Evidence that human cardiac allograft acceptance is associated with a decrease in donor-reactive helper T lymphocytes

We have reported that acute cardiac allograft rejection is associated with increased numbers of donor-reactive helper T lymphocytes (HTL) in the peripheral blood of patients. Further, increased frequencies of circulating donor-reactive HTL may predict allograft rejection episodes diagnosed by endomyocardial biopsy. The present study evaluates the relationship between donor-reactive HTL and allograft "acceptance" in cardiac transplant recipients bearing long-term allografts (> 1 year). Patients were categorized as either long-term acceptors or persistent rejecters based on the number of rejection episodes and the ability to withdraw steroid therapy. Limiting dilution analysis for IL-2-producing HTL was utilized, with cadaver donor splenocytes as a source of donor alloantigens. Donor-reactive HTL frequencies were determined from peripheral blood samples obtained before transplant, and at 1 month and 1 year after transplant. Individuals who accommodated their allografts and were withdrawn from steroid therapy had reduced numbers of donor-reactive HTL at 1 year after transplant as compared with earlier time points. Further, PBMC obtained from these individuals at 1 year after transplant responded weakly to donor alloantigens in a mixed lymphocyte response (MLR). This relationship between donor-reactive HTL and allograft accommodation was exemplified in a cardiac/liver transplant patient who was diagnosed with progressive multifocal leukoencephalopathy and removed from all immunosuppression. No subsequent rejection episodes were diagnosed. Donor-reactive HTL were not detectable and this individual failed to mount an MLR to donor alloantigens. However, a vigorous donor-reactive response was observed when MLR cultures were supplemented with exogenous IL-2. Therefore, nonresponsiveness to the allograft appeared to be due to a deficit in IL-2 production. In contrast, patients who experienced persistent rejection episodes and required continued steroid therapy maintained large numbers of donor-reactive HTL at 1 year after transplant. PBMC from these individuals responded vigorously to donor alloantigens in an MLR. Hence, monitoring donor-reactive HTL may identify individuals who have accommodated their graft and may tolerate a reduction in immunosuppression.     

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.     

Unwrapping of Digital Speckle-Pattern Interferometry Phase Maps by use of a Minimum L(0)-Norm Algorithm

The performance of a minimum L(0)-norm unwrapping algorithm is investigated by use of synthetic digital speckle-pattern interferometry (DSPI) wrapped phase maps that simulate experimentally obtained data. This algorithm estimates its own weights to mask inconsistent pixels. Particular features usually included in DSPI wrapped phase distributions, such as shears, speckle noise, fringe cuts, object physical limits, and superimposed phase maps, are analyzed. Some adequate approaches to solving these features are discussed. Finally, it is shown that a complex case in which shears and fringe cuts coexist in the wrapped phase cannot be solved satisfactorily with the minimum L(0)-norm algorithm by itself. To cope with this problem, we propose a new scheme.     

Effects of heating in air and chlorine atmosphere on the crystalline structure of pure Ta2O5 or mixed with carbon

Structure changes undergone by pure amorphous hydrated tantalum oxide mixed with different types of carbon when heated in air or chlorine atmospheres were monitored by X-ray diffraction (XRD) and scanning electronic microscopy (SEM). Heating in air of pure Ta2O5 causes the appearance of the hexagonal structure -Ta2O5 at 973 K and the ortho-rhombic structure -Ta2O5 at 1173 K. Heating in chlorine atmosphere markedly lowers the temperature at which transformation to the orthorhombic phase occurs. This effect is attributed to recrystallization of tantalum oxide from tantalum chloride and oxygen, both in gaseous phase, formed in a previous chlorination step of the amorphous oxide. When the thermal treatment is performed in chlorine atmosphere the presence of carbon permits the detection of the hexagonal form at 753 K; this temperature varies with the type of carbon and the oxide : carbon ration. © 1998 Kluwer Academic Publishers     

The distributed permutation flowshop scheduling problem

This paper studies a new generalization of the regular permutation flowshop scheduling problem (PFSP) referred to as the distributed permutation flowshop scheduling problem or DPFSP. Under this generalization, we assume that there are a total of F identical factories or shops, each one with m machines disposed in series. A set of n available jobs have to be distributed among the F factories and then a processing sequence has to be derived for the jobs assigned to each factory. The optimization criterion is the minimization of the maximum completion time or makespan among the factories. This production setting is necessary in today's decentralized and globalized economy where several production centers might be available for a firm. We characterize the DPFSP and propose six different alternative mixed integer linear programming (MILP) models that are carefully and statistically analyzed for performance. We also propose two simple factory assignment rules together with 14 heuristics based on dispatching rules, effective constructive heuristics and variable neighborhood descent methods. A comprehensive computational and statistical analysis is conducted in order to analyze the performance of the proposed methods.     

Two-stage cascaded classification approach based on genetic fuzzy learning for speech/music discrimination

Automatic discrimination of speech and music is an important tool in many multimedia applications. The paper presents a robust and effective approach for speech/music discrimination, which relies on a two-stage cascaded classification scheme. The cascaded classification scheme is composed of a statistical pattern recognition classifier followed by a genetic fuzzy system. For the first stage of the classification scheme, other widely used classifiers, such as neural networks and support vector machines, have also been considered in order to assess the robustness of the proposed classification scheme. Comparison with well-proven signal features is also performed. In this work, the most commonly used genetic learning algorithms (Michigan and Pittsburgh) have been evaluated in the proposed two-stage classification scheme. The genetic fuzzy system gives rise to an improvement of about 4% in the classification accuracy rate. Experimental results show the good performance of the proposed approach with a classification accuracy rate of about 97% for the best trial.     

Graphical versus textual software measurement modelling: an empirical study

Model-driven Engineering (MDE) has attained great importance in both the Software Engineering industry and the research community, where it is now widely used to provide a suitable approach with which to improve productivity when developing software artefacts. In this scenario, measurement models (software artefacts) have become a fundamental point in improvement of productivity, where MDE and Software Measurement can reap mutual benefits. MDE principles and techniques can be used in software measurement to build more automatic and generic solutions, and to achieve this, it is fundamental to be able to develop software measurement models. To facilitate this task, a domain-specific language named “Software Measurement Modelling Language” (SMML) has been developed. This paper tackles the question of whether the use of SMML can assist in the definition of software measurement models. An empirical study was conducted, with the aim of verifying whether SMML makes it easier to construct measurement models which are more usable and maintainable as regards textual notation. The results show that models which do not use the language are more difficult—in terms of effort, correctness and efficiency—to understand and modify than those represented with SMML. Additional feedback was also obtained, to verify the suitability of the graphical representation of each symbol (element or relationship) of SMML.     

Size-reduction heuristics for the unrelated parallel machines scheduling problem

In this paper we study the unrelated parallel machines problem where n independent jobs must be assigned to one out of m parallel machines and the processing time of each job differs from machine to machine. We deal with the objective of the minimisation of the maximum completion time of the jobs, usually referred to as makespan or C_max. This is a type of assignment problem that has been frequently studied in the scientific literature due to its many potential applications. We propose a set of metaheuristics based on a size-reduction of the original assignment problem that produce solutions of very good quality in a short amount of time. The underlying idea is to consider only a few of the best possible machine assignments for the jobs and not all of them. The results are simple, yet powerful methods. We test the proposed algorithms with a large benchmark of instances and compare them with current state-of-the-art methods. In most cases, the proposed size-reduction algorithms produce results that are statistically proven to be better by a significant margin.