From Collapse to Freezing in Random Heteropolymers

We consider a two-letter self-avoiding (square) lattice heteropolymer model of N_H (out ofN) attracting sites. At zero temperature, permanent links are formed leading to collapse structures for any fraction rho_H=N_H/N. The average chain size scales as R = N^{1/d}F(rho_H) (d is space dimension). As rho_H --> 0, F(rho_H) ~ rho_H^z with z={1/d-nu}=-1/4 for d=2. Moreover, for 0 < rho_H < 1, entropy approaches zero as N --> infty (being finite for a homopolymer). An abrupt decrease in entropy occurs at the phase boundary between the swollen (R ~ N^nu) and collapsed region. Scaling arguments predict different regimes depending on the ensemble of crosslinks. Some implications to the protein folding problem are discussed.Comment: 4 pages, Revtex, figs upon request. New interpretation and emphasis. Submitted to Europhys.Let

T helper cell subsets specific for pseudomonas aeruginosa in healthy individuals and patients with cystic fibrosis

Background: We set out to determine the magnitude of antigen-specific memory T helper cell responses to Pseudomonas aeruginosa in healthy humans and patients with cystic fibrosis. Methods: Peripheral blood human memory CD4+ T cells were co-cultured with dendritic cells that had been infected with different strains of Pseudomonas aeruginosa. The T helper response was determined by measuring proliferation, immunoassay of cytokine output, and immunostaining of intracellular cytokines. Results: Healthy individuals and patients with cystic fibrosis had robust antigen-specific memory CD4+ T cell responses to Pseudomonas aeruginosa that not only contained a Th1 and Th17 component but also Th22 cells. In contrast to previous descriptions of human Th22 cells, these Pseudomonal-specific Th22 cells lacked the skin homing markers CCR4 or CCR10, although were CCR6+. Healthy individuals and patients with cystic fibrosis had similar levels of Th22 cells, but the patient group had significantly fewer Th17 cells in peripheral blood. Conclusions: Th22 cells specific to Pseudomonas aeruginosa are induced in both healthy individuals and patients with cystic fibrosis. Along with Th17 cells, they may play an important role in the pulmonary response to this microbe in patients with cystic fibrosis and other conditions

Synthesis and structural characterization of a mimetic membrane-anchored prion protein

During pathogenesis of transmissible spongiform encephalopathies (TSEs) an abnormal form (PrPSc) of the host encoded prion protein (PrPC) accumulates in insoluble fibrils and plaques. The two forms of PrP appear to have identical covalent structures, but differ in secondary and tertiary structure. Both PrPC and PrPSc have glycosylphospatidylinositol (GPI) anchors through which the protein is tethered to cell membranes. Membrane attachment has been suggested to play a role in the conversion of PrPC to PrPSc, but the majority of in vitro studies of the function, structure, folding and stability of PrP use recombinant protein lacking the GPI anchor. In order to study the effects of membranes on the structure of PrP, we synthesized a GPI anchor mimetic (GPIm), which we have covalently coupled to a genetically engineered cysteine residue at the C-terminus of recombinant PrP. The lipid anchor places the protein at the same distance from the membrane as does the naturally occurring GPI anchor. We demonstrate that PrP coupled to GPIm (PrP-GPIm) inserts into model lipid membranes and that structural information can be obtained from this membrane-anchored PrP. We show that the structure of PrP-GPIm reconstituted in phosphatidylcholine and raft membranes resembles that of PrP, without a GPI anchor, in solution. The results provide experimental evidence in support of previous suggestions that NMR structures of soluble, anchor-free forms of PrP represent the structure of cellular, membrane-anchored PrP. The availability of a lipid-anchored construct of PrP provides a unique model to investigate the effects of different lipid environments on the structure and conversion mechanisms of PrP

Evaluation of Chemotherapeutic Outcomes for Thymic Carcinoma Patients

Background and Hypothesis: Thymic Epithelial Tumors are uncommon tumors of the anterior mediastinum composed of thymomas and thymic carcinomas (TC). TC’s are known to have worse disease outcomes and lower rates of survival in comparison to thymomas and are suspected to have lower response rates to chemotherapy as well. As these tumors are rare, little data exists assessing the true efficacy of chemotherapeutic regimens for TC patients. Due to this lack of data, and that the Indiana University Health Simon Cancer Center treats a high percentage of TET patients, a database of these patients covering a variety different disease characteristics and treatments has been established. We hypothesize, upon evaluation of this database, response rates to anthracycline based regimens (PAC) will be superior to non-anthracycline based regimens (i.e., PE, Carbo/Taxol) for TC patients. Methods: In this project, a collection of patients seen by Dr. Patrick Loehrer and/or Dr. Kenneth Kesler was acquired, and a database was created using these patients in RedCap. Once established, we evaluated patient medical records in Cerner and entered data related to disease characteristics and treatments. These patients were then analyzed accordingly to evaluate chemotherapy response rates. Results: The database yielded 123 instances of chemotherapy treatment for TC. Of which, the most popular treatments were PAC and Carbo/Taxol. The data suggests that PAC generates a higher response rate (65.5%) than other therapies (Carbo/Taxol: 27.6%, PE: 58.3%, etc.). Therefore, there is evidence that anthracycline based regimens may be more effective at generating response rates in comparison to non-anthracycline based regimens. Conclusion and Potential Impact: This project will help elucidate the effectiveness of recommended systemic therapies for thymic carcinoma patients from one of the largest TET databases constructed. Ultimately, we hope that with clarity of the effectiveness of treatment, this can serve as a reliable reference for evidence-based medicine for the care of TC patients

Sequential NMR assignments of labile protons in DNA using two-dimensional nuclear-overhauser-enhancemnt spectroscopy with three jump-and-return pulse sequences

Two-dimensional nuclear Overhauser enhancement (NOESY) spectra of labile protons were recorded in H2O solutions of a protein and of a DNA duplex, using a modification of the standard NOESY experiment with all three 90&#176; pulses replaced by jump-and-return sequences. For the protein as well as the DNA fragment the strategically important spectral regions could be recorded with good sensitivity and free of artifacts. Using this procedure, sequence-specific assignments were obtained for the imino protons, C2H of adenine, and C4NH2 of cytosine in a 23-base-pair DNA duplex which includes the 17-base-pair OR3 repressor binding site of bacteriophage &#955;. Based on comparison with previously published results on the isolated OR3 binding site, these data were used for a study of chain termination effects on the chemical shifts of imino proton resonances of DNA duplexes

Optimising the acceptability and feasibility of acceptance and commitment therapy for treatment-resistant generalised anxiety disorder in older adults

BACKGROUND:generalised anxiety disorder (GAD) is common in later life with a prevalence of 3-12%. Many only partially respond to cognitive behavioural therapy or pharmacotherapy and can be classified as treatment resistant. These patients experience poor quality of life, and are at increased risk of comorbid depression, falls and loneliness. Acceptance and commitment therapy (ACT) is an emerging therapy, which may be particularly suited to this population, but has not been tailored to their needs. OBJECTIVES:to optimise the acceptability and feasibility of ACT for older adults with treatment-resistant GAD. DESIGN:a person-based approach to ground the adapted ACT intervention in the perspectives and lives of those who will use it. METHODS:first, we conducted qualitative interviews with 15 older adults with GAD and 36 healthcare professionals to develop guiding principles to inform the intervention. Second, we consulted service users and clinical experts and interviewed the same 15 older adults using 'think aloud' techniques to enhance its acceptability and feasibility. RESULTS:in Stage 1, older adults' concerns and needs were categorised in four themes: 'Expert in one's own condition', 'Deep seated coping strategies', 'Expert in therapy' and 'Support with implementation'. In Stage 2, implications for therapy were identified that included an early focus on values and ACT as a collaborative partnership, examining beliefs around 'self as worrier' and the role of avoidance, validating and accommodating individuals' knowledge and experience and compensating for age-related cognitive changes. DISCUSSION:Our systematic approach combined rigour and transparency to develop a therapeutic intervention tailored to the specific needs of older adults with treatment-resistant GAD

A randomized study evaluating cinacalcet to treat hypercalcemia in renal transplant recipients with persistent hyperparathyroidism

Persistent hyperparathyroidism (HPT) after kidney transplantation (KTx) is associated with hypercalcemia, hypophosphatemia and abnormally high levels of parathyroid hormone (PTH). In this randomized trial, cinacalcet was compared to placebo for the treatment of hypercalcemia in adult patients with persistent HPT after KTx. Subjects were randomized 1:1 to cinacalcet or placebo with randomization stratified by baseline corrected total serum calcium levels ( 6411.2 mg/dL [2.80 mmol/L] or >11.2 mg/dL [2.80 mmol/L]). The primary end point was achievement of a mean corrected total serum calcium value <10.2 mg/dL (2.55 mmol/L) during the efficacy period. The two key secondary end points were percent change in bone mineral density (BMD) at the femoral neck and absolute change in phosphorus; 78.9% cinacalcet- versus 3.5% placebo-treated subjects achieved the primary end point with a difference of 75.4% (95% confidence interval [CI]: 63.8, 87.1), p < 0.001. There was no statistical difference in the percent change in BMD at the femoral neck between cinacalcet and placebo groups, p = 0.266. The difference in the change in phosphorus between the two arms was 0.45 mg/dL (95% CI: 0.26, 0.64), p < 0.001 (nominal). No new safety signals were detected. In conclusion, hypercalcemia and hypophosphatemia were effectively corrected after treatment with cinacalcet in patients with persistent HPT after KTx. This randomized, placebo-controlled trial demonstrates that cinacalcet effectively and safely corrects hypercalcemia in adult patients with persistent hyperparathyroidism after successful kidney transplantation. See editorial by Coyne and Delos Santos on page 2446

The makewaves tsunami tests and their relevance to tsunami engineering and risk management

MAKEWAVES is an international multi-partner collaborative project bringing together nine academic institutions and two commercial consultancies. The objective of the collaboration is to develop experimental data and associated numerical modelling on tsunami inundation and interaction with boulders, buildings, natural and engineered barriers, towards the development of new internationally accepted guidance for structural codes and standards. Using a pneumatic tsunami simulator (TS) developed jointly by HR Wallingford and UCL the team conducted experiments between November 2022 and April 2023 within a highly instrumented 100m long flume. The TS is capable of simulating realistic trough and crest-led tsunami waves at 1:50, including traces from the The TS is capable of generating very long trough and crest-led waves, and can reproduce at 1:50 scale waves from real life events such as the Mercator trace from the 2004 Indian Ocean event and the and 2011 Tohoku tsunamis. The TS capability has been further extended to include bore-waves. The characteristics of the waves are controlled by adjusting the flow rate and total volume of water drawn in and discharged by the TS. The experimental campaign is was subdivided into discrete research areas, each aimed at furthering knowledge on how different tsunami wave characteristics affect their interaction with manmade and natural structures environments. These include tests aimed at understanding: (1) how roughness representative of coastal forests and mangroves affects tsunami inundation characteristics, (2) how tsunami interact with boulders (3) the effectiveness of offshore breakwaters as tsunami barriers (4) how structural loads and foundation scour are affected by building permeability. This paper presents an overview of the tests conducted and some of the important early observations made that are relevant to future engineering standards and to tsunami disaster management