274 research outputs found
Probing complex RNA structures by mechanical force
RNA secondary structures of increasing complexity are probed combining single
molecule stretching experiments and stochastic unfolding/refolding simulations.
We find that force-induced unfolding pathways cannot usually be interpretated
by solely invoking successive openings of native helices. Indeed, typical
force-extension responses of complex RNA molecules are largely shaped by
stretching-induced, long-lived intermediates including non-native helices. This
is first shown for a set of generic structural motifs found in larger RNA
structures, and then for Escherichia coli's 1540-base long 16S ribosomal RNA,
which exhibits a surprisingly well-structured and reproducible unfolding
pathway under mechanical stretching. Using out-of-equilibrium stochastic
simulations, we demonstrate that these experimental results reflect the slow
relaxation of RNA structural rearrangements. Hence, micromanipulations of
single RNA molecules probe both their native structures and long-lived
intermediates, so-called "kinetic traps", thereby capturing -at the single
molecular level- the hallmark of RNA folding/unfolding dynamics.Comment: 9 pages, 9 figure
Prediction and statistics of pseudoknots in RNA structures using exactly clustered stochastic simulations
Ab initio RNA secondary structure predictions have long dismissed helices
interior to loops, so-called pseudoknots, despite their structural importance.
Here, we report that many pseudoknots can be predicted through long time scales
RNA folding simulations, which follow the stochastic closing and opening of
individual RNA helices. The numerical efficacy of these stochastic simulations
relies on an O(n^2) clustering algorithm which computes time averages over a
continously updated set of n reference structures. Applying this exact
stochastic clustering approach, we typically obtain a 5- to 100-fold simulation
speed-up for RNA sequences up to 400 bases, while the effective acceleration
can be as high as 100,000-fold for short multistable molecules (<150 bases). We
performed extensive folding statistics on random and natural RNA sequences, and
found that pseudoknots are unevenly distributed amongst RNAstructures and
account for up to 30% of base pairs in G+C rich RNA sequences (Online RNA
folding kinetics server including pseudoknots : http://kinefold.u-strasbg.fr/
).Comment: 6 pages, 5 figure
Anomalous fluctuations of active polar filaments
Using a simple model, we study the fluctuating dynamics of inextensible,
semiflexible polar filaments interacting with active and directed force
generating centres such as molecular motors. Taking into account the fact that
the activity occurs on time-scales comparable to the filament relaxation time,
we obtain some unexpected differences between both the steady-state and
dynamical behaviour of active as compared to passive filaments. For the
statics, the filaments have a {novel} length-scale dependent rigidity.
Dynamically, we find strongly enhanced anomalous diffusion.Comment: 5 pages, 3 figure
Carcinomatous Meningitis from Unknown Primary Carcinoma
Carcinomatous meningitis (CM) occurs in 3 to 8% of cancer patients. Patients present with a focal symptom, and multifocal signs are often found following neurological examination. The gold standard for diagnosis remains the demonstration of carcinomatous cells in the cerebrospinal fluid on cytopathological examination. Despite the poor prognosis, palliative treatment could improve quality of life and, in some cases, overall survival. We report on a patient who presented with vertigo, tinnitus and left-sided hearing loss followed by progressive diffuse facial nerve paralysis. Lumbar cerebrospinal fluid confirmed the diagnosis of CM. However, no primary tumor was discovered, even after multiple invasive investigations. This is the first reported case in the English-language medical literature of CM resulting from a carcinoma of unknown primary origin
Entanglement, elasticity and viscous relaxation of actin solutions
We have investigated the viscosity and the plateau modulus of actin solutions
with a magnetically driven rotating disc rheometer. For entangled solutions we
observed a scaling of the plateau modulus versus concentration with a power of
7/5. The measured terminal relaxation time increases with a power 3/2 as a
function of polymer length. We interpret the entanglement transition and the
scaling of the plateau modulus in terms of the tube model for semiflexible
polymers.Comment: 5 pages, 4 figures, published versio
Polymer Induced Bundling of F-actin and the Depletion Force
The inert polymer polyethylene glycol (PEG) induces a "bundling" phenomenon
in F-actin solutions when its concentration exceeds a critical onset value C_o.
Over a limited range of PEG molecular weight and ionic strength, C_o can be
expressed as a function of these two variables. The process is reversible, but
hysteresis is also observed in the dissolution of the bundles, with ionic
strength having a large influence. Additional actin filaments are able to join
previously formed bundles. Little, if any, polymer is associated with the
bundle structure.
Continuum estimates of the Asakura-Oosawa depletion force, Coulomb repulsion,
and van der Waals potential are combined for a partial explanation of the
bundling effect and hysteresis. Conjectures are presented concerning the
apparent limit in bundle size
Field Theory of the RNA Freezing Transition
Folding of RNA is subject to a competition between entropy, relevant at high
temperatures, and the random, or random looking, sequence, determining the low-
temperature phase. It is known from numerical simulations that for random as
well as biological sequences, high- and low-temperature phases are different,
e.g. the exponent rho describing the pairing probability between two bases is
rho = 3/2 in the high-temperature phase, and approximatively 4/3 in the
low-temperature (glass) phase. Here, we present, for random sequences, a field
theory of the phase transition separating high- and low-temperature phases. We
establish the existence of the latter by showing that the underlying theory is
renormalizable to all orders in perturbation theory. We test this result via an
explicit 2-loop calculation, which yields rho approximatively 1.36 at the
transition, as well as diverse other critical exponents, including the response
to an applied external force (denaturation transition).Comment: 96 pages, 188 figures. v2: minor correction
Two phase I studies of BI 836880, a vascular endothelial growth factor/angiopoietin-2 inhibitor, administered once every 3 weeks or once weekly in patients with advanced solid tumors
BACKGROUND: BI 836880 is a humanized bispecific nanobody® that inhibits vascular endothelial growth factor and angiopoietin-2. Here, we report results from two phase I, nonrandomized, dose-escalation studies (NCT02674152 and NCT02689505; funded by Boehringer Ingelheim) evaluating BI 836880 in patients with confirmed locally advanced or metastatic solid tumors, refractory to standard therapy, or for which standard therapy was ineffective. PATIENTS AND METHODS: Patients aged ≥18 years, with an Eastern Cooperative Oncology Group performance status of 0-2 and adequate organ function received escalating intravenous doses of BI 836880 once every 3 weeks (Q3W; Study 1336.1) or once weekly (QW; Study 1336.6). Primary objectives were maximum tolerated dose (MTD) and recommended phase II dose of BI 836880, based on dose-limiting toxicities (DLTs) during the first cycle. RESULTS: Patients received one of five dosages of 40-1000 mg Q3W (29 patients) or 40-240 mg QW (24 patients). One DLT occurred with Q3W treatment [Grade (G) 3 pulmonary embolism (1000 mg)]. Five DLTs occurred in four patients treated QW [G2 proteinuria (120 mg); G3 hypertension (180 mg); G3 proteinuria and G3 hypertension (240 mg); and G4 respiratory distress (240 mg)]. All patients experienced adverse events, most commonly hypertension with Q3W treatment (89.7%; G3 41.4%), and asthenia with QW treatment (62.5%). Two patients treated Q3W (both 1000 mg) and three patients treated QW (120 mg, 2 patients; 180 mg, 1 patient) experienced partial response. CONCLUSIONS: The MTD of BI 836880 was 720 mg Q3W and 180 mg QW. BI 836880 was generally manageable and demonstrated preliminary efficacy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.govNCT02674152; https://clinicaltrials.gov/ct2/show/NCT02674152 and NCT02689505; https://clinicaltrials.gov/ct2/show/NCT0268950
Statistical mechanics of secondary structures formed by random RNA sequences
The formation of secondary structures by a random RNA sequence is studied as
a model system for the sequence-structure problem omnipresent in biopolymers.
Several toy energy models are introduced to allow detailed analytical and
numerical studies. First, a two-replica calculation is performed. By mapping
the two-replica problem to the denaturation of a single homogeneous RNA in
6-dimensional embedding space, we show that sequence disorder is perturbatively
irrelevant, i.e., an RNA molecule with weak sequence disorder is in a molten
phase where many secondary structures with comparable total energy coexist. A
numerical study of various models at high temperature reproduces behaviors
characteristic of the molten phase. On the other hand, a scaling argument based
on the extremal statistics of rare regions can be constructed to show that the
low temperature phase is unstable to sequence disorder. We performed a detailed
numerical study of the low temperature phase using the droplet theory as a
guide, and characterized the statistics of large-scale, low-energy excitations
of the secondary structures from the ground state structure. We find the
excitation energy to grow very slowly (i.e., logarithmically) with the length
scale of the excitation, suggesting the existence of a marginal glass phase.
The transition between the low temperature glass phase and the high temperature
molten phase is also characterized numerically. It is revealed by a change in
the coefficient of the logarithmic excitation energy, from being disorder
dominated to entropy dominated.Comment: 24 pages, 16 figure
Individual Actin Filaments in a Microfluidic Flow Reveal the Mechanism of ATP Hydrolysis and Give Insight Into the Properties of Profilin
A novel microfluidic approach allows the analysis of the dynamics of individual actin filaments, revealing both their local ADP/ADP-Pi-actin composition and that Pi release is a random mechanism
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