Structural features of tight-junction proteins

Tight junctions are complex supramolecular entities composed of integral membrane proteins, membrane-associated and soluble cytoplasmic proteins engaging in an intricate and dynamic system of protein-protein interactions. Three-dimensional structures of several tight-junction proteins or their isolated domains have been determined by X-ray crystallography, nuclear magnetic resonance spectroscopy, and cryo-electron microscopy. These structures provide direct insight into molecular interactions that contribute to the formation, integrity, or function of tight junctions. In addition, the known experimental structures have allowed the modeling of ligand-binding events involving tight-junction proteins. Here, we review the published structures of tight-junction proteins. We show that these proteins are composed of a limited set of structural motifs and highlight common types of interactions between tight-junction proteins and their ligands involving these motifs

Expansion velocity of a one-dimensional, two-component Fermi gas during the sudden expansion in the ballistic regime

We show that in the sudden expansion of a spin-balanced two-component Fermi gas into an empty optical lattice induced by releasing particles from a trap, over a wide parameter regime, the radius $R_n$ of the particle cloud grows linearly in time. This allow us to define the expansion velocity $V_{ex}$ from $R_n=V_{ex}t$. The goal of this work is to clarify the dependence of the expansion velocity on the initial conditions which we establish from time-dependent density matrix renormalization group simulations, both for a box trap and a harmonic trap. As a prominent result, the presence of a Mott-insulating region leaves clear fingerprints in the expansion velocity. Our predictions can be verified in experiments with ultra-cold atoms.Comment: 8 pages 10 figures, version as published with minor stylistic change

Functional interaction of CCAAT/enhancer-binding-protein-α basic region mutants with E2F transcription factors and DNA

The transcription factor CCAAT/enhancer-binding protein {alpha} (C/EBP{alpha}) regulates cell cycle arrest and terminal differentiation of neutrophils and adipocytes. Mutations in the basic leucine zipper domain (bZip) of C/EBP{alpha} are associated with acute myeloid leukemia. A widely used murine transforming C/EBP{alpha} basic region mutant (BRM2) entails two bZip point mutations (I294A/R297A). BRM2 has been discordantly described as defective for DNA binding or defective for interaction with E2F. We have separated the two BRM2 mutations to shed light on the intertwined reciprocity between C/EBP{alpha}-E2F-DNA interactions. Both, C/EBP{alpha} I294A and R297A retain transactivation capacity and interaction with E2F-DP. The C/EBP{alpha} R297A mutation destabilized DNA binding, whereas the C/EBP{alpha} I294A mutation enhanced binding to DNA. The C/EBP{alpha} R297A mutant, like BRM2, displayed enhanced interaction with E2F-DP but failed to repress E2F-dependent transactivation although both mutants were readily suppressed by E2F1 for transcription through C/EBP cis-regulatory sites. In contrast, the DNA binding enhanced C/EBP{alpha} I294A mutant displayed increased repression of E2F-DP mediated transactivation and resisted E2F-DP mediated repression. Thus, the efficient repression of E2F dependent S-phase genes and the activation of differentiation genes reside in the balanced DNA binding capacity of C/EBP{alpha}

Structural basis of gene regulation by the Grainyhead/CP2 transcription factor family

Grainyhead (Grh)/CP2 transcription factors are highly conserved in multicellular organisms as key regulators of epithelial differentiation, organ development and skin barrier formation. In addition, they have been implicated as being tumor suppressors in a variety of human cancers. Despite their physiological importance, little is known about their structure and DNA binding mode. Here, we report the first structural study of mammalian Grh/CP2 factors. Crystal structures of the DNA-binding domains of grainyhead-like (Grhl) 1 and Grhl2 reveal a closely similar conformation with immunoglobulin-like core. Both share a common fold with the tumor suppressor p53, but differ in important structural features. The Grhl1 DNA-binding domain binds duplex DNA containing the consensus recognition element in a dimeric arrangement, supporting parsimonious target-sequence selection through two conserved arginine residues. We elucidate the molecular basis of a cancer-related mutation in Grhl1 involving one of these arginines, which completely abrogates DNA binding in biochemical assays and transcriptional activation of a reporter gene in a human cell line. Thus, our studies establish the structural basis of DNA target-site recognition by Grh transcription factors and reveal how tumor-associated mutations inactivate Grhl proteins. They may serve as points of departure for the structure-based development of Grh/CP2 inhibitors for therapeutic applications

Effectiveness of a procalcitonin algorithm to guide antibiotic therapy in respiratory tract infections outside of study conditions: a post-study survey

All published evidence on procalcitonin (PCT)-guided antibiotic therapy was obtained in trials where physicians knew that they were being monitored, possibly resulting in higher adherence to the PCT algorithm. This study investigates the effectiveness of PCT guidance in an observational quality control survey. We monitored antibiotic therapy and algorithm adherence in consecutive patients with respiratory tract infections admitted to the Kantonsspital Aarau, Switzerland, between May 2008 and February 2009. The results were compared to the site-specific results of the former ProHOSP study. Overall and more pronounced for patients with community-acquired pneumonia, the median duration of antibiotic treatment in this survey was shorter than the ProHOSP control patients (6 vs. 7days, P = 0.048 and 7 vs. 9days, P < 0.001). In 72.5% of patients, antibiotics were administered according to the prespecified PCT algorithm. No significant differences concerning adverse medical outcome could be detected. This study mirrors the use of PCT-guided antibiotic therapy in clinical practice, outside of trial conditions. If algorithm adherence is reinforced, antibiotic exposure can be markedly reduced with subsequent reduction of antibiotic-associated side effects and antibiotic resistance. The integration of the PCT algorithm into daily practice requires ongoing reinforcement and involves a learning process of the prescribing physician

The solution space of metabolic networks: producibility, robustness and fluctuations

Flux analysis is a class of constraint-based approaches to the study of biochemical reaction networks: they are based on determining the reaction flux configurations compatible with given stoichiometric and thermodynamic constraints. One of its main areas of application is the study of cellular metabolic networks. We briefly and selectively review the main approaches to this problem and then, building on recent work, we provide a characterization of the productive capabilities of the metabolic network of the bacterium E.coli in a specified growth medium in terms of the producible biochemical species. While a robust and physiologically meaningful production profile clearly emerges (including biomass components, biomass products, waste etc.), the underlying constraints still allow for significant fluctuations even in key metabolites like ATP and, as a consequence, apparently lay the ground for very different growth scenarios.Comment: 10 pages, prepared for the Proceedings of the International Workshop on Statistical-Mechanical Informatics, March 7-10, 2010, Kyoto, Japa

Optimized patient transfer using an innovative multidisciplinary assessment in the Kanton Aargau (OPTIMA I): an observational survey in lower respiratory tract infections

BACKGROUND: Current medical scores have limited efficiency and safety profiles to enable assignment to the most appropriate treatment site in patients with lower respiratory tract infections (LRTIs). We describe our current triage practice and assess the potential of a combination of CURB65 with proadrenomedullin (ProADM) levels for triage decisions. METHODS: Consecutive patients with LRTIs presenting to our emergency department were prospectively followed and retrospectively classified according to CURB65 and ProADM levels (CURB65-A). Low medical risk patients were further subgrouped according to biopsychosocial and functional risks. We compared the proportion of patients virtually allocated to triage sites with actual triage decisions and assessed the added impact of ProADM in a subgroup. RESULTS: Overall, 93% of 146 patients were hospitalised. Among the 138 patients with available CURB65-A, 17.4% had a low medical risk indicating possible treatment in an outpatient or non-acute medical setting; 34.1% had an intermediate medical risk (short-hospitalisation); and 48.6% had a high medical risk (hospitalisation). Fewer patients were in a low CURB65-A class (I) than a low CURB65 class (0,1) (17.4% vs. 46.3%, p >0.001). Mean length of hospitalisation was 9.8 days including 3.6 days after reaching medical stability. In 60.3% of patients, hospitalisation was prolonged after medical stability mainly for medical reasons. CONCLUSIONS: Current rates of hospitalisation are high in patients with LRTI and length of stay frequently extended beyond time of medical stabilization. The lower proportion of patients reclassified as low risk by adding ProADM to the CURB65 score might improve confidence in the triage algorithm

Prevalence of malnutrition in, 1760 patients at hospital admission: a controlled population study of body composition

Abstractö Objective: Malnutrition, de¢ned as low or excessive body weight, is associated with increased hospital length of stay and cost of care. The purpose of this study was to determine if fat-free mass (FFM) and body fat (BF) di¡ered between patients at hospital admission in Geneva and Berlin and healthy volunteers, and if there is a di¡erence in the prevalence of low FFM (percentile Po10) and high BF (percentile P490) between patients and volunteers. Methods: In total, 1760 patients (Geneva: 525 men, 470 women; Berlin: 397 men, 368 women) were evaluated for malnutrition by BMI, serum albumin, and FFM and BF, determined by bioelectrical impedance analysis (BIA), and compared to 1760 healthy volunteers matched for age and height, and further compared to FFM and BF percentiles, previously determined in 5225 healthy adults. Results:The prevalence of FFM Po10 was greater in patients than controls.The prevalence of albumino35 g/l (14.9% and 11.2% in Geneva and Berlin patients, respectively) and BMIo20.0 kg/m 2 was lower than the prevalence of low FFM (31.3% and 17.3%, respectively).The prevalence of high BF in Berlin patients was three-fold the prevalence of volunteers. Twelve and twenty percent of Geneva and Berlin patients, respectively, with normal BMI had high BF, compared to 4% of volunteers. Conclusions: Geneva and Berlin patients had lower FFM and higher BF than age-and height-matched volunteers and a higher prevalence of low FFM and high BF. Serum albumin and BMI underestimated the prevalence of malnutrition in patients at hospital admission. Body composition measurements identi¢ed patients with low FFM and low or high BF reserves.

Systems analysis of bioenergetics and growth of the extreme halophile Halobacterium salinarum

Halobacterium salinarum is a bioenergetically flexible, halophilic microorganism that can generate energy by respiration, photosynthesis, and the fermentation of arginine. In a previous study, using a genome-scale metabolic model, we have shown that the archaeon unexpectedly degrades essential amino acids under aerobic conditions, a behavior that can lead to the termination of growth earlier than necessary. Here, we further integratively investigate energy generation, nutrient utilization, and biomass production using an extended methodology that accounts for dynamically changing transport patterns, including those that arise from interactions among the supplied metabolites. Moreover, we widen the scope of our analysis to include phototrophic conditions to explore the interplay between different bioenergetic modes. Surprisingly, we found that cells also degrade essential amino acids even during phototropy, when energy should already be abundant. We also found that under both conditions considerable amounts of nutrients that were taken up were neither incorporated into the biomass nor used as respiratory substrates, implying the considerable production and accumulation of several metabolites in the medium. Some of these are likely the products of forms of overflow metabolism. In addition, our results also show that arginine fermentation, contrary to what is typically assumed, occurs simultaneously with respiration and photosynthesis and can contribute energy in levels that are comparable to the primary bioenergetic modes, if not more. These findings portray a picture that the organism takes an approach toward growth that favors the here and now, even at the cost of longer-term concerns. We believe that the seemingly "greedy" behavior exhibited actually consists of adaptations by the organism to its natural environments, where nutrients are not only irregularly available but may altogether be absent for extended periods that may span several years. Such a setting probably predisposed the cells to grow as much as possible when the conditions become favorable

A Memetic Algorithm for Community Detection in Complex Networks

Community detection is an important issue in the field of complex networks. Modularity is the most popular partition-based measure for community detection of networks represented as graphs. We present a hybrid algorithm mixing a dedicated crossover operator and a multi-level local optimization procedure. Experimental evaluations on a set of 11 well-known benchmark graphs show that the proposed algorithm attains easily all the current best solutions and even improves 6 of them in terms of maximum modularity