Broca's Region: Novel Organizational Principles and Multiple Receptor Mapping

There is a considerable contrast between the various functions assigned to Broca''s region and its relatively simple subdivision into two cytoarchitectonic areas (44 and 45). Since the regional distribution of transmitter receptors in the cerebral cortex has been proven a powerful indicator of functional diversity, the subdivision of Broca''s region was analyzed here using a multireceptor approach. The distribution patterns of six receptor types using in vitro receptor autoradiography revealed previously unknown areas: a ventral precentral transitional cortex 6r1, dorsal and ventral areas 44d and 44v, anterior and posterior areas 45a and 45p, and areas op8 and op9 in the frontal operculum. A significant lateralization of receptors was demonstrated with respect to the cholinergic M₂ receptor, particularly in area 44v+d. We propose a new concept of the anterior language region, which elucidates the relation between premotor cortex, prefrontal cortex, and Broca''s region. It offers human brain homologues to the recently described subdivision of area 45, and the segregation of the ventral premotor cortex in macaque brains. The results provide a novel structural basis of the organization of language regions in the brain.     

Protein Stability and Dynamics Modulation: The Case of Human Frataxin

Frataxin (FXN) is an α/β protein that plays an essential role in iron homeostasis. Apparently, the function of human FXN (hFXN) depends on the cooperative formation of crucial interactions between helix α1, helix α2, and the C-terminal region (CTR) of the protein. In this work we quantitatively explore these relationships using a purified recombinant fragment hFXN90–195. This variant shows the hydrodynamic behavior expected for a monomeric globular domain. Circular dichroism, fluorescence, and NMR spectroscopies show that hFXN90–195 presents native-like secondary and tertiary structure. However, chemical and temperature induced denaturation show that CTR truncation significantly destabilizes the overall hFXN fold. Accordingly, limited proteolysis experiments suggest that the native-state dynamics of hFXN90–195 and hFXN90–210 are indeed different, being the former form much more sensitive to the protease at specific sites. The overall folding dynamics of hFXN fold was further explored with structure-based protein folding simulations. These suggest that the native ensemble of hFXN can be decomposed in at least two substates, one with consolidation of the CTR and the other without consolidation of the CTR. Explicit-solvent all atom simulations identify some of the proteolytic target sites as flexible regions of the protein. We propose that the local unfolding of CTR may be a critical step for the global unfolding of hFXN, and that modulation of the CTR interactions may strongly affect hFXN physiological function.     

Human Population Dynamics: Cross-Disciplinary Perspectives

Human Population Dynamics: Cross-Disciplinary Perspectives. Helen Macbeth and Paul Collinson, eds. Cambridge: Cambridge University Press, 2002. 224 pp.     

The Evolutionary Dynamics of Human Influenza B Virus

Despite their close phylogenetic relationship, type A and B influenza viruses exhibit major epidemiological differences in humans, with the latter both less common and less often associated with severe disease. However, it is unclear what processes determine the evolutionary dynamics of influenza B virus, and how influenza viruses A and B interact at the evolutionary scale. To address these questions we inferred the phylogenetic history of human influenza B virus using complete genome sequences for which the date (day) of isolation was available. By comparing the phylogenetic patterns of all eight viral segments we determined the occurrence of segment reassortment over a 30-year sampling period. An analysis of rates of nucleotide substitution and selection pressures revealed sporadic occurrences of adaptive evolution, most notably in the viral hemagglutinin and compatible with the action of antigenic drift, yet lower rates of overall and nonsynonymous nucleotide substitution compared to influenza A virus. Overall, these results led us to propose a model in which evolutionary changes within and between the antigenically distinct 'Yam88' and 'Vic87' lineages of influenza B virus are the result of changes in herd immunity, with reassortment continuously generating novel genetic variation. Additionally, we suggest that the interaction with influenza A virus may be central in shaping the evolutionary dynamics of influenza B virus, facilitating the shift of dominance between the Vic87 and the Yam88 lineages.     

Analysing the Effect of Mutation on Protein Function and Discovering Potential Inhibitors of CDK4: Molecular Modelling and Dynamics Studies

The cyclin-dependent kinase 4 (CDK4)-cyclin D1 complex plays a crucial role in the transition from the G1 phase to S phase of the cell cycle. Among the CDKs, CDK4 is one of the genes most frequently affected by somatic genetic variations that are associated with various forms of cancer. Thus, because the abnormal function of the CDK4-cyclin D1 protein complex might play a vital role in causing cancer, CDK4 can be considered a genetically validated therapeutic target. In this study, we used a systematic, integrated computational approach to identify deleterious nsSNPs and predict their effects on protein-protein (CDK4-cyclin D1) and protein-ligand (CDK4-flavopiridol) interactions. This analysis resulted in the identification of possible inhibitors of mutant CDK4 proteins that bind the conformations induced by deleterious nsSNPs. Using computational prediction methods, we identified five nsSNPs as highly deleterious: R24C, Y180H, A205T, R210P, and R246C. From molecular docking and molecular dynamic studies, we observed that these deleterious nsSNPs affected CDK4-cyclin D1 and CDK4-flavopiridol interactions. Furthermore, in a virtual screening approach, the drug 5_7_DIHYDROXY_ 2_ (3_4_5_TRI HYDROXYPHENYL) _4H_CHROMEN_ 4_ONE displayed good binding affinity for proteins with the mutations R24C or R246C, the drug diosmin displayed good binding affinity for the protein with the mutation Y180H, and the drug rutin displayed good binding affinity for proteins with the mutations A205T and R210P. Overall, this computational investigation of the CDK4 gene highlights the link between genetic variation and biological phenomena in human cancer and aids in the discovery of molecularly targeted therapies for personalized treatment.     

The Degrees of Freedom Problem in Human Standing Posture: Collective and Component Dynamics

The experiment was setup to investigate the coordination and control of the degrees of freedom (DFs) of human standing posture with particular reference to the identification of the collective and component variables. Subjects stood in 3 postural tasks: feet side by side, single left foot quiet stance and single left foot stance with body rocking at the ankle joint in the sagittal plane. All three postural tasks showed very high coherence (∼1) of center of pressure (COP) - center of mass (COM) in the low frequency range. The ankle and hip coherence was mid range (∼.5) with the tasks having different ankle/hip compensatory cophase patterns. The findings support the view that the in-phase relation of the low frequency components of the COP-COM dynamic is the collective variable in the postural tasks investigated. The motions of the individual joints (ankle, knee, hip, neck) and couplings of pair wise joint synergies (e.g., ankle-hip) provide a supporting cooperative role to the preservation of the collective variable in maintaining the COM within the stability region of the base of support (BOS) and minimizing the amount of body motion consistent with the task constraint.     

An Interactive Model of Human and Companion Animal Dynamics: The Ecology and Economics of Dog Overpopulation and the Human Costs of Addressing the Problem

Companion animal overpopulation is a problem of human creation with significant human costs that can only be addressed through human action. A model was constructed to understand the dynamics of canine overpopulation and the effectiveness of various policy options for reducing euthanasia. The model includes economic and ecological factors in human and dog populations. According to the model, a no-kill society is an achievable goal at an acceptable human cost. Spay/neuter programs were generally found to be the most effective, with increasing adoptions also being an effective option. However, spay/neuter policies need to be evaluated over a very long time horizon since full impact may not be achieved for 30 years or more. Spay/neuter efforts can have a large impact even if they only effect a small portion of the human population. Adoption and spay/neuter programs were found to work well in combination, and to continue being effective as society approaches no-kill dynamics.     

Operational Principles for the Dynamics of the In Vitro ParA-ParB System

In many bacteria the ParA-ParB protein system is responsible for actively segregating DNA during replication. ParB proteins move by interacting with DNA bound ParA-ATP, stimulating their unbinding by catalyzing hydrolysis, that leads to rectified motion due to the creation of a wake of depleted ParA. Recent in vitro experiments have shown that a ParB covered magnetic bead can move with constant speed over a DNA covered substrate that is bound by ParA. It has been suggested that the formation of a gradient in ParA leads to diffusion-ratchet like motion of the ParB bead but how it forms and generates a force is still a matter of exploration. Here we develop a deterministic model for the in vitro ParA-ParB system and show that a ParA gradient can spontaneously form due to any amount of initial spatial noise in bound ParA. The speed of the bead is independent of this noise but depends on the ratio of the range of ParA-ParB force on the bead to that of removal of surface bound ParA by ParB. We find that at a particular ratio the speed attains a maximal value. We also consider ParA rebinding (including cooperativity) and ParA surface diffusion independently as mechanisms for ParA recovery on the surface. Depending on whether the DNA covered surface is undersaturated or saturated with ParA, we find that the bead can accelerate persistently or potentially stall. Our model highlights key requirements of the ParA-ParB driving force that are necessary for directed motion in the in vitro system that may provide insight into the in vivo dynamics of the ParA-ParB system.