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At least 1,063 records · Page 59Linked to original sources
PubMed1996

High-resolution solution structure of the EGF-like domain of heregulin-alpha.

The solution structure of the 63-residue heregulin-alpha (HRG-alpha) epidermal growth factor (EGF)-like domain, corresponding to residues 177-239 of HRG-alpha, has been determined to high resolution using data from two-dimensional and three-dimensional homo- and heteronuclear NMR spectroscopy. The structure is based on a total of 887 internuclear distance and dihedral restraints derived from data obtained using unlabeled and uniformly 15N-labeled protein samples, at pH 4.5, 20 degrees C. A total of 20 structures were calculated using a hybrid distance geometry-simulated annealing approach with the program DGII, followed by restrained molecular dynamics using the program DISCOVER. The average maximum violations are 0.12 +/- 0.01 angstroms and 1.4 +/- 0.3 degrees for distance and dihedral restraints, respectively. The backbone (N,C(alpha),C) atomic rms distribution about the mean coordinates for residues 3-23 and 31-49 is 0.29 +/- 0/07 angstroms. The N-and C-terminal residues (1-2 and 50-63) and 24-30 are disordered. Comparison of the HRG-alpha EGF-like domain structure with the previously determined structure of human EGF [Hommel et al. (1992) J. Mol. Biol. 227, 271-282] reveals a high degree of structural similarity; excluding the N-terminal region (residues 1-13), the disordered phi-loop region (residues 24-30) that contains a three-residue insertion in HRG-alpha relative to hEGF, and the disordered C-terminal region (residues 50-63), the C(alpha) alignment between the HRG-alpha and hEGF minimized mean structures has a rms difference of approximately 1 angstrom. In HRG-alpha the N-terminal residues 2-6 form a well-defined beta strand rather than being disordered as found for hEGF. This structural difference correlates with functional data which suggest that the N-terminal region of the HRG-alpha EGF-like domain is responsible for the observed receptor specificity differences between HRG-alpha and EGF.

Amino Acid Sequence↗
PubMed2004

Sequential rearrangements of the ensemble activity of putamen neurons in the monkey brain as a correlate of continuous behavior.

Simultaneous recordings were made of the spike activity of groups of 6-7 neurons in the putamen in two monkeys (Macaca nemestrina and Macaca mulatta) during performance of alternative spatial selection. Discriminant analysis was used to evaluate the magnitude of rearrangements in spike activity in groups of neurons during transitions from each step of the behavioral program to the next, along with the degree of differences in reactivity mosaics formed at each step in different versions of task execution. Rearrangements in spike activity were noted at all steps of the program. The dynamics of rearrangements on selection of the right and left feeders were different, leading to the appearance of significant differences in the reactivity mosaics at the decision-taking and reinforcement-receiving steps. The rearrangements preceding voluntary movement of one hand were more marked in the contralateral hemisphere. During performance of movements, the volume of rearrangements could increase, though differences in rearrangements accompanying movements of the right and left hands decreased. On receipt of reinforcement, rearrangements were greater when the animals selected a specified feeder (the left feeder) independently of which hemisphere was recorded.

Action Potentials↗
PubMed2026

Genomic and structural analysis of dacB variants associated with cephalosporin resistance in Pseudomonas aeruginosa.

The rise of resistance to fourth-generation cephalosporin in Pseudomonas aeruginosa (P. aeruginosa) is a global concern. The resistance is largely driven by variants of chromosomally encoded AmpC β-lactamase, known as Pseudomonas-derived cephalosporinase (PDC), which arise from the mutations in the ampC gene. In addition, alteration in dacB, which encode the penicillin-binding protein 4 (PBP4), can lead to the overexpression of ampC, thereby contributing to β-lactam resistance. Present work analyzed 208 clinical isolates of P. aeruginosa using whole-genome sequencing (WGS) and detected multiple nonsynonymous single nucleotide polymorphisms (nsSNPs), such as Y264C, G444D, and a double mutation (A394P-T428P). All nsSNPs were predicted to be deleterious by several prediction program. Molecular dynamics (MD) simulations suggested that these substitutions destabilize PBP4, increase structural flexibility, and contribute to the resistance mechanism, which favored their selection. To determine the effective therapeutics against these mutations, molecular docking was conducted with various antibiotics. Cefoperazone exhibited the highest binding affinity (-7.3 kcal/mol) among multiple PBP4 variants. The Molecular dynamics (MD) simulations and Molecular Mechanics Poisson Boltzmann Surface Area calculations (MMPBSA) further confirmed the favorable interactions between cefoperazone and PBP4 variants. In vitro MIC analyses supported these findings, indicating that cefoperazone displayed significant activity against clinical dacB mutants of P. aeruginosa. The study offers structural insight of dacB variants leading to antibiotic resistance and emphasizes the need to prioritize specific antibiotics to address the challenges arising from protein mutations.

Pseudomonas aeruginosa↗
PubMed2001

Static micromixers based on large-scale industrial mixer geometry.

Mixing liquids at the micro-scale is difficult because the low Reynolds numbers in microchannels and in microreactors prohibit the use of conventional mixing techniques based on mechanical actuators and induce turbulence. Static mixers can be used to solve this mixing problem. This paper presents micromixers with geometries very close to conventional large-scale static mixers used in the chemical and food-processing industry. Two kinds of geometries have been studied. The first type is composed of a series of stationary rigid elements that form intersecting channels to split, rearrange and combine component streams. The second type is composed of a series of short helix elements arranged in pairs, each pair comprised of a right-handed and left-handed element arranged alternately in a pipe. Micromixers of both types have been designed by CAD and manufactured with the integral microstereolithography process, a new microfabrication technique that allows the manufacturing of complex three-dimensional objects in polymers. The realized mixers have been tested experimentally. Numerical simulations of these micromixers using the computational fluid dynamics (CFD) program FLUENT are used to evaluate the mixing efficiency. With a low pressure drop and good mixing efficiency these truly three-dimensional micromixers can be used for mixing of reactants or liquids containing cells in many microTAS applications.

Journal Article↗
PubMed2004

CisModule: de novo discovery of cis-regulatory modules by hierarchical mixture modeling.

The regulatory information for a eukaryotic gene is encoded in cis-regulatory modules. The binding sites for a set of interacting transcription factors have the tendency to colocalize to the same modules. Current de novo motif discovery methods do not take advantage of this knowledge. We propose a hierarchical mixture approach to model the cis-regulatory module structure. Based on the model, a new de novo motif-module discovery algorithm, CisModule, is developed for the Bayesian inference of module locations and within-module motif sites. Dynamic programming-like recursions are developed to reduce the computational complexity from exponential to linear in sequence length. By using both simulated and real data sets, we demonstrate that CisModule is not only accurate in predicting modules but also more sensitive in detecting motif patterns and binding sites than standard motif discovery methods are.

Algorithms↗
PubMed2005

Activated mitofusin 2 signals mitochondrial fusion, interferes with Bax activation, and reduces susceptibility to radical induced depolarization.

Mitochondrial fusion in higher eukaryotes requires at least two essential GTPases, Mitofusin 1 and Mitofusin 2 (Mfn2). We have created an activated mutant of Mfn2, which shows increased rates of nucleotide exchange and decreased rates of hydrolysis relative to wild type Mfn2. Mitochondrial fusion is stimulated dramatically within heterokaryons expressing this mutant, demonstrating that hydrolysis is not requisite for the fusion event, and supporting a role for Mfn2 as a signaling GTPase. Although steady-state mitochondrial fusion required the conserved intermembrane space tryptophan residue, this requirement was overcome within the context of the hydrolysis-deficient mutant. Furthermore, the punctate localization of Mfn2 is lost in the dominant active mutants, indicating that these sites are functionally controlled by changes in the nucleotide state of Mfn2. Upon staurosporine-stimulated cell death, activated Bax is recruited to the Mfn2-containing puncta; however, Bax activation and cytochrome c release are inhibited in the presence of the dominant active mutants of Mfn2. The dominant active form of Mfn2 also protected the mitochondria against free radical-induced permeability transition. In contrast to staurosporine-induced outer membrane permeability transition, pore opening induced through the introduction of free radicals was dependent upon the conserved intermembrane space residue. This is the first evidence that Mfn2 is a signaling GTPase regulating mitochondrial fusion and that the nucleotide-dependent activation of Mfn2 concomitantly protects the organelle from permeability transition. The data provide new insights into the critical relationship between mitochondrial membrane dynamics and programmed cell death.

Animals↗
PubMed2000

Computational simulation of accumulation of expired air in the infant cot.

Accumulation and re-breathing of CO2 in expired air has been suggested as one possible explanation for the strong association between prone sleeping position and sudden infant death syndrome (SIDS). This preliminary study applying a modern computational fluid dynamics (CFD) program to simulate the aerodynamics in an infant cot supports the idea that accumulation of expired air may occur in the prone position. The literature dealing with the potential association between re-breathing of accumulated CO2 and SIDS is briefly reviewed.

Air↗
PubMed1985

Contraception for the adolescent.

The primary care physician is in an excellent position to counsel adolescents about contraception. However, an adequate understanding of the biologic and psychosocial development of this particular age-group is imperative. In addition, communication skills are necessary to advise adolescents on use of contraceptives. The goal in counseling the adolescent about sexuality is to instill a sense of sexual responsibility and to provide individualized instruction in selecting the appropriate birth control method. General factors to remember in selecting the proper method include motivation, moral-ethical responsibility, frequency of intercourse, side effects of the various contraceptive methods, and patient's preference.

Adolescent↗
PubMed1992

Institutional contexts and mortality: the case of Peru.

"This analysis examines the institutional context of infant mortality in Peru using economic, social, health care, and public health measures as indicators of development and equity. Using linked data from population and economic censuses, government agencies, and health surveys on twenty-four Peruvian provinces, I explore how economic development and institutional contexts influence health outcomes. Regional inequities based on rural population, subsistence activity, women's illiteracy, monthly income, Gross Domestic Product, medical care, and health facilities are compared. Then a cluster analysis identifies institutional contexts that have internal similarities.... My conclusion is that understanding regional inequities--defined in terms of economic development, social institutions, and health services--leads to enhanced explanations of disparities in health outcomes."

Americas↗
PubMed1996

Supporting children in need through a community-based orphan visiting programme.

There is an urgent need for programmes to be established to support the growing number of orphans in countries severely affected by AIDS. Most orphans are being cared for by extended families under difficult circumstances. Few descriptions of community-based orphan support programmes exist. We describe one such programme established in Zimbabwe in 1993. Twenty-five volunteers identified 300 orphan households. During one year, volunteers made 1725 home visits and 123 households received an average of $11 in material support or school fees. In 292 orphan households there were 702 orphans, 14.7% of children under 15 years in the area. The rate of parental deaths was increasing with 3.5% of households in the area having a parental death in 1994. Forty-five per cent of caregivers were grandparents and 33% of caregivers were over 60 years. Three per cent of orphans were cared for by adolescent siblings. The poorest orphan households were those in receipt of school fees, with out-of-school children or with an older sibling as caregiver. Community members initiated activities to help orphans. The programme described is targeted, effective and replicable. Community-based organizations such as local churches and women's groups can be mobilized to administer programmes which provide support to the poorest orphan households.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Migration: the limits of governmental control.

"The first issue addressed in the present article is why it is so difficult for governments to intervene successfully in migration processes. Within the analytical framework of the article, the point is made that the variables addressed by governmental measures form only a small part of the relevant variables. Addressing these variables effectively is further hampered by the conflicting interests of various economic sectors and by the conflicting roles various administrative institutions have defined for themselves. Finally the article addresses the question of whether a ¿root-cause' approach offers better prospects for the management of migration. This does not appear to be the case at the moment."

Demography↗