495 research outputs found
Boolean network model predicts cell cycle sequence of fission yeast
A Boolean network model of the cell-cycle regulatory network of fission yeast
(Schizosaccharomyces Pombe) is constructed solely on the basis of the known
biochemical interaction topology. Simulating the model in the computer,
faithfully reproduces the known sequence of regulatory activity patterns along
the cell cycle of the living cell. Contrary to existing differential equation
models, no parameters enter the model except the structure of the regulatory
circuitry. The dynamical properties of the model indicate that the biological
dynamical sequence is robustly implemented in the regulatory network, with the
biological stationary state G1 corresponding to the dominant attractor in state
space, and with the biological regulatory sequence being a strongly attractive
trajectory. Comparing the fission yeast cell-cycle model to a similar model of
the corresponding network in S. cerevisiae, a remarkable difference in
circuitry, as well as dynamics is observed. While the latter operates in a
strongly damped mode, driven by external excitation, the S. pombe network
represents an auto-excited system with external damping.Comment: 10 pages, 3 figure
Leflunomide in the treatment of patients with early rheumatoid arthritisβresults of a prospective non-interventional study
Leflunomide is effective and well tolerated in the treatment of rheumatoid arthritis (RA), however, data on its use in early RA are scarce. This study seeks to evaluate effectiveness and safety of leflunomide in the treatment of early RA in daily practice. This prospective, open-label, non-interventional, multi-center study was carried out over 24Β weeks including adults with early RA (β€1Β year since diagnosis). Leflunomide treatment was according to label instructions. Three hundred thirty-four patients were included. Disease activity score in 28 joints (DAS28) response (reduction in DAS28 of >1.2 or reduction of >0.6 and a DAS28 of β€5.1) was 71.9% at weekβ12 and 84.6% at week 24. 25.0% of patients achieved clinical remission (DAS28ββ€β2.6). Most frequently reported adverse drug reactions (ADR) were diarrhea (3.0%), nausea (2.4%), hypertension (1.8%), and headache (1.5%). Serious ADR were reported in four patients (1.2%). Leflunomide showed the effectiveness which was to be expected from controlled studies without revealing any new or hitherto unknown side effects. Onset of action was quick and significant improvement of disease was seen after 12Β weeks of therapy and at even higher rates after 24Β weeks irrespective of the use of a loading dose. Interestingly, the DAS28-remission rate achieved was similar to the rate seen with methotrexate or biologic therapy in other studies
Early start and stop of biologics: has the time come?
Despite considerable advances in the management of rheumatoid arthritis, results are still not satisfactory for all patients. The treatment goal in rheumatoid arthritis is remission, and there currently are numerous conventional and biological medications available to reach this aim. There are also different treatment strategies but with only limited comparative evidence about their efficacies. More patients now achieve remission while on treatment, but it remains elusive in the majority of patients. Treatment-free remission, the ultimate goal of therapy, is only achieved in very few patients; even when this happens, it is most likely due to the natural course of the disease rather than to any specific therapies. Modern treatment is based on the initiation of aggressive therapy as soon as the diagnosis is established, and on modifying or intensifying therapy guided by frequent assessment of disease activity. In this commentary we will discuss the current treatment paradigm as well as the possibility of an induction-maintenance regimen with biological disease-modifying antirheumatic drugs in early rheumatoid arthriti
Rational design of a ligand-controlled protein conformational switch
Design of a regulatable multistate protein is a challenge for protein engineering. Here we design a protein with a unique topology, called uniRapR, whose conformation is controlled by the binding of a small molecule. We confirm switching and control ability of uniRapR in silico, in vitro, and in vivo. As a proof of concept, uniRapR is used as an artificial regulatory domain to control activity of kinases. By activating Src kinase using uniRapR in single cells and whole organism, we observe two unique phenotypes consistent with its role in metastasis. Activation of Src kinase leads to rapid induction of protrusion with polarized spreading in HeLa cells, and morphological changes with loss of cellβcell contacts in the epidermal tissue of zebrafish. The rational creation of uniRapR exemplifies the strength of computational protein design, and offers a powerful means for targeted activation of many pathways to study signaling in living organisms
Molecular Constraints on Synaptic Tagging and Maintenance of Long-Term Potentiation: A Predictive Model
Protein synthesis-dependent, late long-term potentiation (LTP) and depression
(LTD) at glutamatergic hippocampal synapses are well characterized examples of
long-term synaptic plasticity. Persistent increased activity of the enzyme
protein kinase M (PKM) is thought essential for maintaining LTP. Additional
spatial and temporal features that govern LTP and LTD induction are embodied in
the synaptic tagging and capture (STC) and cross capture hypotheses. Only
synapses that have been "tagged" by an stimulus sufficient for LTP and learning
can "capture" PKM. A model was developed to simulate the dynamics of key
molecules required for LTP and LTD. The model concisely represents
relationships between tagging, capture, LTD, and LTP maintenance. The model
successfully simulated LTP maintained by persistent synaptic PKM, STC, LTD, and
cross capture, and makes testable predictions concerning the dynamics of PKM.
The maintenance of LTP, and consequently of at least some forms of long-term
memory, is predicted to require continual positive feedback in which PKM
enhances its own synthesis only at potentiated synapses. This feedback
underlies bistability in the activity of PKM. Second, cross capture requires
the induction of LTD to induce dendritic PKM synthesis, although this may
require tagging of a nearby synapse for LTP. The model also simulates the
effects of PKM inhibition, and makes additional predictions for the dynamics of
CaM kinases. Experiments testing the above predictions would significantly
advance the understanding of memory maintenance.Comment: v3. Minor text edits to reflect published versio
- β¦