The driving force behind genomic diversity

Eukaryote genomes contain excessively introns, intergenic and other non-genic sequences that appear to have no vital functional role or phenotype manifestation. Their existence, a long-standing puzzle, is viewed from the principle of increasing entropy. According to thermodynamics of open systems, genomes evolve toward diversity by various mechanisms that increase, decrease and distribute genomic material in response to thermodynamic driving forces. Evolution results in an excessive genome, a high-entropy ecosystem of its own, where copious non-coding segments associate with low-level functions and conserved sequences code coordinated activities. The rate of entropy increase, equivalent to the rate of free energy decrease, is identified with the universal fitness criterion of natural selection that governs populations of genomic entities as well as other species.     

Molecular motors: Dynein's gearbox

A new optical trapping study shows that the stepsize of cytoplasmic dynein varies according to the applied force, suggesting that this motor can change gear. Complementary biochemical kinetic work on yeast dynein mutants hints at the allosteric mechanisms involved.     

Balint groups as a driving force of ego development

This paper gives an overview of one of the main components in the process of Balint groups. The paper is based on the authors' research on the work of Balint groups and the study of literature which deals with the development of ego and the role of Balint groups in the development of participants' ego. This field is of great interest to the Balint movement and education in medicine. The special place in the discussions on the Balint method is given to the issue of benefit and the nature of influence of the Balint groups on participants. The Balint movement is of special interest for Croatia since it was perhaps among the first in the world to introduce Balint seminars as an official part of education of family doctors. The Croatian Society of Balint Groups as early as in 1970's became a part of the International Federation of Balint Groups. Professor Betlheim was Michael Balint's friend and his followers introduced the method not only in medicine but also in other professions: social work, pedagogy, psychology, sociology etc. The Balint's method is also very interesting and useful to stomatologists, orthopedists and physiotherapists. Croatian dentists joined the Balint Groups in 1983 and orthopaedists in 1987. These were the unique cases in the European context. The Balint groups are very efficient and necessary in the process of strengthening ego and selfawareness of these professionals. The paper also discusses the increase of the doctor's self-awareness and self-consciousness during the process of training in the Balint Groups. The Balint Groups only insist on the doctor-patient relationship and do not interfere with the unconscious of the doctor's preoccupations. The approach of Enid Balint strives to find harmony between the Balint's approach and the psychoanalytic approach to the object of the research. According to her understanding, the development of the group atmosphere is similar to the one in the family. The authors reach a similar conclusion in their research.     

Molecular motors: kinesin's interesting limp

An ingenious new experiment used a form of kinesin with one slow head and one fast head to demonstrate definitively that this motor protein moves along a microtubule using alternating left and right steps.     

Molecular recognition templates of peptides: driving force for molecular evolution of peptide transporters

Small peptides derived from protein hydrolysis occur ubiquitously. To utilize these structurally diverse compounds, organisms possess generic peptide transporters for di- (Dpp), tri- (Tpp), and oligopeptides (Opp). Using conformational analysis, we describe the predominant conformers of di-, tri-, and oligopeptides in water; dipeptides occur as nine main groups, defined by specific combinations of torsional angles. The molecular recognition templates (MRTs) of substrates for Dpp and Tpp comprise distinct groups of dipeptide conformers plus folded tripeptide conformers with matching spatial distribution of recognition features; for Opp, the MRT involves specific oligopeptide conformers with extended backbones. For any peptide, the proportion of its conformers in a particular MRT correlates with its relative binding and transport by each transporter. Thus, peptide transporters have evolved complementary specificities to optimize utilization of the universal peptide pool. The general applicability of MRTs should facilitate rational design and targeting of peptide-based prodrugs.     

Molecular motors: Kinesin's string variable

A recent model suggests that the walking action of kinesin is due to a 13 residue 'fundamental engine' called the neck linker domain, which cyclically zips and unzips to the main part of the heads. New experiments confirm one prediction of the model: that crosslinking the neck linker to the head should block motility.     

Molecular motors in neuronal development, intracellular transport and diseases

Molecular motors such as kinesin superfamily proteins (KIFs), dynein superfamily proteins and myosin superfamily proteins have diverse and fundamental roles in many cellular processes, including neuronal development and the pathogenesis of neuronal diseases. During neuronal development, KIFs take significant roles in the regulation of axon-collateral branch extension, which is essential for brain wiring. Cytoplasmic dynein together with LIS1 takes pivotal roles in neocortical layer formation. In axons, anterograde transport is mediated by KIFs, whereas retrograde transport is mediated mainly by cytoplasmic dynein, and dysfunction of motors results in neurodegenerative diseases. In dendrites, the transport of NMDA and AMPA receptors is mediated by KIFs, and the motor has been shown to play a significant part in establishing learning and memory.     

Molecular motors: thermodynamics and the random walk

The biochemical cycle of a molecular motor provides the essential link between its thermodynamics and kinetics. The thermodynamics of the cycle determine the motor's ability to perform mechanical work, whilst the kinetics of the cycle govern its stochastic behaviour. We concentrate here on tightly coupled, processive molecular motors, such as kinesin and myosin V, which hydrolyse one molecule of ATP per forward step. Thermodynamics require that, when such a motor pulls against a constant load f, the ratio of the forward and backward products of the rate constants for its cycle is exp [-(DeltaG + u(0)f)/kT], where -DeltaG is the free energy available from ATP hydrolysis and u(0) is the motor's step size. A hypothetical one-state motor can therefore act as a chemically driven ratchet executing a biased random walk. Treating this random walk as a diffusion problem, we calculate the forward velocity v and the diffusion coefficient D and we find that its randomness parameter r is determined solely by thermodynamics. However, real molecular motors pass through several states at each attachment site. They satisfy a modified diffusion equation that follows directly from the rate equations for the biochemical cycle and their effective diffusion coefficient is reduced to D-v(2)tau, where tau is the time-constant for the motor to reach the steady state. Hence, the randomness of multistate motors is reduced compared with the one-state case and can be used for determining tau. Our analysis therefore demonstrates the intimate relationship between the biochemical cycle, the force-velocity relation and the random motion of molecular motors.     

Molecular motors: Kinesin's dynamically dockable neck

Kinesin is a molecular walking machine with two identical motor heads connected to a coiled-coil tail. Details of the coordination mechanism, which causes kinesin to walk directionally, and the tracking mechanism, which guides each detaching head to its next site on the microtubule, are beginning to emerge.     

Molecular motors: single-molecule recordings made easy

A fusion protein of kinesin and gelsolin binds a short actin filament which can be visualized using a standard fluorescence microscope. This technique has provided new insight into the mechanism of kinesin action, and in principle it can be extended to allow single-molecule assays of any protein.     

Molecular motors: strategies to get along

The majority of active transport in the cell is driven by three classes of molecular motors: the kinesin and dynein families that move toward the plus-end and minus-end of microtubules, respectively, and the unconventional myosin motors that move along actin filaments. Each class of motor has different properties, but in the cell they often function together. In this review we summarize what is known about their single-molecule properties and the possibilities for regulation of such properties. In view of new results on cytoplasmic dynein, we attempt to rationalize how these different classes of motors might work together as part of the intracellular transport machinery. We propose that kinesin and myosin are robust and highly efficient transporters, but with somewhat limited room for regulation of function. Because cytoplasmic dynein is less efficient and robust, to achieve function comparable to the other motors it requires a number of accessory proteins as well as multiple dyneins functioning together. This necessity for additional factors, as well as dynein's inherent complexity, in principle allows for greatly increased control of function by taking the factors away either singly or in combination. Thus, dynein's contribution relative to the other motors can be dynamically tuned, allowing the motors to function together differently in a variety of situations.     

Molecular dynamics simulation of mammalian 15S-lipoxygenase with AMBER force field

A molecular dynamics simulation study of mononuclear iron 15S-lipoxygenase (15S-LOX) from rabbit reticulocytes was performed to investigate its structure and dynamics; newly developed AMBER force field parameters were employed for the first coordination sphere of the catalytic iron (II). The results obtained from this study demonstrate that the structural features of the catalytic iron coordination site are in good agreement with available data obtained from experiments. The motional flexibility of the N-terminal β-barrel domain is greater than the C-terminal catalytic domain; flexibility was assessed in terms of B-factors and secondary structure calculations. The significant features obtained for the relative motional flexibility of these two domains of 15S-LOX in solution as well as the isolated C-terminal domain were analyzed in terms of radius of gyration and maximum diameter, which correlated well with the structural flexibility of 15-lipoxygenase-1 in solution as probed by small-angle X-ray scattering. The motional flexibility indicates interdomain motion between the N-terminal β-barrel and the C-terminal catalytic domain; this was further verified by the evaluation of central bending in the solvated LOX molecule, which identified an unstructured stretch of amino acids as the interdomain linker. The average bending angle confirmed significant central bending between these two domains, which was linked to the high degree of motional freedom of the N-terminal β-barrel domain in aqueous solutions. This can be considered to have biological relevance for membrane binding as well as for regulating the catalytic domain.     

Molecular motors of the bacterial flagella

The bacterial flagellum, which is responsible for motility, is a biological nanomachine consisting of a reversible rotary motor, a universal joint, a helical screw, and a protein export apparatus dedicated for flagellar assembly. The motor is fueled by an inward-directed electrochemical gradient of protons or sodium ions across the cytoplasmic membrane. The motor consists of a rotor, a drive shaft, a bushing, and about a dozen stator units. The flagellar protein export apparatus is located at the cytoplasmic side of the rotor. Interactions between the rotor and the stators and those between soluble and membrane components of the export apparatus are highly dynamic. The structures of flagellar basal body components including those of the export apparatus, being revealed at high resolution by X-ray crystallography and electron cryomicroscopy and cryotomography, are giving insights into their mechanisms.     

Inflammation: A driving force speeds cancer metastasis

It has been increasingly recognized that tumor microenvironment plays an important role in carcinogenesis. Inflammatory component is present and contributes to tumor proliferation, angiogenesis, metastasis, and resistance to hormonal and chemotherapy. This review highlights the role of inflammation in the tumor metastasis. We focus on the function of proinflammatory factors, particularly cytokines during tumor metastasis. Understanding of the mechanisms by which inflammation contributes to metastasis will lead to innovative approach for treating cancer.

How tumor spreads remains an enigma and has received great attention in recent years, as metastasis is the major cause of cancer mortality. The complex and highly selective metastatic cascade not only depends on the intrinsic properties of tumor cells but also the microenvironment that they derive from. An inflammatory milieu consisting of infiltrated immune cells and their secretory cytokines, chemokines, and growth factors contribute significantly to the invasive and metastatic traits of cancer cells. Here, we review new insights into the molecular pathways that link inflammation in the tumor microenvironment to metastasis.     

Membrane traffic: a driving force in cytokinesis

Dividing animal and plant cells maintain a constant chromosome content through temporally separated rounds of replication and segregation. Until recently, the mechanisms by which animal and plant cells maintain a constant surface area have been considered to be distinct. The prevailing view was that surface area was maintained in dividing animal cells through temporally separated rounds of membrane expansion and membrane invagination. The latter event, known as cytokinesis, produces two physically distinct daughter cells and has been thought to be primarily driven by actomyosin-based constriction. By contrast, membrane addition seems to be the primary mechanism that drives cytokinesis in plants and, thus, the two events are linked mechanistically and temporally. In this article (which is part of the Cytokinesis series), we discuss recent studies of a variety of organisms that have made a convincing case for membrane trafficking at the cleavage furrow being a key component of both animal and plant cytokinesis.