65 research outputs found
Lateral Separation of Macromolecules and Polyelectrolytes in Microlithographic Arrays
A new approach to separation of a variety of microscopic and mesoscopic
objects in dilute solution is presented. The approach takes advantage of unique
properties of a specially designed separation device (sieve), which can be
readily built using already developed microlithographic techniques. Due to the
broken reflection symmetry in its design, the direction of motion of an object
in the sieve varies as a function of its self-diffusion constant, causing
separation transverse to its direction of motion. This gives the device some
significant and unique advantages over existing fractionation methods based on
centrifugation and electrophoresis.Comment: 4 pages with 3 eps figures, needs RevTeX 3.0 and epsf, also available
in postscript form http://cmtw.harvard.edu/~deniz
Gel-Electrophoresis and Diffusion of Ring-Shaped DNA
A model for the motion of ring-shaped DNA in a gel is introduced and studied
by numerical simulations and a mean-field approximation. The ring motion is
mediated by finger-shaped loops (hernias) that move in an amoeba-like fashion
around the gel obstructions. This constitutes an extension of previous
reptation tube treatments. It is shown that tension is essential for describing
the dynamics in the presence of hernias. It is included in the model as long
range interactions over stretched DNA regions. The mobility of ring-shaped DNA
is found to saturate much as in the well-studied case of linear DNA.
Experiments in polymer gels, however, show that the mobility drops
exponentially with the DNA ring size. This is commonly attributed to
dangling-ends in the gel that can impale the ring. The predictions of the
present model are expected to apply to artificial 2D obstacle arrays (W.D.
Volkmuth, R.H. Austin, Nature 358,600 (1992)) which have no dangling-ends. In
the zero-field case an exact solution of the model steady-state is obtained,
and quantities such as the average ring size are calculated. An approximate
treatment of the ring dynamics is given, and the diffusion coefficient is
derived. The model is also discussed in the context of spontaneous symmetry
breaking in one dimension.Comment: 8 figures, LaTeX, Phys. Rev. E - in pres
A new bond fluctuation method for a polymer undergoing gel electrophoresis
We present a new computational methodology for the investigation of gel
electrophoresis of polyelectrolytes. We have developed the method initially to
incorporate sliding motion of tight parts of a polymer pulled by an electric
field into the bond fluctuation method (BFM). Such motion due to tensile force
over distances much larger than the persistent length is realized by non-local
movement of a slack monomer at an either end of the tight part. The latter
movement is introduced stochastically. This new BFM overcomes the well-known
difficulty in the conventional BFM that polymers are trapped by gel fibers in
relatively large fields. At the same time it also reproduces properly
equilibrium properties of a polymer in a vanishing filed limit. The new BFM
thus turns out an efficient computational method to study gel electrophoresis
in a wide range of the electric field strength.Comment: 15 pages, 11 figure
Rectification and Phase Locking for Particles on Two Dimensional Periodic Substrates
We show that a novel rectification phenomena is possible for overdamped
particles interacting with a 2D periodic substrate and driven with a
longitudinal DC drive and a circular AC drive. As a function of DC amplitude,
the longitudinal velocity increases in a series of quantized steps with
transverse rectification occuring near these transitions. We present a simple
model that captures the quantization and rectification behaviors.Comment: 4 pages, 4 postscript figure
Brownian motion exhibiting absolute negative mobility
We consider a single Brownian particle in a spatially symmetric, periodic
system far from thermal equilibrium. This setup can be readily realized
experimentally. Upon application of an external static force F, the average
particle velocity is negative for F>0 and positive for F<0 (absolute negative
mobility).Comment: 4 pages, 3 figures, to be published in PR
Anaphylaxis in Elderly Patients-Data From the European Anaphylaxis Registry
Background: Elicitors and symptoms of anaphylaxis are age dependent. However, little is known about typical features of anaphylaxis in patients aged 65 years or more.
Methods: The data from the Network for Online Registration of Anaphylaxis (NORA) considering patients aged ≥65 (elderly) in comparison to data from adults (18–64 years) regarding elicitors, symptoms, comorbidities, and treatment measures were analyzed.
Results: We identified 1,123 elderly anaphylactic patients. Insect venoms were the most frequent elicitor in this group (p < 0.001), followed by drugs like analgesics and antibiotics. Food allergens elicited less frequently anaphylaxis (p < 0.001). Skin symptoms occurred less frequently in elderly patients (77%, p < 0.001). The clinical symptoms were more severe in the elderly (51% experiencing grade III/IV reactions), in particular when skin symptoms (p < 0.001) were absent. Most strikingly, a loss of consciousness (33%, p < 0.001) and preexisting cardiovascular comorbidity (59%, p < 0.001) were more prevalent in the elderly. Finally, adrenaline was used in 30% of the elderly (vs. 26% in the comparator group, p < 0.001) and hospitalization was more often required (60 vs. 50%, p < 0.001).
Discussion and Conclusion: Anaphylaxis in the elderly is often caused by insect venoms and drugs. These patients suffer more often from cardiovascular symptoms, receive more frequently adrenaline and require more often hospitalization. The data indicate that anaphylaxis in the elderly tends to be more frequently life threatening and patients require intensified medical intervention. The data support the need to recognize anaphylaxis in this patient group, which is prone to be at a higher risk for a fatal outcome
Peanut‐induced anaphylaxis in children and adolescents: Data from the European Anaphylaxis Registry
Background Peanut allergy has a rising prevalence in high-income countries, affecting 0.5%-1.4% of children. This study aimed to better understand peanut anaphylaxis in comparison to anaphylaxis to other food triggers in European children and adolescents. Methods Data was sourced from the European Anaphylaxis Registry via an online questionnaire, after in-depth review of food-induced anaphylaxis cases in a tertiary paediatric allergy centre. Results 3514 cases of food anaphylaxis were reported between July 2007 - March 2018, 56% in patients younger than 18 years. Peanut anaphylaxis was recorded in 459 children and adolescents (85% of all peanut anaphylaxis cases). Previous reactions (42% vs. 38%; p = .001), asthma comorbidity (47% vs. 35%; p < .001), relevant cofactors (29% vs. 22%; p = .004) and biphasic reactions (10% vs. 4%; p = .001) were more commonly reported in peanut anaphylaxis. Most cases were labelled as severe anaphylaxis (Ring&Messmer grade III 65% vs. 56% and grade IV 1.1% vs. 0.9%; p = .001). Self-administration of intramuscular adrenaline was low (17% vs. 15%), professional adrenaline administration was higher in non-peanut food anaphylaxis (34% vs. 26%; p = .003). Hospitalization was higher for peanut anaphylaxis (67% vs. 54%; p = .004). Conclusions The European Anaphylaxis Registry data confirmed peanut as one of the major causes of severe, potentially life-threatening allergic reactions in European children, with some characteristic features e.g., presence of asthma comorbidity and increased rate of biphasic reactions. Usage of intramuscular adrenaline as first-line treatment is low and needs to be improved. The Registry, designed as the largest database on anaphylaxis, allows continuous assessment of this condition
Dynamics of self-threading ring polymers in a gel
We study of the dynamics of ring polymers confined to diffuse in a background
gel at low concentrations. We do this in order to probe the inter-play between
topology and dynamics in ring polymers. We develop an algorithm that takes into
account the possibility that the rings hinder their own motion by passing
through themselves, i.e. "self-threading". Our results suggest that the number
of self-threadings scales extensively with the length of the rings and that
this is substantially independent of the details of the model. The slowing down
of the rings' dynamics is found to be related to the fraction of segments that
can contribute to the motion. Our results give a novel perspective on the
motion of ring polymers in gel, for which a complete theory is still lacking,
and may help us to understand the irreversible trapping of ring polymers in gel
electrophoresis experiments.Comment: 11 pages,14 figures, Soft Matter 201
31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two
Background
The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd.
Methods
We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background.
Results
First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001).
Conclusions
In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival
DNA Separation in Gradient of Confined Nanospace Generated by Nanoparticles in a Microchannel
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