Inertial vestibular coding of motion: concepts and evidence

Central processing of inertial sensory information about head attitude and motion in space is crucial for motor control. Vestibular signals are coded relative to a non-inertial system, the head, that is virtually continuously in motion. Evidence for transformation of vestibular signals from head-fixed sensory coordinates to gravity-centered coordinates have been provided by studies of the vestibulo-ocular reflex. The underlying central processing depends on otolith afferent information that needs to be resolved in terms of head translation related inertial forces and head attitude dependent pull of gravity. Theoretical solutions have been suggested, but experimental evidence is still scarce. It appears, along these lines, that gaze control systems are intimately linked to motor control of head attitude and posture.     

Sensorimotor pathways processing vibratory signals from the femoral chordotonal organ of the stick insect

The femoral chordotonal organ of stick insects senses position and velocity of movements in the femur-tibia joint, as well as tibial vibration. While sensory information about large-scale tibial movements is processed by a well-known neuronal network and elicits resistance reflexes in extensor and flexor tibiae motoneurons, it is not yet known how sensory information about vibration of the tibia is processed. We investigated the transmission of vibration stimuli to tibial extensor motoneurons and their premotor interneurons. Vibration stimuli applied to the femoral chordotonal organ evoked responses in tibial extensor and flexor muscles. During ongoing vibration this response adapted rapidly. This adaptation had no effect on the motoneuronal response to large-scale tibial movements. Recording from premotor interneurons revealed that vibratory signals were processed in part by the same interneuronal pathways as (large-scale) velocity and position information. While only certain parts of the interneuronal reflex pathways showed little or no response during vibration stimuli, most neurons responded to both position or velocity stimuli and vibration at the femoral chordotonal organ. We conclude that sensory information about vibration of the tibia shares part of the interneuronal pathways that transmit sensory information about large-scale tibial movements to the motoneurons. Accepted: 25 April 1999     

Oligosaccharide receptors for bacteria: a view to a kill

Oligosaccharide recognition is a major means of bacterial—host cell attachment. Bacterial—host receptor binding can subvert host signaling pathways to cause pathology. In addition, pathogenic bacteria can utilize more than one recognition system to bind host cells. Recent studies of Helicobacter pylori illustrate both these points. Together with this redundancy in recognition, the importance of multivalent sugar binding has become apparent. Multivalent sugar receptor analogs have been used to both prevent and detach adherent bacteria. Several new chemical technologies for the generation of bioactive glycopolymers have been developed and may be successfully adapted to address both these issues.     

Motor function in microgravity: movement in weightlessness

Microgravity provides unique, though experimentally challenging, opportunities to study motor control. A traditional research focus has been the effects of linear acceleration on vestibular responses to angular acceleration. Evidence is accumulating that the high-frequency vestibulo-ocular reflex (VOR) is not affected by transitions from a 1 g linear force field to microgravity (<1 g); however, it appears that the three-dimensional organization of the VOR is dependent on gravitoinertial force levels. Some of the observed effects of microgravity on head and arm movement control appear to depend on the previously undetected inputs of cervical and brachial proprioception, which change almost immediately in response to alterations in background force levels. Recent studies of post-flight disturbances of posture and locomotion are revealing sensorimotor mechanisms that adjust over periods ranging from hours to weeks.     

Will combinatorial chemistry deliver real medicines?

Over the next decade, the impact of library synthesis will play a major role in shortening the lead optimization phase of drug discovery. The prognosis for combinatorial chemistry to discover fundamentally different new classes of therapeutically active small molecules against some of the more difficult biological targets is less certain. Expectations are high because the technology potentially allows us to sample available drug space by synthesizing all possible small molecule ligands (variously estimated to be between 10³⁰–10⁵⁰ compounds). Some caution is advised, however, since, despite recent increases in high-throughput screening of substantially greater numbers of synthetic compounds and natural products, we are not routinely finding a plethora of new structures. The outcome may be that combinatorial chemistry offers us the ability to work faster on finding ligands for well-established tractable targets, such as G-protein-coupled receptors, ion channels or proteases, rather than, say, the more complex protein—protein interactions which from the majority of targets in signal transduction pathways.     

The whole-body shortening reflex of the medicinal leech: motor pattern,sensory basis,and interneuronal pathways

The leech whole-body shortening reflex consists of a rapid contraction of the body elicited by a mechanical stimulus to the anterior of the animal. We used a variety of reduced preparations — semi-intact, body wall, and isolated nerve cord — to begin to elucidate the neural basis of this reflex in the medicinal leech Hirudo medicinalis. The motor pattern of the reflex involved an activation of excitatory motor neurons innervating dorsal and ventral longitudinal muscles (dorsal excitors and ventral excitors respectively), as well as the L cell, a motor neuron innervating both dorsal and ventral longitudinal muscles. The sensory input for the reflex was provided primarily by the T (touch) and P (pressure) types of identified mechanosensory neuron. The S cell network, a set of electrically-coupled interneurons which makes up a fast conducting pathway in the leech nerve cord, was active during shortening and accounted for the shortest-latency excitation of the L cells. Other, parallel, interneuronal pathways contributed to shortening as well. The whole-body shortening reflex was shown to be distinct from the previously described local shortening behavior of the leech in its sensory threshold, motor pattern, and (at least partially) in its interneuronal basis.Abbreviations conn connective - DE dorsal excitor motor neuron - DI dorsal inhibitor motor neuron - DP dorsal posterior nerve - DP:B1 dorsal posterior nerve branch 1 - DP:B2 dorsal posterior nerve branch 2 - MG midbody ganglion - VE ventral excitor motor neuron - VI ventral inhibitor motor neuron     

GEFs, GAPs, GDIs and effectors: taking a closer (3D) look at the regulation of Ras-related GTP-binding proteins

Cell biology depends on the interactions of macromolecules, such as protein—DNA, protein—protein or protein—nucleotide interactions. GTP-binding proteins are no exception to the rule. They regulate cellular processes as diverse as protein biosynthesis and intracellular membrane trafficking. Recently, a large number of genes encoding GTP-binding proteins and the proteins that interact witht these molecular switches have been cloned and expressed. The 3D structures of some of these have also been elucidated     

Coupling cell division and cell death to microtubule dynamics

The mitotic spindle is a self-organizing structure that is constructed primarily from microtubules. Among the most important spindle microtubules are those that bind to kinetochores and form the fibers along which chromosomes move. Chemotherapeutics such as taxol and the vinca alkaloids perturb kinetochore—microtubule attachment and disrupt chromosome segregation. This activates a checkpoint pathway that delays cell cycle progression and induces programmed cell death. Recent work has identified at least four mammalian spindle assembly checkpoint proteins.     

Two-component signal transduction systems in eukaryotic microorganisms

Conserved signal transduction pathways that use phosphorelay from histidine kinases through an intermediate transfer protein (H2) to response regulators have been found in a variety of eukaryotic microorganisms. Several of these pathways are linked to mitogen-activated protein kinase cascades. These networks control different physiological responses including osmoregulation, cAMP levels and cellular morphogenesis.     

SCF and APC: the Yin and Yang of cell cycle regulated proteolysis

Progression through the cell cycle requires the activity of two ubiquitination complexes, the Skp1—cullin—F-box-protein complex (SCF) and the anaphase-promoting complex/cyclosome (APC). Observations in the past year have revealed unexpected similarities between the SCF and the APC and have allowed detailed insight into the regulation of their activities. Both complexes are now known to exist in different forms that target different substrates for ubiquitin-dependent proteolysis.     

Computational approaches to molecular recognition

Recent advances in the computation of free energies have facilitated the understanding of host—guest and protein—ligand recognition. Rigorous perturbation methods have been assessed and expanded, and more approximate techniques have been developed that allow faster treatment of diverse systems.     

Zebrafish: tools for investigating cellular differentiation

Two recent large-scale genetic screens in zebrafish have identified many mutations that affect differentiation in a variety of organ systems, particularly the notochord, the neural crest and the blood. The combination of these newly identified mutations and well established embryological methods makes zebrafish uniquely suited among vertebrate experimental systems to simultaneously address the roles of specific genes and specific cell—cell interactions during differentiation.     

Protein-biotin interactions

The three-dimensional structures of several biotin-binding proteins are now known, giving insights into the molecular architecture of the binding sites for biotin. In combination with biochemical and computational approaches, these structural insights provide the basis for our present understanding of biotin—protein interactions which, in some cases, give rise to spectacular binding constants.     

A role for the cerebellum in the control of limb movement velocity

Accepting, rejecting or modifying the many different theories of the cerebellum's role in the control of movement requires an understanding of the signals encoded in the discharge of cerebellar neurons and how those signals are transformed by the cerebellar circuitry. Particularly challenging is understanding the sensory and motor signals carried by the two types of action potentials generated by cerebellar Purkinje cells, the simple spikes and complex spikes. Advances have been made in understanding this signal processing in the context of voluntary arm movements. Recent evidence suggests that mossy fiber afferents to the cerebellar cortex are a source of kinematic signals, providing information about movement direction and speed. In turn, the simple spike discharge of Purkinje cells integrates this mossy fiber information to generate a movement velocity signal. Complex spikes may signal errors in movement velocity. It is proposed that the cerebellum uses the signals carried by the simple and complex spike discharges to control movement velocity for both step and tracking arm movements.     

Dorsal-ventral signaling in limb development

In both Drosophila wings and vertebrate limbs, signaling between dorsal and ventral cells establishes an organizer that promotes limb formation. Significant progress has been made recently towards characterizing the signaling interactions that occur at the dorsal—ventral limb border. Studies of chicks have indicated that, as in Drosophila, this signaling process requires the participation of Fringe. Studies of Drosophila have indicated that Fringe functions by inhibiting the ability of Notch to be activated by one ligand, Serrate, while potentiating the ability of Notch to be activated by another ligand, Delta. Recent studies of both Drosophila and vertebrates have also shed new light on the signaling activity of the dorsal—ventral boundary limb organizer, and have highlighted how this organizer is maintained by feedback mechanisms with neighboring cells.     

Functions and structures of the motor cortices in humans

Humans and non-human primates have several motor areas. Exactly how many is a matter of current debate. A proper parcellation of motor areas must be based on correlated structural and functional differences. Recent studies indicate that the primary motor cortex may be, in reality, two areas (4a and 4p). Similarly, there are undoubtedly two or more cingulate motor areas and perhaps two supplementary motor areas. The homologies between human and monkey brains are striking in some cases, making monkey models of human motor cortices attractive. The doctrine of a strict ‘homuncular’ somatotopical organization of motor areas will have to be abandoned. The engagement of motor areas in different types of voluntary seems merely a matter of degree of activation rather than exclusive specific contributions.     

Liver stem cells: a two compartment system

Hepatocytes and biliary epithelia are phenotypically very dissimilar, but share a common ancestry. Hepatocytes regenerate very efficiently, and their division potential indicates that many of them are functional stem cells. When hepatocyte-damaging agents also impair the regenerative ability of surviving hepatocytes, a potential stem cell system of biliary origin is activated to generate new hepatocytes — a reversal of ontogeny. Now both bile duct derived cells and hepatocytes can be isolated from the liver, genetically modified in vitro and returned to their in vivo origins where, after considerable population expansion, they can function as hepatocytes — paving the way for ex vivo gene therapy.     

Cortical control of reaching movements

Recent studies provide further support for the hypothesis that spatial representations of limb position, target locations, and potential motor actions are expressed in the neuronal activity in parietal cortex. In contrast, precentral cortical activity more strongly expresses processes involved in the selection and execution of motor actions. As a general conceptual framework, these processes may be interpreted in terms of such formalisms as sensorimotor transformation and ‘internal models’.     

Escape behavior — brainstem and spinal cord circuitry and function

Recent work has demonstrated that the neural circuits mediating escape reactions in lower vertebrates and mammals have a common framework, with only two excitatory central synapses in the reflex arc. This relatively direct linkage from sense organs to muscles and the fact that segments of the network also transmit other motor commands help guarantee that escape always has priority over ongoing behaviors. Yet, modulation and plasticity contribute some variability to the expression of escape and, therefore, to the adequacy of its survival function.