEB4 is inactive and undergoes liquid-liquid phase separation. Elife, Nature, The aim of our work is to characterize in detail the liquid-liquid phase separation process undergone by CPEB4, to determine the inter-molecular interactions that stabilize the droplets and to study the effect of post-translational modifications.
Optical Binding Phenomena: Observations and Mechanisms - Durham e-Theses
It is also of great relevance to study the LLPS of different isoforms of the protein of great biomedical relevance, as mis-splicing of CPEB4 gives rise to autism-like phenotype. In this communication we will present evidence that the latter severely alters the phase diagram of CPEB4 and will propose possible rationales for this behavior.
Recently emerged reports have established that in eukaryotic cells, many biochemical processes take place in temporary membrane-less compartments which are formed by the association of certain RNA binding proteins RBPs. These compartments e. Once the biochemical process is accomplished, these compartments dissolve back into the bulk solution nucleoplasm or cytoplasm. Owing to the difficulty in purification, most studies on TDP have been carried out on its truncated versions or short peptides.
We purified full length TDP through oxidative refolding and subjected to various buffer conditions in which different polyol osmolytes were present as macromolecular crowder. The recombinantly purified TDP underwent LLPS and droplets were visualized under the microscope and the extent of droplet formation was quantified through light scattering.
Ours is the first of very few attempts to study the role of osmolytes in modulation of LLPS process. This investigation has a potential to unravel the role of osmolytes in modulation of LLPS behaviour and thus a possible clue in phase separation could be gleaned by studying their mechanism of action. Above pI, surface patch binding caused associative interactions and complex coacervation though both biopolymers had similar net charge.
Network density was used as a descriptor to distinguish between the coacervate and gel samples. Their microstructures were probed by small angle neutron scattering SANS , and viscoelastic properties by rheology. A simple modeling shows formation of interpolymer complex was favored in higher protein containing samples. Mixing ratio dependent selective coacervation a kinetic process and bicontinuous gelation a thermodynamic process are rarely seen to coexist in biopolymer interactions.
Formation of droplets by phase separation plays an important role in the spatio-temporal organization of matter in biological cells. Precise control over the droplets' properties is necessary to regulate intracellular processes. To achieve this, cells drive chemical reactions affecting the droplet material. By varying the reaction rates, the size and growth of such active droplets can be controlled.
We study the dynamics of active droplets by numerically solving a modified Cahn-Hilliard equation and comparing the results with analytical predictions. In the first project, we aim to understand the dynamics of active droplets in heterogeneous environments. We start by considering a single droplet in an external chemical gradient.
This helps us to examine two and more active droplets in close vicinity. In the second project, we study pattern formation of active droplets. In particular we investigate the two-dimensional case, where hexagonal patterns are formed. Exploiting an analogy with equilibrium systems with long-range interactions, we determine droplet sizes and spacings. Both these projects will help us to understand the dynamics of active droplets and how cells could use chemical reactions to organize intracellular matter.
Tau is an intrinsically-disordered protein, which diffuses on microtubules. In neurodegenerative diseases, collectively termed tauopathies, tau malfunction and its detachment from axonal microtubules is correlated with microtubule degradation. Using in vitro reconstitution, we show that tau molecules on microtubules cooperatively form cohesive islands which are kinetically more stable than molecules diffusing individually. Dependent on the flux between diffusive and stable phase of tau, islands reversibly grow or shrink by addition or release of molecules at their boundaries.
We observe such flow in bulk measurements as well as in single molecule experiments, where we see individual tau molecules switching between states. Furthermore, we show that while the diffusive state is of hydrophilic nature, the stable, cooperative state is more hydrophobic in nature. In this case, an external magnetic field is not able to change the populations on singlet and triplet Frenkel excitons 18 , leading to negligible magneto-PL and magneto-EL when spatially extended excited states are absent.
We should further note that Frenkel excitons are the primary light-emitting states formed in organic materials under optical excitation. Therefore, magneto-PL provides a convenient experimental tool to explore whether the light-emitting states possess spatially extended characteristics or localized excitonic wavefunctions in the microcavity to understand the EL spectral narrowing phenomenon.
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In particular, the microcavities were fabricated with high-Q, intermediate-Q, and low-Q structures. This observation indicates that the microcavity induces the formation of spatially extended excited states, in addition to the light-emitting Frenkel excitons, in the F8BT layer under optical excitation. Furthermore, a similar phenomenon was also observed under electrical injection: the microcavity-based OLED shows an appreciable magneto-EL, indicating the formation of spatially extended excited states, while the cavity-free OLED does not exhibit any detectable magneto-EL, lacking the formation of spatially extended excited states.
Our studies indicate that the optical microcavity can indeed influence the characteristics of excited states to generate spatially extended states functioning as intermediate states, leading to the spectral narrowing phenomenon under optical and electrical excitations. The Q-factor of the microcavity structures is varied from 94 high-Q to 40 intermediate-Q and 13 low-Q. It can be seen in Fig. Clearly, by increasing the Q factor the PL spectrum becomes gradually narrowed in the microcavity. It is known that an optical excitation generates Frenkel excitons due to low dielectric constants and give rise to broad PL spectra in organic light-emitting materials with inhomogeneous morphologies 2 , 3.
Here, it remains as a fundamental question on how the narrowed PL is generated by the Frenkel excitons in the microcavity. Essentially, addressing this question requires an understanding on the effects of microcavity on light-emitting states in the cavity-based F8BT OLEDs.
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Optical characterizations of cavity-based organic OLEDs. To explore the effects of microcavity on light-emitting states, magneto-PL studies were performed by optically exciting the cavity-based F8BT OLEDs with high, intermediate, and low Q-values. Without using the microcavity, the F8BT shows this common phenomenon similar to other organic light-emitting materials: non-detectable magneto-PL due to the Frenkel excitons under optical excitation.
Clearly, the microcavity causes a large PL spectral narrowing phenomenon.
This spectral narrowing phenomenon brings about an open question: whether the microcavity influences the characteristics of excited states during the development of spectral narrowing phenomenon? To address this question, we explored magneto-PL from the microcavities with high, intermediate, and low Q factors under optical excitation. When the microcavity is not used, the cavity-free OLED shows a non-detectable, which is a normal phenomenon observed on Frenkel excitons in organic light-emitting materials 18 , 20 , Specifically, the PL intensity gradually increases and then becomes saturated with increasing magnetic field, generating a magneto-PL signal at room temperature in cavity-based F8BT OLEDs under photoexcitation.
Decreasing the Q factor can directly decrease the magneto-PL signal, simultaneously accompanied with spectral broadening phenomenon. The high-Q and intermediate-Q cavities give the magneto-PL with the amplitudes of 2.