Folding and insertion thermodynamics of the transmembrane WALP peptide

The anchor of most integral membrane proteins consists of one or several helices spanning the lipid bilayer. The WALP peptide, GWW(LA)$_n$(L)WWA, is a common model helix to study the fundamentals of protein insertion and folding, as well as helix-helix association in the membrane. Its structural properties have been illuminated in a large number of experimental and simulation studies. In this combined coarse-grained and atomistic simulation study, we probe the thermodynamics of a single WALP peptide, focusing on both the insertion across the water-membrane interface, as well as folding in both water and a membrane. The potential of mean force characterizing the peptide's insertion into the membrane shows qualitatively similar behavior across peptides and three force fields. However, the Martini force field exhibits a pronounced secondary minimum for an adsorbed interfacial state, which may even become the global minimum---in contrast to both atomistic simulations and the alternative PLUM force field. Even though the two coarse-grained models reproduce the free energy of insertion of individual amino acids side chains, they both underestimate its corresponding value for the full peptide (as compared with atomistic simulations), hinting at cooperative physics beyond the residue level. Folding of WALP in the two environments indicates the helix as the most stable structure, though with different relative stabilities and chain-length dependence.Comment: 12 pages, 5 figure

Exact solution of a linear molecular motor model driven by two-step fluctuations and subject to protein friction

We investigate by analytical means the stochastic equations of motion of a linear molecular motor model based on the concept of protein friction. Solving the coupled Langevin equations originally proposed by Mogilner et al. (A. Mogilner et al., Phys. Lett. {\bf 237}, 297 (1998)), and averaging over both the two-step internal conformational fluctuations and the thermal noise, we present explicit, analytical expressions for the average motion and the velocity-force relationship. Our results allow for a direct interpretation of details of this motor model which are not readily accessible from numerical solutions. In particular, we find that the model is able to predict physiologically reasonable values for the load-free motor velocity and the motor mobility.Comment: 12 pages revtex, 6 eps-figure

A Constitutive Model for Long Time Duration Mechanical Behavior in Insensitive High Explosives

An anisotropic constitutive model for the long term dimensional stability of insensitive high explosives is proposed. Elastic, creep, thermal, and ratchet growth strains are developed. Pressure and temperature effects are considered. The constitutive model is implemented in an implicit finite element code and compared to a variety of experimental data

Tolerance to the Neuron-Specific Paraneoplastic HuD Antigen

Experiments dating back to the 1940's have led to the hypothesis that the brain is an immunologically privileged site, shielding its antigens from immune recognition. The paraneoplastic Hu syndrome provides a powerful paradigm for addressing this hypothesis; it is believed to develop because small cell lung cancers (SCLC) express the neuron-specific Hu protein. This leads to an Hu-specific tumor immune response that can develop into an autoimmune attack against neurons, presumably when immune privilege in the brain is breached. Interestingly, all SCLC express the onconeural HuD antigen, and clinically useful tumor immune responses can be detected in up to 20% of patients, yet the paraneoplastic neurologic syndrome is extremely rare. We found that HuD-specific CD8+ T cells are normally present in the mouse T cell repertoire, but are not expanded upon immunization, although they can be detected after in vitro expansion. In contrast, HuD-specific T cells could be directly activated in HuD null mice, without the need for in vitro expansion. Taken together, these results demonstrate robust tolerance to the neuronal HuD antigen in vivo, and suggest a re-evaluation of the current concept of immune privilege in the brain

Codon-based analysis of selection pressure and genetic structure in the Psammobates tentorius (Bell, 1828) species complex, and phylogeny inferred from both codons and amino acid sequences

This study used codon analysis (dN/dS and Tv/Ti) to investigate selection pressure and genetic structure in the highly polymorphic Psammobates tentorius species complex, and amino acid sequences to construct a phylogeny tree for it. Our results revealed a strong selection signal at node ‘C2 + C3’, possibly driven by aridity intensification resulting from the development of the Benguela Current. A similar signal was noticed at C3, possibly due to the same driving force. These findings suggest that environmental selection pressure favoured those groups and that further cladogenic events were possible. Selection pressure was also found to be high at C1, C4 and C7, which may indicate that they are also favoured by the current selection pressure. The codon-based phylogeny did not retrieve any potentially undescribed species, but nonetheless provided support for the validity of the seven distinct clades retrieved with the DNA sequence data. The amino acid sequence-based phylogeny generally supported the seven lineages as valid putative species. Investigation at the genomic scale could, however, help to solve the issue. In general, we found the codon, dN, dS, Tv, Ti and amino acid sequence-based phylogenetic inferences useful in species delimitation and recommend their use in species delimitation studies

Analysis of a multiple-well interference test in Miocene tuffaceous rocks at the C-Hole complex, May--June 1995, Yucca Mountain, Nye County, Nevada

A multiple-well interference (pumping) test was conducted in Miocene tuffaceous rocks at the C-hole complex at Yucca Mountain, Nev., from May 22 to June 12, 1995, by the US Geological Survey, in cooperation with the US Department of Energy. This pumping test was conducted as part of investigations to determine the suitability of Yucca Mountain as a potential site for the storage of high-level nuclear waste in a mined geologic repository. During the test, borehole UE-25 c{number_sign}3 was pumped for 10 days at an average rate of 17.9 liters per second. Drawdown in 6 observation wells completed in Miocene tuffaceous rocks 29.0--3,525.6 meters from the pumping well ranged from 0 to 0.42 meters 14,000 minutes after pumping started. The spatial distribution of this drawdown indicates that a northwest-trending zone of discontinuous faults might be affecting ground-water movement in the Miocene tuffaceous rocks near the C-holes. No drawdown was observed in a borehole completed in a regional Paleozoic carbonate aquifer 630.0 meters from the pumping well. Consequently, it could not be determined during the pumping test if the Miocene tuffaceous rocks are connected hydraulically to the regional aquifer. Analyses of drawdown and recovery indicate that the Miocene tuffaceous rocks in the vicinity of the C-holes have transmissivity values of 1,600--3,200 meters squared per day, horizontal hydraulic conductivity values of 6.5--13 meters per day, vertical hydraulic conductivity values of 0.2--1.7 meters per day, storativity values of 0.001--0.003, and specific yield values of 0.01--0.2

Harnessing Naturally Occurring Tumor Immunity: A Clinical Vaccine Trial in Prostate Cancer

International audienceBACKGROUND:Studies of patients with paraneoplastic neurologic disorders (PND) have revealed that apoptotic tumor serves as a potential potent trigger for the initiation of naturally occurring tumor immunity. The purpose of this study was to assess the feasibility, safety, and immunogenicity of an apoptotic tumor-autologous dendritic cell (DC) vaccine.METHODS AND FINDINGS:We have modeled PND tumor immunity in a clinical trial in which apoptotic allogeneic prostate tumor cells were used to generate an apoptotic tumor-autologous dendritic cell vaccine. Twenty-four prostate cancer patients were immunized in a Phase I, randomized, single-blind, placebo-controlled study to assess the safety and immunogenicity of this vaccine. Vaccinations were safe and well tolerated. Importantly, we also found that the vaccine was immunogenic, inducing delayed type hypersensitivity (DTH) responses and CD4+ and CD8+ T cell proliferation, with no effect on FoxP3+ regulatory T cells. A statistically significant increase in T cell proliferation responses to prostate tumor cells in vitro (p = 0.002), decrease in prostate specific antigen (PSA) slope (p = 0.016), and a two-fold increase in PSA doubling time (p = 0.003) were identified when we compared data before and after vaccination.CONCLUSIONS:An apoptotic cancer cell vaccine modeled on naturally occurring tumor immune responses in PND patients provides a safe and immunogenic tumor vaccine