Non-Lytic Antibacterial Peptides That Translocate Through Bacterial Membranes to Act on Intracellular Targets.

The advent of multidrug resistance among pathogenic bacteria has attracted great attention worldwide. As a response to this growing challenge, diverse studies have focused on the development of novel anti-infective therapies, including antimicrobial peptides (AMPs). The biological properties of this class of antimicrobials have been thoroughly investigated, and membranolytic activities are the most reported mechanisms by which AMPs kill bacteria. Nevertheless, an increasing number of works have pointed to a different direction, in which AMPs are seen to be capable of displaying non-lytic modes of action by internalizing bacterial cells. In this context, this review focused on the description of the in vitro and in vivo antibacterial and antibiofilm activities of non-lytic AMPs, including indolicidin, buforin II PR-39, bactenecins, apidaecin, and drosocin, also shedding light on how AMPs interact with and further translocate through bacterial membranes to act on intracellular targets, including DNA, RNA, cell wall and protein synthesis.

Don't watch where you're going: The neural correlates of decoupling eye and arm movements.

"Standard" visually-guided reaching movements consist of a saccade and an arm movement to the same target location. In the current study, functional magnetic resonance imaging was used to contrast brain activity during standard visually-guided reaches with activity during a "non-standard" visuomotor mapping where the targets of the saccade and arm movement were spatially decoupled. Multi-voxel pattern analysis approaches showed discrimination of standard versus non-standard visuomotor mapping in the cuneus and medial premotor regions without accompanying task-related differences in MRI signal amplitude in these areas. Contrasts of signal amplitude did reveal greater activity associated with the non-standard task relative to the standard task in the right inferior parietal lobule and a portion of the left superior posterior cerebellum. The findings of this study shed light on brain regions involved in overcoming our default tendency to spatially couple eye and arm movements during visually-guided reaching. Further, the results suggest that the regions reported here may be important in neurological disorders such as optic ataxia, Alzheimer's disease, and mild cognitive impairment, which are associated with deficits in producing non-standard visuomotor mappings while leaving standard visuomotor mapping relatively intact.

Proprioceptive guidance of saccades in eye-hand coordination.

The saccade generator updates memorized target representations for saccades during eye and head movements. Here, we tested if proprioceptive feedback from the arm can also update handheld object locations for saccades, and what intrinsic coordinate system(s) is used in this transformation. We measured radial saccades beginning from a central light-emitting diode to 16 target locations arranged peripherally in eight directions and two eccentricities on a horizontal plane in front of subjects. Target locations were either indicated 1) by a visual flash, 2) by the subject actively moving the handheld central target to a peripheral location, 3) by the experimenter passively moving the subject's hand, or 4) through a combination of the above proprioceptive and visual stimuli. Saccade direction was relatively accurate, but subjects showed task-dependent systematic overshoots and variable errors in radial amplitude. Visually guided saccades showed the smallest overshoot, followed by saccades guided by both vision and proprioception, whereas proprioceptively guided saccades showed the largest overshoot. In most tasks, the overall distribution of saccade endpoints was shifted and expanded in a gaze- or head-centered cardinal coordinate system. However, the active proprioception task produced a tilted pattern of errors, apparently weighted toward a limb-centered coordinate system. This suggests the saccade generator receives an efference copy of the arm movement command but fails to compensate for the arm's inertia-related directional anisotropy. Thus the saccade system is able to transform hand-centered somatosensory signals into oculomotor coordinates and combine somatosensory signals with visual inputs, but it seems to have a poorly calibrated internal model of limb properties.

Hand and joint paths during reaching movements with and without vision.

This study examines whether the kinematics of pointing movements are altered by the sensory systems used to select spatial targets and to guide movement. Hand and joint paths of visually guided reaching movements of human subjects were compared with two non-visual conditions where only proprioception was available: (1) movements of the same subjects with blindfolds, and (2) movements by congenitally blind subjects. While hand-path curvatures were overall quite small, sighted subjects wearing a blindfold showed a statistical increase in hand-path curvature compared with their visually guided movements. Blindfolded subjects also showed greater hand-path curvature than blind subjects. These increases in hand-path curvature for blindfolded subjects did not always lead to a decrease in joint-path curvature. While there were differences between blind subjects and sighted subjects using vision for some movement directions, there was no systematic difference between these two groups. The magnitude of joint-path curvature showed much greater variation than hand-path curvature across the movement directions. We found variation in joint-path curvature to be correlated to two factors, one spatial and one geometrical. For all subject groups, joint-path curvature tended to be smaller for sagittal-plane movements than for transverse or diagonal movements. As well, we found that the magnitude of joint-path curvature was also related to the relative motion at each joint. Joint-path curvature tended to increase when movements predominantly involved changes in shoulder angle and was minimal when movements predominantly involved elbow motion. The consistently small curvatures of hand trajectory across blind and sighted subjects emphasize the powerful tendency of the motor system to generate goal-directed reaching movements with relatively straight hand trajectories, even when deprived of visual feedback from very early in life.

Changes in the temporal pattern of primary motor cortex activity in a directional isometric force versus limb movement task.

We recorded the activity of 75 proximal-arm-related cells in caudal primary motor cortex (MI) while a monkey generated either isometric forces or limb movements against an inertial load. The forces and movements were in eight directions in a horizontal plane. The isometric force generated at the hand increased monotonically in the direction of the target force level. The force exerted against the load in the movement task was more complex, including a transient decelerative phase during the movement as the hand approached the target. Electromyographic (EMG) activity of proximal-arm muscles reflected the task-dependent changes in dynamics, showing a ramp increase in activity during the isometric task and a reciprocal triphasic burst pattern in the movement task. A sliding 50-ms window analysis showed that the directionality of the EMG, when expressed in hand-centered spatial coordinates, remained stable throughout the isometric ramp but often showed a significant transient shift during the limb movements. Many cells in M1 showed corresponding significant changes in activity pattern and instantaneous directionality between the two tasks. This momentary dissociation of discharge from the directional kinematics of hand displacement is evidence that the activity of many single proximal-arm related M1 cells is not coupled only to the direction and velocity of hand motion.

Cortical control of whole-arm motor tasks.

Making an arbitrary motor response to a sensory signal would appear to require at least two sequential steps--planning the appropriate response and generating a motor command to implement it. However, neuronal correlates of these two putative steps do not occur in strict serial order, nor are they subserved by separate cortical regions. Instead, they are distributed in a continuous, overlapping and non-uniform manner across the cerebral cortex, including primary motor, premotor and parietal regions. These processes take the form of temporal and spatial gradients of cell activity that are distributed within and across cortical regions. Instead of two serial steps, these neuronal events may be better described in terms of two parallel functions--action specification and action selection. These processes occur continuously, both before and during movement. Recent studies show that the activity of single cells in the caudal part of the primary motor cortex is strongly modulated by arm geometry and by task dynamics during whole-arm isometric and reaching tasks. This indicates that these cells contribute to the transformation between neural representations of the global attributes of motor actions and of the mechanical details of their implementation.

Reaching movements with similar hand paths but different arm orientations. II. Activity of individual cells in dorsal premotor cortex and parietal area 5.

Reaching movements with similar hand paths but different arm orientations. II. Activity of individual cells in dorsal premotor cortex and parietal area 5. J. Neurophysiol. 78: 2413-2426, 1997. Neuronal activity in primary motor cortex (MI) is altered when monkeys make reaching movements along similar handpaths at shoulder level with two different arm orientations, either in the natural orientation with the elbow positioned below the level of the shoulder and hand or in an abducted orientation with the elbow abducted nearly to shoulder level. The present study examines to what degree two other cortical areas, the dorsal premotor (PMd) and parietal area 5, also show modulation of cell activity related to arm geometry during reaching. The activity of most (89%) of the 207 cells in PMd recorded while monkeys made reaching movements showed a statistically significant change in activity between orientations [analysis of variation (ANOVA), P < 0.01]. A common effect of arm orientation on cell activity was a change in the overall level of discharge either before, during, and/or after movement (67%, ANOVA, task main effect, P < 0.01). Many cells (76%) showed a statistical change in their response to movement direction (ANOVA, task x direction interaction term, P < 0.01), including changes in dynamic range and changes in the preferred direction of cells that were directionally tuned in both arm orientations. Overall, these effects were similar qualitatively but not as strong quantitatively as those observed in MI. A sample of cells was recorded in area 5 of one monkey. Most (95%) of the 79 area 5 cells showed a change in activity when reaching movements were performed using different arm orientations (ANOVA, P < 0.01). As in PMd and MI, many area 5 cells (56, 71%) showed changes in their tonic discharge before, during, and/or after movement, and 70 cells (89%) showed changes in their response to movement direction (ANOVA, task x direction interaction term, P < 0.01). The observed changes in neuronal activity related to posture and movement in MI, PMd and area 5 demonstrate that single-cell activity in these cortical areas is not simply related to the spatial attributes of hand trajectory but is also strongly influenced by attributes of movement related to arm geometry.

Systematic changes in directional tuning of motor cortex cell activity with hand location in the workspace during generation of static isometric forces in constant spatial directions.

We examined the activity of 46 proximal-arm-related cells in the primary motor cortex (MI) during a task in which a monkey uses the arm to exert isometric forces at the hand in constant spatial directions while the hand is in one of nine different spatial locations on a plane. The discharge rate of all 46 cells was significantly affected by both hand location and by the direction of static force during the final static-force phase of the task. In addition, all cells showed a significant interaction between force direction and hand location. That is, there was a significant modulation in the relationship between cell activity and the direction of exerted force as a function of hand location. For many cells, this modulation was expressed in part as a systematic arclike shift in the cell's directional tuning at the different hand locations, even though the direction of static force output at the hand remained constant. These effects of hand location in the workspace indicate that the discharge of single MI cells does not covary exclusively with the level and direction of force output at the hand. Sixteen proximal-arm-related muscles showed similar effects in the task, reflecting their dependence on various mechanical factors that varied with hand location. The parallel changes found for both MI cell activity and muscle activity for static force production at different hand locations are further evidence that MI contributes to the transformation between extrinsic and intrinsic representations of limb movement.

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 transformations and 'internal models'.

Coordination of multiple muscles in two degree of freedom elbow movements.

The present study quantifies electromyographic (EMG) magnitude, timing, and duration in one and two degree of freedom elbow movements involving combinations of flexion-extension and pronation-supination. The aim is to understand the organization of commands subserving motion in individual and multiple degrees of freedom. The muscles tested in this study fell into two categories with respect to agonist burst magnitude: those whose burst magnitude varied with motion in a second degree of freedom at the elbow, and those whose burst magnitude depended on motion in one degree of freedom only. In multiarticular muscles contributing to motion in two degrees of freedom at the elbow, we found that the magnitude of the agonist burst was greatest for movements in which a muscle acted as agonist in both degrees of freedom. The burst magnitudes for one degree of freedom movements were, in turn, greater than for movements in which the muscle was agonist in one degree of freedom and antagonist in the other. It was also found that, for movements in which a muscle acted as agonist in two degrees of freedom, the burst magnitude was, in the majority of cases, not different from the sum of the burst magnitudes in the component movements. When differences occurred, the burst magnitude for the combined movement was greater than the sum of the components. Other measures of EMG activity such as burst onset time and duration were not found to vary in a systematic manner with motion in these two degrees of freedom. It was also seen that several muscles which produced motion in one degree of freedom at the elbow, including triceps brachii (long head), triceps brachii (lateral head), and pronator quadratus displayed first agonist bursts whose magnitude did not vary with motion in a second degree of freedom. However, for the monoarticular elbow flexors brachialis and brachioradialis, agonist burst magnitude was affected by pronation or supination. Lastly, it was observed that during elbow movements in which muscles acted as agonist in one degree of freedom and antagonist in the other, the muscle activity often displayed both agonist and antagonist components in the same movement. It was found that, for pronator teres and biceps brachii, the timing of the bursts was such that there was activity in these muscles concurrent with activity in both pure agonists and pure antagonists.(ABSTRACT TRUNCATED AT 400 WORDS)

Coordination of mono- and bi-articular muscles in multi-degree of freedom elbow movements.

We investigated the coordination of mono- and bi-articular muscles during movements involving one or more degrees of freedom at the elbow. Subjects performed elbow flexion (or extension) alone, forearm pronation (or supination) alone, and combinations of the two. In bi-articular muscles such as biceps brachii and pronator teres, the amplitude of agonist electromyographic (EMG) activity was dependent on motion in the two degrees of freedom. Agonist burst amplitudes for combined movements were approximately the sum of the agonist burst amplitudes for movements in the individual degrees of freedom. Activity levels in individual degrees of freedom were, in turn, greater than activity levels observed when a muscle acted as agonist in one degree of freedom and antagonist in the other. Other muscles such as triceps, brachialis, and pronator quadratus acted primarily during motion in a single degree of freedom. The relative magnitude and the timing of activity between sets of muscles also changed with motion in a second degree of freedom. These patterns are comparable with those reported previously in isometric studies.

Three-dimensional kinematic analysis of frog hindlimb movement in reflex wiping.

The three-dimensional kinematics of the hindlimb back-wipe were examined in spinal frogs. The component movements were identified and the relationship between stimulus position and hindlimb configuration was assessed. The planes of motion of the hindlimb were examined throughout the movement. The back-wipe comprises three essential phases: a placing phase (I), in which the foot is drawn over the back of the frog and placed in a position near to the stimulus; a pre-whisk phase (II), in which the endpoint of the foot moves away from the stimulus; and a whisk/extension phase (III), in which the stimulus is removed. The pre-whisk phase contributes to force production for the whisk/extension (III). In the placing phase a systematic relationship was found between limb endpoint position and stimulus position in the rostro-caudal direction. The hip, knee and metatarsal joint angles were related to the position of the endpoint in the rostro-caudal direction. However, different frogs tended to adopt different strategies to remove the stimulus. In one strategy, when the knee angle was strongly related to the rostro-caudal stimulus position, the metatarsal angle was weakly related and vice versa. Other strategies were observed as well. There was no adjustment in limb endpoint position for stimulus placement in the medial-lateral direction. Consistent with this finding, the point on the foot at which stimulus contact occurred changed systematically as a function of medial-lateral stimulus placement. Thus, in order to remove the stimulus in different medial-lateral positions, the frog used a different part of the foot rather than moving the foot in the direction of the stimulus. In two frogs a relationship was observed between the elevation of the femur and the medial-lateral stimulus position. The motion planes of the hindlimb were studied by examining the instantaneous plane of motion of the endpoint and the planes of motion of adjacent limb segments. The motion of the endpoint was found not to be planar in any phase of the wipe. In contrast, planar motion of the femur and tibia was observed for all phases. Systematic changes in the orientation of these planes characterized the different phases. The position of the hindlimb was found to be variable prior to the placing phase. This variability was not related to stimulus position. However, in trials with multiple wipes, once an initial limb configuration was assumed, the limb returned to this configuration before each wipe in the sequence. Evidence for motor equivalence was sought in two ways.(ABSTRACT TRUNCATED AT 400 WORDS)