Evolution of the ATP-binding-cassette transmembrane transporters of vertebrates

The ATP-binding-cassette transmembrane transporters (ABC transporters) known from vertebrates belong to four major subfamilies: (1) the P- glycoproteins (Pgp); (2) the cystic fibrosis transmembrane conductance regulators (CFTR); (3) the Tap proteins encoded with the major histocompatibility complex of mammals; and (4) the peroxisomal membrane proteins. Both Pgp and CFTR have a structure suggesting a past internal gene duplication; a phylogenetic analysis indicated that these duplications occurred independently, while an independent tandem gene duplication occurred in the case of the Tap family. Both the Pgp and Tap proteins show evidence of relationship to bacterial ABC transporters lacking internal duplication, and both are significantly more closely related to the HlyB and MsbA families of transporters from purple bacteria than they are to ABC transporters from nonpurple bacteria. The simplest hypothesis to explain this observation is that eukaryotic Pgp and Tap genes are descended from a mitochondrial gene or genes that were subsequently translocated to the nuclear genome. The Pgp genes of eukaryotes are characterized by a remarkable degree of convergent evolution between the ATP-binding cassettes of their N- terminal and C-terminal halves, whereas no such convergence is seen between the two halves of CFTR genes or between the duplicated Tap genes. Exon 13 of the CFTR gene, which encodes a putative regulatory domain not found in other ABC transporters apart from CFTR, showed high levels of both synonymous and nonsynonymous difference in comparisons among different mammalian species, suggesting that this region is a mutational hot spot.      

Evidence for the presence of β-lactamase inStreptomyces glaucescens and its inhibition by sodium clavulanate

Streptomyces glaucescens is shown to possess -lactamase activity which is inhibitable by clavulanate. This is important in regard to its use as a cloning host for enzymes of \-lactam biosynthesis.     

Three-Dimensional Trabecular Alignment Model

The Shear-slip Mesh Update Method (SSMUM) is being used in flow simulations involving large but regular displacements of one or more boundaries of the computational domain. We follow up the earlier discussion of the method with notes on practical implementation aspects. In order to establish a benchmark problem for this class of flow problems, we define and report results from a two-dimensional viscous flow around a rotating stirrer in a square chamber. The application potential of the method is demonstrated in the context of biomedical design problem, as we perform an analysis of blood flow in a centrifugal left ventricular assist device, or blood pump, which involves a rotating impeller in a non-axisymmetric housing.     

Impairment in Task-Specific Modulation of Muscle Coordination Correlates with the Severity of Hand Impairment following Stroke

Significant functional impairment of the hand is commonly observed in stroke survivors. Our previous studies suggested that the inability to modulate muscle coordination patterns according to task requirements may be substantial after stroke, but these limitations have not been examined directly. In this study, we aimed to characterize post-stroke impairment in the ability to modulate muscle coordination patterns across tasks and its correlation with hand impairment. Fourteen stroke survivors, divided into a group with severe hand impairment (8 subjects) and a group with moderate hand impairment (6 subjects) according to their clinical functionality score, participated in the experiment. Another four neurologically intact subjects participated in the experiment to serve as a point of comparison. Activation patterns of nine hand and wrist muscles were recorded using surface electromyography while the subjects performed six isometric tasks. Patterns of covariation in muscle activations across tasks, i.e., muscle modules, were extracted from the muscle activation data. Our results showed that the degree of reduction in the inter-task separation of the multi-muscle activation patterns was indicative of the clinical functionality score of the subjects (mean value = 26.2 for severely impaired subjects, 38.1 for moderately impaired subjects). The values for moderately impaired subjects were much closer to those of the impaired subjects (mean value = 46.1). The number of muscle modules extracted from the muscle activation patterns of a subject across six tasks, which represents the degree of motor complexity, was found to be correlated with the clinical functionality score (R = 0.68). Greater impairment was also associated with a change in the muscle module patterns themselves, with greater muscle coactivation. A substantial reduction in the degrees-of-freedom of the multi-muscle coordination post-stroke was apparent, and the extent of the reduction, assessed by the stated metrics, was strongly associated with the level of clinical impairment.     

CURRICULUM GUIDE FOR RESEARCH ETHICS WORKSHOPS FOR COUNTRIES IN THE MIDDLE EAST

To help ensure the ethical conduct of research, many have recommended educational efforts in research ethics to investigators and members of research ethics committees (RECs). One type of education activity involves multi‐day workshops in research ethics. To be effective, such workshops should contain the appropriate content and teaching techniques geared towards the learning styles of the targeted audiences. To ensure consistency in content and quality, we describe the development of a curriculum guide, core competencies and associated learning objectives and activities to help educators organize research ethics workshops in their respective institutions. The curriculum guide is divided into modular units to enable planners to develop workshops of different lengths and choose content materials that match the needs, abilities, and prior experiences of the target audiences. The content material in the curriculum guide is relevant for audiences in the Middle East, because individuals from the Middle East who participated in a Certificate Program in research ethics selected and developed the training materials (e.g., articles, powerpoint slides, case studies, protocols). Also, many of the activities incorporate active‐learning methods, consisting of group work activities analyzing case studies and reviewing protocols. The development of such a workshop training curriculum guide represents a sustainable educational resource to enhance research ethics capacity in the Middle East.     

Polymorphism and evolution in the constant region of the T-cell receptor beta chain in an advanced teleost fish

Sequence, PCR and Southern data are presented as evidence that, as in mammals, two gene loci encode C regions of the TCR beta chain in the bicolor damselfish, Stegastes partitus. The loci are distinguished by an insertion of ten amino acids in the c-d loop at one locus and by a high interlocus divergence of the third intron and fourth exon sequences. Unlike their mammalian counterparts, the damselfish TCRBC genes encode highly polymorphic regions. None of the eight complete cDNA or four partial genomic DNA sequences presented from a single animal are identical; and three of the four animals examined are heterozygous at both loci, suggesting high heterozygosity in the damselfish population. Coding regions of the eight cDNA clones differ by up to 12% at the DNA level and 23% at the amino acid level. Polymorphism is concentrated primarily in the less evolutionarily conserved regions, suggesting that this variation may be selectively neutral. However, a comparison of the variation between synonymous and non-synonymous sites suggests that at least a portion of the observed variation results from selection. As in mammals, a gradient of sequence homogenization between the two loci is observed. Data presented here suggest that both interlocus homogenization and the sharing of polymorphic segments are likely achieved by partial gene conversion.     

Simulation of the Seated Postural Stability of Healthy and Spinal Cord-Injured Subjects Using Optimal Feedback Control Methods

A two-dimensional, biomechanical computer model was developed, using the software package Working Model(TM), to simulate the postural control of seated individuals. Both able-bodied and spinal cord-injured subjects were represented. The model incorporated active control of the upper body through full-state feedback. Specifically, a linear quadratic regulator scheme was implemented in the model. Nonlinearities were included in the torque computations to mimic physiological constraints and disability. Interactions between the subject and the wheelchair were also included in the model. Simulation results were compared with those obtained from experiments in which the subjects had attempted to remain stable during the application of significant disturbance moments, similar to those experienced during braking in a vehicle. While subjects exhibited more complex control schemes, the model was able to simulate overall stability. Therefore, it is believed that the model could prove beneficial to future research examining the effects of various restraints on stability.     

Phylogenetic tests of the hypothesis of block duplication of homologous genes on human chromosomes 6, 9, and 1

There are 10 gene families that have members on both human chromosome 6 (6p21.3, the location of the human major histocompatibility complex [MHC]) and human chromosome 9 (mostly 9q33-34). Six of these families also have members on mouse chromosome 17 (the mouse MHC chromosome) and mouse chromosome 2. In addition, four of these families have members on human chromosome 1 (1q21-25 and 1p13), and two of these have members on mouse chromosome 1. One hypothesis to explain these patterns is that members of the 10 gene families of human chromosomes 6 and 9 were duplicated simultaneously as a result of polyploidization or duplication of a chromosome segment ("block duplication"). A subsequent block duplication has been proposed to account for the presence of representatives of four of these families on human chromosome 1. Phylogenetic analyses of the 9 gene families for which data were available decisively rejected the hypothesis of block duplication as an overall explanation of these patterns. Three to five of the genes on human chromosomes 6 and 9 probably duplicated simultaneously early in vertebrate history, prior to the divergence of jawed and jawless vertebrates, and shortly after that, all four of the genes on chromosomes 1 and 9 probably duplicated as a block. However, the other genes duplicated at different times scattered over at least 1.6 billion years. Since the occurrence of these clusters of related genes cannot be explained by block duplication, one alternative explanation is that they cluster together because of shared functional characteristics relating to expression patterns.