How evolution makes proteins fold quickly

Sequences of fast-folding model proteins (48 residues long on a cubic lattice) were generated by an evolution-like selection toward fast folding. We find that fast-folding proteins exhibit a specific folding mechanism in which all transition state conformations share a smaller subset of common contacts (folding nucleus). Acceleration of folding was accompanied by dramatic strengthening of interactions in the folding nucleus whereas average energy of nonnucleus interactions remained largely unchanged. Furthermore, the residues involved in the nucleus are the most conserved ones within families of evolved sequences. Our results imply that for each protein structure there is a small number of conserved positions that are key determinants of fast folding into that structure. This conjecture was tested on two protein superfamilies: the first having the classical monophosphate binding fold (CMBF; 98 families) and the second having type-III repeat fold (47 families). For each superfamily, we discovered a few positions that exhibit very strong and statistically significant "conservatism of conservatism"-amino acids in those positions are conserved within every family whereas the actual types of amino acids varied from family to family. Those amino acids are in spatial contact with each other. The experimental data of Serrano and coworkers [Lopez-Hernandez, E. & Serrano, L. (1996) Fold. Des. (London) 1, 43-55]. for one of the proteins of the CMBF superfamily (CheY) show that residues identified this way indeed belong to the folding nucleus. Further analysis revealed deep connections between nucleation in CMBF proteins and their function.     

Comparison of molecular changes in lung cancers in HIV-positive and HIV-indeterminate subjects

CONTEXT: Human immunodeficiency virus (HIV) infection has been associated with an increasing incidence of malignancy, and HIV-infected persons have an increased incidence of primary lung carcinoma compared with the general population. OBJECTIVE: To investigate the molecular changes present in HIV-associated lung tumors and compare them with those present in lung carcinomas arising in HIV-indeterminate subjects ("sporadic tumors"). DESIGN: Convenience sample. SUBJECTS: Archival tissues from 11 HIV-positive persons and from 35 persons of indeterminate HIV status. SETTING: University-based medical centers and affiliated hospitals. MAIN OUTCOME MEASURES: Analysis of frequency of loss of heterozygosity (LOH) and microsatellite alteration (MA) using polymerase chain reaction and 16 polymorphic microsatellite markers at 8 chromosomal regions frequently deleted in lung cancer. Presence of HIV and human papillomavirus (HPV) sequences. RESULTS: The overall frequency of LOH at all chromosomal regions tested and the frequencies at most of the individual regions were similar in the 2 groups. Frequency of MA present in the HIV-associated tumors (0.18) was 6-fold higher than in sporadic tumors (0.03) (P<.001). At least 1 MA was present in 10 (91%) of 11 HIV-associated tumors vs 17 (48%) of 35 sporadic tumors (P=.02). Molecular changes were independent of tumor stage and gender. HIV and HPV sequences were not detected in the HIV-associated lung carcinomas. CONCLUSIONS: Microsatellite alterations, which reflect widespread genomic instability, occur at greatly increased frequency in HIV-associated lung carcinomas. Although the mechanism underlying the development of increased MAs is unknown, it may play a crucial role in the development of many HIV-associated tumors.     

Longitudinal assessment of inpatient use and functioning of seriously mentally ill veterans with and without co-occurring substance use disorders

Within a fungal species, a subset of individuals may have more than the minimal complement of chromosomes. If the extra chromosomes are composed primarily of DNA not found in all representatives of the species, they are most appropriately referred to as supernumerary chromosomes. The patterns of repeated DNA sequences on certain supernumerary chromosomes suggest that they have a different evolutionary history from the essential chromosomes in the same genome. Supernumerary chromosomes can carry functional genes and, in at least two fungal species, genes on such chromosomes play important roles in host-pathogen interactions. Supernumerary chromosomes that confer an adaptive advantage in certain habitats, such as the ability to cause disease on a specific host, may be referred to as "conditionally dispensable" chromosomes in order to reflect their importance in some, but not all, growth conditions. In addition to describing the structural and functional characteristics of known supernumerary chromosomes in fungi, this review discusses the relative merits of the terms that have been used to describe them, and establishes experimental criteria for their identification.     

Assessing information quality of e-learning systems: a web mining approach

E-learning systems provide a promising solution as an information exchanging channel. Improved technologies could mean faster and easier access to information but do not necessarily ensure the quality of this information; for this reason it is essential to develop valid and reliable methods of quality measurement and carry out careful information quality evaluations. This paper proposes an assessment model for information quality in e-learning systems based on the quality framework we proposed previously: the proposed framework consists of 14 quality dimensions grouped in three quality factors: intrinsic, contextual representation and accessibility. We use the relative importance as a parameter in a linear equation for the measurement scheme. Formerly, we implemented a goal-question-metrics approach to develop a set of quality metrics for the identified quality attributes within the proposed framework. In this paper, the proposed metrics were computed to produce a numerical rating indicating the overall information quality published in a particular e-learning system. The data collection and evaluation processes were automated using a web data extraction technique and results on a case study are discussed. This assessment model could be useful to e-learning systems designers, providers and users as it provides a comprehensive indication of the quality of information in such systems.     

Using visual design experts in critique-based evaluation of 2D vector visualization methods

We describe an experiment in which art and illustration experts evaluated six 2D vector visualization methods. We found that these expert critiques mirrored previously recorded experimental results; these findings support that using artists, visual designers and illustrators to critique scientific visualizations can be faster and more productive than quantitative user studies. Our participants successfully evaluated how well the given methods would let users complete a given set of tasks. Our results show a statistically significant correlation with a previous objective study: designers' subjective predictions of user performance by these methods match users measured performance. The experts improved the evaluation by providing insights into the reasons for the effectiveness of each visualization method and suggesting specific improvements.     

Influence of patient caregivers on course of patient illness: "expressed emotion" and alternative measures

The influence of the quality of care that patients receive during the course of their illness has been the subject of special scrutiny in the area of mental health. The concept of "expressed emotion" (EE) evolved in an effort to understand the impact of family and social environment on the vulnerability to relapse of schizophrenic patients. A semistructured interview, the Camberwell Family Interview, was developed to assess expressed emotion. This article examines the historical context, generalizability, methodological strengths and limitations of the construct of EE and the Camberwell Family Interview, as well as the nature and effects of treatment intervention programs designed to neutralize adverse effects of patient caretaker attitudes.     

Reduction of disulfide bonds in an amyloidogenic Bence Jones protein leads to formation of "amyloid-like" fibrils in vitro

Motivated by the finding that the amino acid sequence of the Bence Jones protein BJP-DIA was identical to that of the main protein component of the amyloid fibrils obtained from the same patient with AL-amyloidosis, (Klafki, H.-W., Kratzin, H.-D., Pick, A.-I., Eckart, K., Karas, M. & Hilschmann, N. (1992) Biochemistry 31, 3265-3272.), we attempted to create "amyloid-like" fibrils from the Bence Jones protein in vitro, without addition of proteolytic enzymes. Reduction of BJP-DIA, solubilized in PBS, pH 7.4, overnight at 37 degrees C resulted in the formation of a precipitate which had affinity for the dye Congo red. Electron microscopy of negatively stained samples of the reduced protein revealed aggregates of linear unbranched fibrils. SDS-polyacrylamide gel electrophoresis demonstrated that the precipitate consisted almost exclusively of intact light chain molecules. This result makes it possible to deduce a molecular model of these amyloid fibrils generated in vitro.     

Muscle proton T2 relaxation times and work during repetitive maximal voluntary exercise

We studied the effects of progressive maximal voluntary handgrip contractions (MVCs) on muscle proton spin-spin (T2) relaxation times and work, measured as the integrated force vs. time curve (FTI). Six healthy volunteers performed 10, 20, 40, and 80 MVCs in a 0.35-T magnet on four separate occasions. Repeated measures analyses of variance of increases in T2 and FTI during successive bouts were significant (P < 0.005 and P < 0.001, respectively). FTI increased with successive bouts to a greater extent than did muscle T2 (P < 0.05). For T2, the Helmert contrast judged the 10-MVC response lower than the mean of the remaining responses (P < 0.005), and the differences between all others compared with the means of subsequent responses were not significant, indicating a "flattening" of the T2 response after the increase from 10 to 20 repetitions. For FTI, all the single degree of freedom Helmert contrasts were significant (P < 0.001), indicating a continual increase in response over increased MVCs. The curved nature of the T2 response conformed best to a hyperbolic function, suggesting that a limit of approximately 32% exists for the change in T2 during progressively longer bouts of MVCs. A limit in the T2 response is consistent with the existence of a limit in the amount of water that muscle can take up from the vasculature during exertion.     

The smooth (tractor) operator: insights of knowledge engineering

The design of and training for complex systems requires in-depth understanding of task demands imposed on users. In this project, we used the knowledge engineering approach (Bowles et al., 2004) to assess the task of mowing in a citrus grove. Knowledge engineering is divided into four phases: (1) Establish goals. We defined specific goals based on the stakeholders involved. The main goal was to identify operator demands to support improvement of the system. (2) Create a working model of the system. We reviewed product literature, analyzed the system, and conducted expert interviews. (3) Extract knowledge. We interviewed tractor operators to understand their knowledge base. (4) Structure knowledge. We analyzed and organized operator knowledge to inform project goals. We categorized the information and developed diagrams to display the knowledge effectively. This project illustrates the benefits of knowledge engineering as a qualitative research method to inform technology design and training.