Two-State Folding, Folding through Intermediates, and Metastability in a Minimalistic Hydrophobic-Polar Model for Proteins

Within the frame of an effective, coarse-grained hydrophobic-polar protein model, we employ multicanonical Monte Carlo simulations to investigate free-energy landscapes and folding channels of exemplified heteropolymer sequences, which are permutations of each other. Despite the simplicity of the model, the knowledge of the free-energy landscape in dependence of a suitable system order parameter enables us to reveal complex folding characteristics known from real bioproteins and synthetic peptides, such as two-state folding, folding through weakly stable intermediates, and glassy metastability.Comment: 10 pages, 1 figur

Substrate Adhesion of a Nongrafted Flexible Polymer in a Cavity

In a contact density chain-growth study we investigate the solubility-temperature pseudo-phase diagram of a lattice polymer in a cavity with an attractive surface. In addition to the main phases of adsorbed and desorbed conformations we find numerous subphases of collapsed and expanded structures.Comment: 20 pages, 6 figure

Exact microcanonical statistical analysis of transition behavior in Ising chains and strips

Recent analyses of least-sensitive inflection points in derivatives of the microcanonical entropy for the two-dimensional Ising model revealed higher-order transition signals in addition to the well-studied second-order ferromagnetic/paramagnetic phase transition. In this paper, we re-analyze the exact density of states for the one-dimensional Ising chain as well as the strips with widths/lengths of up to 64/1024 spins, in search of potential transition features. While some transitions begin to emerge as the strip width increases, none are found for the chain, as might be expected.Comment: 19 pages, 9 figure

Microcanonical entropy inflection points: Key to systematic understanding of transitions in finite systems

We introduce a systematic classification method for the analogs of phase transitions in finite systems. This completely general analysis, which is applicable to any physical system and extends towards the thermodynamic limit, is based on the microcanonical entropy and its energetic derivative, the inverse caloric temperature. Inflection points of this quantity signal cooperative activity and thus serve as distinct indicators of transitions. We demonstrate the power of this method through application to the long-standing problem of liquid-solid transitions in elastic, flexible homopolymers.Comment: 4 pages, 3 figure

Multicanonical Study of Coarse-Grained Off-Lattice Models for Folding Heteropolymers

We have performed multicanonical simulations of hydrophobic-hydrophilic heteropolymers with two simple effective, coarse-grained off-lattice models to study the influence of specific interactions in the models on conformational transitions of selected sequences with 20 monomers. Another aspect of the investigation was the comparison with the purely hydrophobic homopolymer and the study of general conformational properties induced by the "disorder" in the sequence of a heteropolymer. Furthermore, we applied an optimization algorithm to sequences with up to 55 monomers and compared the global-energy minimum found with lowest-energy states identified within the multicanonical simulation. This was used to find out how reliable the multicanonical method samples the free-energy landscape, in particular for low temperatures.Comment: 11 pages, RevTeX, 10 Postscript figures, Author Information under http://www.physik.uni-leipzig.de/index.php?id=2

Is Elective Vulvar Plastic Surgery Ever Warranted, and What Screening Should Be Conducted Preoperatively?

Introduction.  Elective vulvar plastic surgery was the topic of a heated discussion on the list-serve of the International Society for the Study of Women's Sexual Medicine. At the suggestion of a board member, it was determined that this discussion might of interest to journal readers in the form of a published controversy. Methods.  Six people with expertise and/or strong opinions in the area of vulvar health, several of whom had been involved in the earlier online discussion, were invited to submit evidence-based opinions on the topic. Main Outcome Measure.  To provide food for thought, discussion, and possible further research in a poorly discussed area of sexual medicine. Results.  Goodman believes that patients should make their own decisions. Bachmann further states that, while that is a woman's right, she should be counseled first, because variations in looks of the vulvar region are normal. Johnson furthers this thought, discussing the requirement for counseling before performing reinfibulation surgery on victims of female genital cutting. Fourcroy emphasizes the need to base surgical procedures on safety and efficacy in the long term, and not merely opportunity at the moment. Goldstein and Goldstein state that, based on the four principles of ethical practice of medicine, vulvar plastic surgery is not always ethical, but not always unethical. Sklar pursues this thought further, pointing out specific examples in regard to the principles of ethics. Conclusion.  Vulvar plastic surgery may be warranted only after counseling if it is still the patient's preference, provided that it is conducted in a safe manner and not solely for the purpose of performing surgery. Goodman MP, Bachmann G, Johnson C, Fourcroy JL, Goldstein A, Goldstein G, and Sklar S. Is elective vulvar plastic surgery ever warranted, and what screening should be done preoperatively? J Sex Med 2007;4:269–276.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72245/1/j.1743-6109.2007.00431.x.pd

cAMP-dependent and cholinergic regulation of the electrogenic intestinal/pancreatic Na+/HCO3- cotransporter pNBC1 in human embryonic kidney (HEK293) cells

<p>Abstract</p> <p>Background</p> <p>The renal (kNBC1) and intestinal (pNBC1) electrogenic Na⁺/HCO₃^-cotransporter variants differ in their primary structure, transport direction, and response to secretagogues. Previous studies have suggested that regulatory differences between the two subtypes can be partially explained by unique consensus phosphorylation sites included in the pNBC1, but not the kNBC1 sequence. After having shown activation of NBC by carbachol and forskolin in murine colon, we now investigated these pathways in HEK293 cells transiently expressing a GFP-tagged pNBC1 construct. </p> <p>Results</p> <p>Na⁺- and HCO₃^--dependent pH_irecovery from an acid load (measured with BCECF) was enhanced by 5-fold in GFP-positive cells compared to the control cells in the presence of CO₂/HCO₃^-. Forskolin (10^-5M) had no effect in untransfected cells, but inhibited the pH_irecovery in cells expressing pNBC1 by 62%. After preincubation with carbachol (10^-4M), the pH_irecovery was enhanced to the same degree both in transfected and untransfected cells, indicating activation of endogenous alkalizing ion transporters. Acid-activated Na⁺/HCO₃^-cotransport via pNBC1 expressed in renal cells is thus inhibited by cAMP and not affected by cholinergic stimulation, as opposed to the findings in native intestinal tissue. </p> <p>Conclusion</p> <p>Regulation of pNBC1 by secretagogues appears to be not solely dependent on its primary structure, but also on properties of the cell type in which it is expressed.</p

Regional differences in health care of patients with inflammatory bowel disease in Germany

Background: The regional availability of specialized physicians is an important aspect in healthcare of patients with IBD. The association between physician density and healthcare is not yet clear. Most studies did not consider district type, which reflects population density. Our research question was, “Do specialist density and district type influence the healthcare of IBD patients in Germany?” Methods: We combined a claims dataset from a German health insurance fund with population and physician data. Four main aspects were investigated: regular specialist visits, drug therapies, surveillance colonoscopy, and IBD-related hospitalizations. Various regression analyses were performed. Results: The study cohort was comprised of 21,771 individuals, including 9282 patients with Crohn disease and 12,489 patients with ulcerative colitis. Patients who were living in districts with higher specialist densities were more likely to attend specialist visits on a regular basis. No difference in the frequencies of TNF-alpha inhibitor therapies was found. However, individuals from urban areas were more likely to receive a permanent immunosuppressive therapy with continuous specialist support. Conclusions: The results revealed that some aspects had positive effects on the probability of implementing healthcare in accordance with pathways and guidelines. No clear evidence of a general healthcare undersupply in rural areas was found.DF

Dendritic Cell-Based Immunotherapy for Prostate Cancer

Dendritic cells (DCs) are professional antigen-presenting cells (APCs), which display an extraordinary capacity to induce, sustain, and regulate T-cell responses providing the opportunity of DC-based cancer vaccination strategies. Thus, clinical trials enrolling prostate cancer patients were conducted, which were based on the administration of DCs loaded with tumor-associated antigens. These clinical trials revealed that DC-based immunotherapeutic strategies represent safe and feasible concepts for the induction of immunological and clinical responses in prostate cancer patients. In this context, the administration of the vaccine sipuleucel-T consisting of autologous peripheral blood mononuclear cells including APCs, which were pre-exposed in vitro to the fusion protein PA2024, resulted in a prolonged overall survival among patients with metastatic castration-resistent prostate cancer. In April 2010, sipuleucel-T was approved by the United States Food and Drug Administration for prostate cancer therapy