374 research outputs found
Joint scaling laws in functional and evolutionary categories in prokaryotic genomes
We propose and study a class-expansion/innovation/loss model of genome
evolution taking into account biological roles of genes and their constituent
domains. In our model numbers of genes in different functional categories are
coupled to each other. For example, an increase in the number of metabolic
enzymes in a genome is usually accompanied by addition of new transcription
factors regulating these enzymes. Such coupling can be thought of as a
proportional "recipe" for genome composition of the type "a spoonful of sugar
for each egg yolk". The model jointly reproduces two known empirical laws: the
distribution of family sizes and the nonlinear scaling of the number of genes
in certain functional categories (e.g. transcription factors) with genome size.
In addition, it allows us to derive a novel relation between the exponents
characterising these two scaling laws, establishing a direct quantitative
connection between evolutionary and functional categories. It predicts that
functional categories that grow faster-than-linearly with genome size to be
characterised by flatter-than-average family size distributions. This relation
is confirmed by our bioinformatics analysis of prokaryotic genomes. This proves
that the joint quantitative trends of functional and evolutionary classes can
be understood in terms of evolutionary growth with proportional recipes.Comment: 39 pages, 21 figure
Hierarchy and Feedback in the Evolution of the E. coli Transcription Network
The E.coli transcription network has an essentially feedforward structure,
with, however, abundant feedback at the level of self-regulations. Here, we
investigate how these properties emerged during evolution. An assessment of the
role of gene duplication based on protein domain architecture shows that (i)
transcriptional autoregulators have mostly arisen through duplication, while
(ii) the expected feedback loops stemming from their initial cross-regulation
are strongly selected against. This requires a divergent coevolution of the
transcription factor DNA-binding sites and their respective DNA cis-regulatory
regions. Moreover, we find that the network tends to grow by expansion of the
existing hierarchical layers of computation, rather than by addition of new
layers. We also argue that rewiring of regulatory links due to
mutation/selection of novel transcription factor/DNA binding interactions
appears not to significantly affect the network global hierarchy, and that
horizontally transferred genes are mainly added at the bottom, as new target
nodes. These findings highlight the important evolutionary roles of both
duplication and selective deletion of crosstalks between autoregulators in the
emergence of the hierarchical transcription network of E.coli.Comment: to appear in PNA
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
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
Neo/adjuvant chemotherapy does not improve outcome in resected primary synovial sarcoma: a study of the French Sarcoma Group
Background: There are only scarce data about the benefit of adjunctive chemotherapy in patients with localized synovial sarcoma (SS). Patients and methods: Data from 237 SS patients recorded in the database of the French Sarcoma Group were retrospectively analyzed. The respective impact of radiotherapy, neo-adjuvant chemotherapy and adjuvant chemotherapy on overall survival (OS), local recurrence-free survival (LRFS) and distant recurrence-free survival (DRFS) were assessed after adjustment to prognostic factors. Results: The median follow-up was 58 months (range 1-321). Adjuvant, neo-adjuvant chemotherapy and postoperative radiotherapy were administered in 112, 45 and 181 cases, respectively. In all, 59% of patients treated with chemotherapy received an ifosfamide-containing regimen. The 5-year OS, LRFS and DRFS rates were 64.0%, 70% and 57%, respectively. On multivariate analysis, age >35 years old, grade 3 and not-R0 margins were highly significant independent predictors of worse OS. After adjustment to prognostic factors, radiotherapy significantly improved LRFS but not DRFS or OS. Neither neo-adjuvant nor adjuvant chemotherapy had significant impact on OS, LRFS or DRFS. Conclusion: As for other high-grade soft-tissue sarcomas, well-planned wide surgical excision with adjuvant radiotherapy remains the cornerstone of treatment for SS. Neo-adjuvant or adjuvant chemotherapy should not be delivered outside a clinical trial settin
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 nanobodyÂź 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 â„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
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