Movement regularities are inherently present in automated goal-directed motions of the primate's arm system. They can provide important signatures of intentional behaviours driven by sensory-motor strategies, but it remains unknown if during motor learning new regularities can be uncovered despite high variability in the temporal dynamics of the hand motions.We investigated the conservation and violation of new movement regularity obtained from the hand motions traced by two untrained monkeys as they learned to reach outwardly towards spatial targets while avoiding obstacles in the dark. The regularity pertains to the transformation from postural to hand paths that aim at visual goals.In length-minimizing curves the area enclosed between the Euclidean straight line and the curve up to its point of maximum curvature is 1/2 of the total area. Similar trend is found if one examines the perimeter. This new movement regularity remained robust to striking changes in arm dynamics that gave rise to changes in the speed of the reach, to changes in the hand path curvature, and to changes in the arm's postural paths. The area and perimeter ratios characterizing the regularity co-varied across repeats of randomly presented targets whenever the transformation from posture to hand paths was compliant with the intended goals. To interpret this conservation and the cases in which the regularity was violated and recovered, we provide a geometric model that characterizes arm-to-hand and hand-to-arm motion paths as length minimizing curves (geodesics) in a non-Euclidean space. Whenever the transformation from one space to the other is distance-metric preserving (isometric) the two symmetric ratios co-vary. Otherwise, the symmetric ratios and their co-variation are violated. As predicted by the model we found empirical evidence for the violation of this movement regularity whenever the intended goals mismatched the actions. This was manifested in unintended curved "after-effect" trajectories executed in the absence of obstacles. In this case, the system was "perturbed" away from the symmetry but after several repeats it recovered its default state.We propose this movement regularity as a sensory-motor transformation invariant of intentional acts. The primate arm-hand system has many more degrees of freedom (d.o.f.) than the three-dimensional physical space in which the system operates. Such excess lends primates great flexibility to interact with the external environment and gives rise to highly versatile behaviours. Any goal-oriented task can be performed in a variety of ways. Even under highly constrained laboratory conditions several repeats of the same motion can be highly variable after the motion has been fully automated. To the naked eye every repeat may seem similar to the previous trial but when examined at a millisecond time-scale resolution, different patterns of variability can be revealed. In spite of the many possible ways that exist to perform voluntary reaches, and of the variability of movement parameters manifested in any family of reaching actions, research in the field of motor control has unveiled a number of regular movement patterns that suggest conservation of some underlying quantities possibly driven by sensory-motor integration strategies to achieve some higher-level goal.Examples abound in motions that are performed under temporal constraints aiming for a particular maximum speed or particular movement duration. Among them the first to be noted was the speed-accuracy trade off known as Fitts' law, discovered by Paul Fitts in 1954 [ring law .Other known regularity of human movements is the symmetric ("bell-shaped") nature of the speed profiles of point-to-point straight motions noted earlier  and modeInvariably these studies however have treated the movement time as a free variable and pre-set the duration of the reach a priori. This has also been the case in animal movement research, which has reproduced the speed profile regularity ,8 in higIn reach to grasp motions that required the bending and twisting of the hand along the motion paths to match some location and orientation in space, the arm system defaulted to the co-articulation of 4 rotational joints roughly projecting to three physical dimensions for transport of the hand and 1 for rotations of the hand. The subjects performing such motions invariably conserved the relationship between the transport and the rotational errors . This coAs one assesses more natural behaviours, movement regularities unveiled in one context do not necessarily transfer to another context. Another known example has been the somewhat controversial human movement pattern known as the 2/3 Power Law. This movement regularity reveals a non-linear relationship between the tangential hand speed and the curvature of its trajectory during curved motions -14. SuchStudies involving motor learning may provide a more natural scenario to test the movement regularities described thus far in fully automated reaches, or in motions with specific spatio-temporal requirements. In most experiments describing such phenomena, the arm has been constrained to move on a plane and/or to move under a pre-defined temporal structure that a priori sets bounds on the total duration of the motion and/or on the motion's maximum speed. It is unknown whether the untrained system, moving naturally at its own pace while learning new dynamics would also manifest movement regularities. In natural settings unconstrained motions of the arm would recruit many of the rotational d.o.f. in the proprioceptive space of sensed postural configurations and the motions would generally be more variable. Would other subtle invariants emerge under such conditions? More importantly, are there motion invariants that remain conserved across different families of reaching actions? Under what conditions such invariants would be violated and repaired? We address these questions here in two untrained monkeys as they learned to avoid obstacles when their hands aimed at visual targets in the dark.Two rhesus macaque monkeys were first trained to perform memory-guided straight reaches directed to visual targets in the dark. Targets were located on a vertically-oriented board figure . A blockThe structure of the paradigm was A-B-A', where A represented the automated straight reaching block, B was the block of curved reaches around obstacles and A' was the last block of straight reaches after exposure to many highly fast and curved OB-avoidance-motion repeats. The experimental paradigm and other aspects of the learning process have been described elsewhere . Here weSince these experiments monitored the two animals over several months until their new reaches turned automated, here we focus on the time period when the animals were still learning. The criteria for learning vs. automatic came from (1) the jerkiness vs. smoothness of the new speed profiles along the curved hand paths, and (2) the ease with which the animals switched from one experimental block to the next. The presence of jerky hand speed profiles when switching from A to B, or from B to A' indicated that the OB-avoidance motor program was still fragile, i.e. undergoing learning .Since our main interest rests on the effects that the high variability inherent in the learning process may have on movement regularities, we will focus on the behavioural data from the earlier days of training. The data was gathered from experimental sessions where the transition from A to B, or from B to A' was not direct. In those days it took many trials to transition from straight paths with smooth speed profiles to curved paths which would also develop smooth speed profiles (going from A to B); or it would take many trials to transition from curved paths with smooth speed profiles to straight paths with smooth speed profiles (going from B to A'). In particular, in the transition from B to A' unintended curved hand trajectories in the absence of OB were coined "after-effect" trajectories from OB-avoidance and we studied the evolution of those trajectories in depth here.The motions of the performing arm were recorded using electro-magnetic sensors (Polhemus Fastrak 120 Hz resolution). The hand sensor was mounted on a piece of Plexiglas, affixed to a custom-made glove and placed on the surface of the moving hand, one cm from the wrist line. The rest of the sensors were mounted on a piece of Plexiglas and affixed to a primate jacket at the shoulder, upperarm and forearm.The monkeys were seated in a primate chair. Since concurrent neural recordings were being obtained, their head was not moving and their eyes were fixating straight ahead. They moved their arm freely in three dimensions and received a juice reward after each successful trial. Successful trials had the following structure . The present study focuses on locations to the right and to the left of the fixation point as these evoked the highest changes in curvature and timing.The subjects were not penalized if the hand collided with the OB(s), as we were interested in the evolution of such trials. However, not enough trials where they hit the OB(s) could be gathered for analyses as both animals were naturally very proficient at successfully avoiding the OB(s) while maintaining eyes fixated in the dark. The data reported here comes from trials where no collision with the OB(s) occurred.All experimental procedures were conducted according to the "Principles of laboratory animal care"  and were approved by the California Institute of Technology Institutional Animal Care and Use Committee.We assessed the effects of task condition and target location on the curvature of the hand trajectories. To this end we measured the deviation of the hand trajectory from the Euclidean straight line and used this as a bending index (denoted κ).The starting and final location of each hand trajectory was joined by the corresponding straight line. The hand trajectories were re-sampled (100 points) to obtain a fine temporal partition at equally spaced points without distorting the spatial path. This was necessary for numerical integration to compute the area and the perimeter ratios explained below and to treat the curve as a geometric object independent of its temporal profile. The latter is justified by empirical evidence indicating that during voluntary motions, primates conserve the hand paths regardless of the motion's speed ,11,19-21normal to this plane at each position was compared to that corresponding to the plane from the previous position in order to measure the twisting of the curve along the hand motion's trajectory . To better visualize this relative to an ideal OB-avoidance modelled geodesic we show in figure We also measured the degree of twisting along the hand paths. At each point along the trajectory the tangent vector to the curve (the velocity vector) and the vector perpendicular to it (the acceleration vector) span a plane (known as the osculating plane ). This pTwo-way ANOVA  as the dependent variable) was used to assess significance in the differences across experimental blocks. Within each block we also performed an ANOVA to ask if the target location had a systematic and significant effect on the bending (or on the twisting) parameter.time length to reach the maximum speed from the start of the reach (denoted tau); the time length to reach the maximum acceleration (denoted α) and the total duration (denoted t). In particular we were interested in the evolution of the magnitude of the acceleration relative to the magnitude of the velocity. Where and when along the curve traced by the hand were these quantities maximal? Was there any evidence that the system was using a particular critical temporal point as a reference while timing the reaches?We measured in each trajectory the timing of several kinematics parameters occurring at different points of the motion. These critical temporal markers were: the We had previously reported that the speed profiles during the learning phase of the new OB-avoidance motion were jerky, with multiple accelerations and decelerations phases and highly variable in duration ranging from 1,500 ms to 700 ms for the same target . Motivatt we used two-way ANOVA with target location and experimental condition as the two factors, and the temporal-dynamics parameters as the dependent variable in each case.To assess the effects of target-dependent curvature/torsion and learning on tau, α and We defined two trajectory ratios:area ratio was defined as the quotient between the partial area under the curve in the first portion of the movement, up to the point of maximum bending κ, and the total area enclosed between the curve and the line. Figure (1) The perimeter ratio was defined as the quotient between the partial perimeter -the sum of the path length and the length of the line connecting the initial hand position and the target up to the point of maximum bending- and the total perimeter given by the total sum of the lengths of the hand path and the initial hand position-to-target line.(2) The the Appendix and qualitatively congruent with previous data from various laboratories showing the conservation of voluntary arm postural and hand paths [It is important to note that the assessment of these quantities in the context of motor learning was motivated by a previous finding involving human subjects. In that study humans performed similar three-dimensional point-to-point straight reaches under visual memory guidance in the dark. Both aforementioned ratios were time-invariant, i.e. remained conserved for multiple speeds along paths of similar curvature. The conservation was in that case also independent of the frame of reference used to cue visual guidance . This wand paths ,10,19-21The novelty of the questions addressed in the present experiments rests in two facts: (1) the animals were untrained to perform the task of interest; (2) there were dramatically different arm force patterns to achieve multiple families of curved hand trajectories.We obtained from each hand trajectory the area and perimeter ratio and used the Friedman test  to assesWe found significant effects of target location and experimental condition in both animals alpha 0.01) on the bending and twisting of the hand trajectories. In the straight-reaching block the target location affected both trajectory parameters significantly. These results extended from the straight-reaching to the OB-avoidance block. There was a significant effect of the block-condition. Figure  on the bThe time to reach the first velocity peak: Each target location in space had a characteristic value of tau specific to that location in each task. This parameter was highly consistent at each location despite the fact that in each experimental block, the repetitions of the reach were made to randomly presented targets. Figure t. This result extended to other families of reaches in the present study.Figure The time to reach the maximum acceleration: The temporal profiles of the magnitude of the acceleration revealed that the hand trajectories in general had several acceleration peaks. We obtained the percentage of the total movement duration time that it took to reach the absolute maximum acceleration for each condition and plotted the distribution of this parameter across all target locations and reach repetitions. Since the total length of the path relates to the overall duration of the reach, we also examined the distance delta travelled to the first velocity peak, as the hand completes the first pulse of the reach.p < 10^-6, dip = 0.09). A mixture of Gaussians fit yielded 55% of trials with the maximum acceleration reached earlier at 10% of the total time and 45% of the trials with the maximum acceleration reached later at 20% of the total time.In straight reaches the distribution of the percent of time that it took to reach the absolute maximum acceleration along the curve turned out to be strongly bimodal according to the Hartigan's dip test ,26 for bFurther analyses of all trial-times in each class revealed that each class of trials was composed of reaches to all target locations (uniformly distributed across space) and trials performed uniformly at all times (early and late) in the block. These results ruled out a possible effect of target location preference  or an effect of fatigue . This bi-modal distribution defined two trial classes in the straight reaches, one in which the peak acceleration preceded the peak velocity and the other in which the peak acceleration followed the peak velocity. The distribution of time stamps in these trials revealed an alternating strategy whereby it took mostly one or two trials across all repetitions to switch from one trial class to the other. This is depicted in figure dip = 0.03, p = 0.6, failed bimodality test) as well as 2 OB(s) .The OB avoidance block yielded a very different picture with a unimodal uniform distribution of the percent of the total time that it took to reach the maximum acceleration α. This was the case when avoiding 1 . Avoiding 1 OB also failed the bimodality test . However learning to avoid 2 OB(s) yielded a significantly non-unimodal distribution . Figure Figure The total time of the motion: The movement duration relates to the total length of the trajectory so we measured both quantities and the other spatio-temporal parameters in each block. The OB-avoidance total path length ranged between 37 cm and 79 cm for ipsi-lateral targets and between 39 cm and 105 cm for contra-lateral targets. The partial distance delta travelled up to the first velocity peak varied between 10 cm and 36 cm for straight reaches and between 11 cm and 60 cm for curved reaches around 1 and 2 OB(s). The total movement duration time t in ms ranged between 420 ms and 1,600 ms for ipsi-lateral targets and between 500 ms and 1000 ms for contra-lateral targets. It was highly variable at the beginning of the learning, for example in a single session it evolved from 1,600 ms until it became stable at 700 ms in the most affected ipsi-lateral target.Automated straight reaches showed consistent movement duration for each location despite the randomness of the target presentation. This contrasted with the earlier trials of the OB-avoidance learning block where the total duration was highly variable yet with a consistent monotonically decreasing trend at each randomly cued target location. The last portion of the OB-avoidance block was characterized by a more consistent duration in each target location. For each target location we observed statistically significant differences between the automated straight and OB-avoidance reaches. Likewise, there were significant differences within the OB-avoidance block when we compared earlier and later trials of the block, with a significant effect of target location . Table Despite significant differences in all trajectory parameters as a function of target location; and as a function of the learning stage of OB-avoidance, the area and the perimeter ratios pooled across all target locations and repeats for each animal formed a unimodal distribution clustered tightly around 1/2. This distribution was similar for both quantities and remained so despite striking differences in temporal dynamics figure  or hand The similarity of the area and the perimeter ratios denoting their co-variation was confirmed by the Friedman's test  yieldingDuring the early trials of the third block of straight reaches (A') both subjects manifested motion trajectories similar to those observed during OB-avoidance. Their hand paths were curved and the temporal profiles along the hand paths were highly variable. A distinct difference was that the consistency of the parameter tau was no longer present. Eventually the simultaneity of the delta-tau pair quantified during the first pulse of automated straight reaches was regained in this block. Attaining this synchronicity however, took many trials (at least 5 per each of the 14 targets). At that stage we found as in the A-block, similar bimodal distribution of the percent of time to reach the maximum acceleration relative to the maximum speed, and a unimodal distribution of the distance delta travelled to reach the first velocity peak. Figure This work investigated (1) if there were new movement regularities conserved across various families of goal-directed voluntary reaches; and (2) if the regular patterns across reaches would remain conserved despite high motion variability during the natural learning of a new procedural act. We found that during intended goal-directed reaches, despite significant statistical effects of target location and learning stage on many relevant spatio-temporal movement parameters, there was a new symmetry linked to hand trajectories. This symmetry was captured by two ratios of the hand trajectories, which significantly co-varied across space and remained invariant to changes in temporal dynamics, to changes in hand path curvature and to changes in the arm postural paths required to achieve differently curved hand trajectories across the three-dimensional physical space.It is important to notice that all research questions addressed here are part of a research program investigating the cross roads between geometry and temporal dynamics during unconstrained intentional actions. This program aims at further developing the idea of an internal model of the body's temporal dynamics ,29 by prIt is generally believed that an internal representation of movement variables -such as position and velocity- is maintained in the neural activity (whether in intrinsic joint and muscles or extrinsic coordinates) and used to update and monitor the state of the system. Such representations are thought to be stored as internal models -31 that when they occur [It is accepted that these internal models can be characterized by dependence on a motion state -a mapping between motor commands and resulting limb motions-rather than by a dependence on the times ey occur . Empiricey occur ,34. No eThe present work uncovered a bimodal distribution of maximum acceleration-magnitude relative to maximum velocity-magnitude suggesting that relative timings are indeed important to learn new curved point-to-point reaches. Each bump of the unveiled bimodal distribution reflected separable acceleration timing relative to the maximum speed, suggesting that -generally for both automated straight and automated curved timings-the peak velocity can serve as a critical reference point.when these states occur. In particular the relative timings of these states' critical points  appear to play an important role in the learning of new curved reaches. Models of motor learning that treat time as a free parameter and that leave out such relative-temporal dependencies will not account for these empirical results of unconstrained three-dimensional complex reaches performed at the subjects' own pace.These data demonstrate that in addition to a dependency on the motions' states, the system's performance in general straight and curved reaches also manifests a dependency on the times where and when in the path the hand attains the speed maximum. The temporal analyses had revealed the speed maximum as a possible critical point of reference to time the reach. The spatial analyses revealed that these critical points largely depended on the reliable path length -used to update relative distances during learning.In both automated straight and curved OB-avoidance reaches studied here the hand path length remained consistent despite the temporal learning and despite the arm's redundant d.o.f. Motivated by these empirical results, in all 3 cases ) we examined the portion of the total path length that it took the hand to reach maximum velocity (denoted delta in cm) and that lasted tau ms. These parameters indicate The questions addressed in this work were motivated by our geometric characterization of intentional arm-hand motions. In each case we had previously characterized the curve to reach a target as the shortest-distance path with respect to a task-dependent Riemannian distance metric. In curved reaches for the -associations, we had proposed that these parameters could play a key interchangeable role in predicting ahead sensory-motor temporal lags . We systThe hand path curvature played a significant role on this motor-learning process as it determined the cases in which the learning of the new motion timing was based on the adjustments of the distances travelled by the hand at a fixed time-length in relation to the maximum speed. In this regard it was important to divide the hand trajectory into different critical temporal land marks defining different segments along the motion path. This further relative-timing refinement revealed that later points along the temporal path were more affected by the error-correction process. This process was driven by the trial-by-trial adjustments of the distance travelled by the hand after the maximum speed had been attained, prior to reaching the intended target. Eventually the hand converged to a smooth timing and travelled two segments. The overall motion then consistently lasted a similar time length.We speculate that it is possible that during the later portions of the movement trajectory sensory-motor feedback was used to correct errors between intended and actual executed dynamics. This was evidenced in the later corrections of the jerky speed profiles, which disappeared as the earlier delta became consistent. In contrast to the later corrections, in the earliest pulse of the trajectory  information on the distance-to-be-travelled seemed more adequate than actual motor feedback (possibly not yet fully available) to estimate adjustments in the upcoming dynamics and to achieve  a systematically consistent overall timing. In this earlier portion of the reach the system may have placed a tighter bound on the variability of the length of time devoted to the segment. This was evidenced in the low variability of the parameter tau throughout the learning process.Regarding the interactions between geometry and relative-timing, the rate of change of the distance accumulated along the highly curved hand path in principle interacts with the acceleration of the curve at each point (the vector perpendicular to the velocity vector tangent to the curve). If there had been extreme changes in distance travelled, the hand would have fallen out of the intended direction along the path and collided with the OB(s). Yet this was not the case during curved-timing learning. Throughout the learning process -despite different dynamics - the curvature of the path and its overall length were systematically conserved across random repeats to the same target.Path length conservation facilitated distance-based adjustments when learning the curved timing. The unveiled bimodal distribution of delta manifested during the adjustment phase contained trials from all targets. This uniformity ruled out an explanation of the non-unimodal distribution solely based on the subjects' biases due to comfort  or effort . The composition of the classes showed mostly an alternating distance-adjusting strategy where if trial n was in the short-length trial class then trial n+1 would most probably be in the long-length trial class. This systematisation suggested that the system was running two learning processes simultaneously, one short-term based on trial-by-trial error corrections and one long-term quantified across days of training. We had previously tracked longitudinally the long term learning  and see , but theThe present results fully agree with previous reports, which had suggested different time scales for motor learning in the context of a different force-field paradigm . In the The data from both animals showed that whenever the intended path geometry and tau were consistent, the symmetries and their co-variation held. We found that the uncovered invariant of hand motions was violated whenever the executed motion path miss-matched the intended path. This was the case during the de-adaptation trials where different forces were still present in the arm system from the previous experimental block. To describe this new phenomena we borrowed the term "after-effects" from the well known motor learning paradigm that uses force fields to alter arm dynamics . In our During the de-adaptation trials tau was highly variable at each target location. This was in contrast to the other blocks of automated straight reaches, and OB-avoidance learning where this temporal landmark of the hand trajectory remained consistent. In those cases, we had found that the variability of tau was negligible compared to the variability of delta. We had quantified the systematic consistency of tau even during the striking changes in overall temporal dynamics from motor learning, yet during de-adaptation tau varied significantly between the mean values of the 2 motor programs for straight and curved paths.During de-adaptation trials the parameter delta also had comparable variability to that of the parameter tau. An immediate sensory-motor strategy was not evident in these trials at first. The inevitable arm state seemed to have over ruled the intended sensory-motor transformation strategy. Yet eventually, after many trial-and-error repeats, with no apparent systematic pattern of variability in the hand trajectories, the system regained synchrony of delta and tau, and the bimodal trial-distribution of α was again quantified. Perhaps systematic de-adaptation patterns could have been identified in the arm muscles domain, but our recordings of the arm kinematics at 120 Hz limited our ability to address different sources of noise and their possible meanings with regards to important lower-level control strategies.The invariance of the uncovered symmetry may reveal a higher-level sensory-motor transformation and integration strategy common to several families of reaches performed by the primate arm system. The learning progression from the straight to the curved timings revealed important features. The non-unimodal distribution of α in the automated straight reaches disappeared when learning the curved timing. As the system built a new curved temporal profile, the α-distribution turned unimodal and the δ-distribution turned non-unimodal. Upon examination of relative timings at the end of the learning process, we discovered that the newly automated curved trajectories had similar non-unimodal relative-timings structure as the automated straight trajectories. The spread of the clusters had however changed and the centres shifted. In the new curved timing there was a contraction of the time-length separation between the speed and the acceleration maxima.The OB-avoidance learning strategy was closely tied to the rate of change of the distance accumulated along the first pulse of the reach in relation to the overall path length: i.e. the percentage of the path covered. The path length remained stable (low variability) throughout the curved-timing learning process both in the postural and in the hand domains. This stability in the face of so many possible postural configurations suggested an initial geometric strategy based on relative distances rather than on relative timings. At the end of the learning process however figure , the strWe speculate here that in visuo-motor acts the learning of complex curves in high dimensions and their projection to three-dimensional space may initially rely on sensing the distances covered by the end effector (proprioceptive sense of posture) and estimating ahead  the remaining distance for various segments. Eventually, through trial and error performance, aiming for a faster, less time-segmented motion, the system may learn to rely on the relative timings, as was manifested in the transfer from automated straight to automated curved reaches. There is evidence that smoothness maximization is important to the motor system [r system ,36, yet In our previous work  the longWe have previously proposed ,11 that According to our geometric model, under normal conditions, the learning of new dynamics along new curved paths would entail building an association between the general notion of distance (in a sensory space) to be travelled along a geodesic direction  and the time lag that it would take for sensory-motor feedback to return and be utilized to complete the segment. Once the motor program became automated, the time lag (which we sense from movement) and the distance  would be interchangeable, so we could have a representational model of the dynamics in a "Least-Action-Principle" sense; i.e. we could have a representational, time-invariant geometric model of the dynamics motion path. To the naïve system distance and time would be separable but to the automated system they would be equivalent. Whenever this association-map became ambiguous or misaligned (as during de-adaptation or brain injury ), such cmemory-guided reaching contexts that adult human Parkinson's and Parietal patients also violated this invariant, yet they could repair the symmetries and their co-variation when the appropriate source of sensory guidance was provided to cue the spared systems. The deficit/repair pattern of the symmetry was specific to the injured site and so was the preferred source of sensory guidance. The present work complements the patient data and strongly suggests that this movement regularity is not merely a by-product of the primate arm's biomechanics and its compliance with the physical laws of motion. We believe that this invariant reflects compliance with intended sensory-motor transformation strategies of the primate brain and conclude that it is a manifestation of mental laws governing the control of voluntary arm movements.We have previously found in similar The author declares that they have no competing interests.All authors read and approved the final manuscript. EBT designed the task, programmed the motion capture recording system, designed the questions addressed in this paper, designed the analyses and modeled the phenomena prior to the experiments. EBT trained the subjects, carried on the experiments, collected and analyzed the data and wrote the paper. EBT did not build the experimental set up which was part of the Andersen laboratory at CALTECH. In addition to this, as part of a broader question, Professor Richard Andersen posed the question of curved trajectories in relation to the Posterior Parietal Cortex and provided the idea of using obstacles to evoke hand path curvature.dq = -G-1∇r° fΔτ (i) described in [Paths generated with the gradient-flow-driven equation ribed in  conserve1-shoulder, and q2-elbow rotations. Parameterization of the surface is compatible with the metric and projects geodesics paths on the Q-Cost to geodesics paths on the X-Cost surface according to equation (i) (fully described in [xtarget pulled back into the corresponding qtarget in Q according to the gradient rule. This gradient flow minimizes the remaining (non-Euclidean) distance between current posture in Q and final target in X subject to any additional priorities and constraints that the task at hand may demand [Figure ribed in ,11) whicy demand ,11. ThisIn the toy-model example of Figure The metric in X is pulled back into the metric in X is The cost function in this case is 2r° f along the path. This is measured by In Figure Figure The results illustrated here in lower dimensions extend to higher dimensions for a more realistic characterization of this problem Figure f-map from postures to hand position. The star marks an abducted posture used later in (D) to simulate a reach. Figure i is given as a visually sensed desired distance quantity and δi is the distance traversed that changes as the gradient flow changes the hand position, (*) is the sign which alternates as each segment is completed to drive the term towards 0 [Figure owards 0 .The distance-based formulation presented here can be converted to a time-based formulation of relative-temporal segments tracking differences between angular and linear velocities and accelerations. In addition the λ-terms can be defined by other smooth-differentiable real-valued functions to represent different tasks. Since the gradient is a linear operator, the gradient of the sum  equals the sum of the individual gradients of each segment. Thus the segmented learning process can be modelled using the general gradient equation (i) and the excess segment-terms that make the motion jerky can be turned to 0 as the system learns to smooth out the timing. Likewise, more complex realistic multi-segmented motions in posture space can be geometrically characterized using the gradient approach. In such cases the limb segments can be synchronized or de-synchronized using a higher level temporal coordination scheme. Figures primate arm motions of several kinds ; (2) the simulated situations in which these symmetries and their co-variation would break down also existed in the empirical case. In the model this violation was predicted for non-isometric mapping of the gradient flow. In the after-effect data the invariants were indeed violated when the system mismatched the intended straight and the actual curved motion-path flow. The real system however, eventually recovered the symmetries and their similarity thus suggesting a default preference for a sensory-motor transformation strategy. This strategy seemed congruent with what the model had specifically predicted under local isometric embedding.Notice that this general gradient-flow solution could be applied to other non-brain problems. Thus, it is not implied here that this is the brain solution to this set of problems. What seemed striking were two findings: (1) this arbitrary model predicted area-perimeter related symmetries that held in actual This suggests that under normal circumstances the geometric transformations that give rise to actual motion paths from the primate arm can be on average well characterized by the local isometric embedding of the proposed PDE. Furthermore despite motor noise the symmetries from the data manifested invariance to straight or curved timings. The actual trajectories could be on average well characterized by different families of length minimizing curves and still preserve the similarity of the time-invariant symmetric ratios so long as -regardless of the sensory space geometry-the transformation from visual to body coordinates was distance-preserving (isometric).Both in the model and in the veridical paths the ratios were shown to be independent of the curvature and timing. Previous empirical data had shown the speed invariance of voluntary postural and hand reaching paths ,10,38,39Supplementary material contains a glossary of geometric terminology and a proposed computational method to further pursuit the study of this invariant symmetry in more complex motions.Click here for file


Changes of breast-cancer (BC) mortality for all women in England and Wales between 1911 and 1975, and for the social-class gradient during the 1950s, were not related to changes in child-bearing. The changes in BC mortality for all women were associated with changes in consumption of fat, sugar and animal protein 1-2 decades earlier. A decline in mortality around 1935 was not obviously related to changes in fat or sugar, but dietary data were sparse. The social-class gradient of BC mortality almost disappeared during the 1950s; rates declined for the upper classes but increased for the lower. These opposite changes could have resulted from the opposite changes in diets of the upper and lower classes which occurred in the early 1940s. In contrast, the geographical variation of BC mortality within the United Kingdom, by region or by urban-rural aggregate area, was closely correlated with child-bearing but poorly correlated with diet. The poor correlation with diet might be a consequence of the small range of variation of diet between regions of the United Kingdom. The regional gradient of BC mortality was low in 1961, a decade after the period of food rationing when regional variation in diet would have been reduced. This suggested that diet did contribute to the regional variation of BC mortality within the United Kingdom, perhaps jointly with contributions from child-bearing.


Radioimmunoassay methods for the determination of oestradiol-17 beta and prolactin have been examined for their reliability and applied to the measurement of hormone concentrations in the plasmas from male and female rats. Prolactin was detectable in all samples (greater than 7 ng RP-1 ng/ml) but the concentration of oestradiol-17 beta was below the sensitivity of the method (greater than 0-10 ng/100 ml) in ovariectomized females. Plasma oestradiol-17 beta concentration rose gradually from metoestrus to proestrus and fell to barely detectable levels in oestrus. Plasma prolactin concentration was very variable even for rats in the same stage of the oestrous cycle but values were minimal in the afternoon of diestrus and a surge in secretion occurred in the afternoon of proestrus. In addition to the stage of the oestrous cycle, the prolactin concentration was influenced by mode of blood collection, degree of haemolysis and choice of serum or plasma. There was no correlation between the concentration of prolactin and that of oestradiol-17 beta in the same sample of plasma.


The classification of polymer samples from their infra-red spectrahas been achieved by the application of a fuzzy c-means clusteralgorithm. The generation of a fuzzy classifier allows thecharacterization of samples which are a combination of more thanone pure polymer.


The 5-year survival of women with localized (early-stage) cervical cancer is much higher than for women with non-localized (late-stage) cancer, but women with localized cancer tend also to be younger than those with advanced cancer. A new method of presenting the long-term survival is suggested, and the registrations of cervical cancers in South Wales are analysed in terms of average age at registration and average age at death. The observed average age at death was very close to 59 years regardless of stage (and age) at diagnosis, and calculations of expected ages at death of the whole populations suggest that more than half the advantage in survival shown by early stage cancers over late stage cancers is due to diagnosis of the former in younger women.


Virology Journal and the authors of this article [The Editor-in-Chief of  article  acknowle


An Israeli Jewish population group consisting of 1298 cases of breast cancer and 1816 cases of benign mastopathy hospitalized in 1960-64 and 10,604 properly selected control women was studied with respect to the relationship of breast diseases to ethnic origin, educational background and socio-economic status. It was found that the percentage of Israeli-born and Orientals was higher in the benign mastopathy group than in the cancer group. For the Westerners the opposite was true. Educational level and socio-economic status were considerably higher in patients than in controls, regardless of ethnic origin. They were also higher in Westerners than in Orientals and among the Orientals higher in Iraqis than in Yemenites. The population groups with high breast cancer incidence rate appear to be on a higher educational and socio-economic level than those with a low incidence rate.


Cultured cells established from the bone marrow of a child with null-cell acute lymphoblastic leukaemia (ALL) have been studied. After 8 months in vitro, the cytological, cytochemical and immunological properties of the cultured cells were very similar to those of the patient's cells. Many of the cultured cells had morphological and cytogenetic abnormalities often found in acute leukaemia. The cells were EBNA-negative. This unique culture of ALL-derived null cells might provide information as to the aetiology and origin of malignant cells.


Proteinuria is a defining criterion for the diagnosis of pre-eclampsia. The amount of protein lost per day has been thought by some to predict both maternal and fetal outcome. The systematic review of 16 primary papers including over 6700 patients by Thangaratinam and colleagues published this month in BMC Medicine suggests otherwise. This finding may influence our management of pre-eclampsia. Proteinuria has been proposed and studied as both an indicator of severity of disease and as a predictor of outcome in pre-eclampsia. Many clinicians still make major management decisions based on the degree of proteinuria in such patients. The systematic review by Thangaratinam and colleagues  publishePre-eclampsia affects 2 to 3% of all pregnancies and is responsible for about 60,000 maternal deaths every year, mainly in poor countries , while iProteinuria is a defining dysfunction of pre-eclampsia . QuantitThe severity of the proteinuria in pre-eclampsia has been regarded by some as a predictor of adverse outcomes for the mother . Others The review by Thangaratinam et al  reportedDespite the rigor and efforts to determine the quality of the studies included in the current review, practice differences, equipment changes, and definitions of pre-eclampsia could have influenced the diagnosis (and management) of pre-eclampsia over the time period of the studies used. Thirty years ago changes in systolic pressure and diastolic pressure during gestation were being used to define pre-eclampsia  and if the diagnosis of pre-eclampsia is differently defined in different studies the validity of the result may be diminished.A very important potential confounding factor to consider in studies of the kind reviewed, is that the test result (in this case severe proteinuria), particularly in the earlier studies, may have dictated management. In the USA at least, proteinuria of 5 g or more per 24 hours is one of the diagnostic criteria for severe pre-eclampsia . If womeDespite these limitations, this metanalysis appears to confirm what clinicians have suspected for a long time. The degree of proteinuria alone does not have a strong association with adverse outcome. Maternal and fetal clinical condition and gestational age, complemented by hematologic and biochemical parameters, should for the time being remain the primary determinants for timing delivery in women with pre-eclampsia.As the results of observational studies may systematically over- or underestimate the predictive value of tests as discussed above, a randomized trial of knowledge versus no knowledge of the level of proteinuria to guide management would be justified.The authors declare that they have no competing interests.MAB and GJH drafted the manuscript and MAB revised it for important intellectual content. MAB and GJH have both given final approval of the version to be published. Each author has participated sufficiently in the work to take public responsibility for the content.The pre-publication history for this paper can be accessed here:


In a population-based case-control study in the Uppsala-Orebro Health Care Region of Sweden, the histories of cancer among parents of 517 histologically confirmed cases of papillary and follicular carcinoma and of a similar number of sex- and age-matched controls were compared. The parental history of cancer was compiled through information from death certificates and from the nationwide Cancer Register. The incidence of malignancies in a cohort of parents of cases of thyroid cancer was also compared with the incidence in the whole Swedish population. A maternal history of cancer was more common among women with follicular carcinoma than among their controls . Parents of probands with papillary carcinoma had an increased risk of thyroid cancer , and mothers of probands with follicular carcinoma had an increased risk of stomach cancer  compared with the general population. Cancer of the lung, breast, and pancreas were less common than in the general population. Familial cases of thyroid cancer were not limited to the papillary type. An inheritable pattern of carcinogenesis is possible for certain differentiated non-medullary thyroid cancers, but shared environmental exposures may also explain the parent-child associations of cancer in this study.


This paper reports on the evaluation and testing of a home-made device. Data-acquisition, treatment of transient signals and the hardware and software involved are discussed. Some practical aspects are developed in order to power the autonomy of procedures using the device. Kinetic and multi-signal calculations are considered in order to cover the actual tendencies in continuous-flow analysis. Somepractical advantages versus the use of classical chart recorders or commercial computerized-instrument devices are pointed out.


It is of great practical importance to develop simple methods for theautomatic detection ofthe controlled state of the analytical methodbeing applied. The key point is to find quantities that greatly affectthe quality of the analytical results and that can be easily estimatedduring the measurement process from the measured data. Thesignal-to-noise ratio has proved to be such a quantity in gaschromatographic methods. The statistical properties of theestimation of the signal-to-noise ratio from gas chromatographicdata have been investigated. The suggested practical method forestimating the signal-to-noise ratio proved to be biased from amathematical statistical point of view, but the bias is usually notgreater than 10%. It has been shown by practical examples that thesignal-to-noise ratio affects the quality of the analytical results andit is easy to estimate its value from practical data.


An introductory clinical trial of the anti-oestrogenic agent IC146474 in late or recurrent carcinoma of the breast is described.Forty-six patients have been treated, of whom 10 have shown a good response. This is of the same order as that seen with oestrogens and androgens.The particular advantage of this drug is the low incidence of troublesome side effects.


Administration of 5-aminolaevulinic acid (ALA) leads to porphyrin accumulation in malignant and premalignant tissues, and ALA is used as a prodrug in photodynamic therapy (PDT). To understand the mechanism of porphyrin accumulation after the administration of ALA and to investigate whether ALA-induced protoporphyrin IX might be a suitable photosensitizer in Barrett's oesophagus and adenocarcinoma, we determined the activities of porphobilinogen deaminase (PBG-D) and ferrochelatase (FC) in various malignant and premalignant as well as in normal tissues of the human oesophagus. A PDT power index for ALA-induced porphyrin accumulation, the ratio of PBG-D to FC normalized for the normal squamous epithelium of the oesophagus, was calculated to evaluate intertissue variation in the ability to accumulate porphyrins. In malignant and premalignant tissue a twofold increased PBG-D activity and a marginally increased FC activity was seen compared with normal squamous epithelium. A significantly increased PDT power index in Barrett's epithelium and adenocarcinoma was found. Our results suggest that, after the administration of ALA, porphyrins will accumulate in a greater amount in Barrett's epithelium and adenocarcinoma of the oesophagus because of an imbalance between PBG-D and FC activities. The PDT power index here defined might be a useful indicative parameter for predicting the susceptibility of these tissues to ALA-PDT.


Xenopus, manipulated to be of comparable size, exhibited stagespecificantibody expression. The production of adult-type higher-affinity anti-DNPantibodies proved to be independent of the age and size of the individual and isconcomitant with the completion of metamorphosis. The appearance of new antibodyspecificities at such a time suggests that their expression occurs with the cell turnoverand renewal during a period of morphological changes.Tadpole and adult


Social relationships are robust predictors of better health and greater longevity in aging adults. The current study examined a relatively understudied aspect of relationship quality - positive relations with others, a domain of eudaimonic well-being - and its independent associations with change in and incidence of mobility limitations in a sample of mid-life and older adults from the Midlife in the United States (MIDUS) study. Using data from all 3 waves of MIDUS, we examined the extent to which positive relations with others predicted smaller increases in limitations and reduced risk of onset of new limitations over a 18-20 follow-up period. Linear and logistic regression models, adjusted for demographic and health confounds, showed that higher positive relations scores predicted slower increase in limitations over time (p=.003) and reduced risk of incidence of new limitations (p=.01). These effects were also observed over and above the associations with more traditional structural and functional measures of social relationships, neither of which was significantly linked to changes in functional abilities. These results suggest that positive relations with others may act as a unique protective factor for functional decline, both in individuals with no initial functional limitations and in those with existing limitations. They also extend prior research on the potential health benefits of social relationships to include a social dimension of eudaimonic well-being. Finally, they suggest that vulnerability to functional limitations and the potential benefits of social connectedness extend to mid-life as well as older adults.


Recent population trends for the United States show substantial increases in racial diversity as well as an increase in the older adult demographic. Accordingly, the expansion in minority older adults suggests the importance of recognizing how race affects future care planning (FCP) in late life. The aim of this paper is to investigate the racial similarities and differences in planning behavior and intentions related to end-of-life care planning. This study utilized data from the Future Care Planning intervention based on the initial assessment with 237 older adults in rural Iowa  with 73 non-White participants. Results indicated that both Whites and non-Whites had similar levels of intentions in terms of future care. However, non-Whites were less likely than Whites to engage in multiple areas of FCP including planning behavior and preparing for end-of-life . These findings suggest a need for more targeted FCP assessments and interventions across race groups in rural contexts.


Ways to address the increasing healthcare needs of older people are a priority for the National Health Service (NHS) in England. The NHS England Test Bed programme was designed to trial new models of care that are supported by digital health technologies. This paper reports on findings from one Test Bed programme, the Lancashire and Cumbria Innovation Alliance (LCIA) – a partnership between NHS England, industry and Lancaster University, which ran from 2016 to 2018. A key aim of the LCIA Test Bed was to explore the extent to which supported self-care telehealth technology helped older people with long-term conditions to better self-manage their own care, promoting independence and enabling them to remain at home for longer. Each patient received a combination of health technologies over a six-month period. This paper presents results from the qualitative data that formed part of a large-scale mixed-methods evaluation. Specifically it draws on the analysis of 34 observational interviews with 17 participants with chronic obstructive pulmonary disease (COPD) to understand the role of these technologies in the self-management of their care. The data revealed that the majority of participants felt more confident about self-managing COPD as a result of their participation in the programme. These increases in confidence were the result of participants’ increased knowledge and skills in managing their COPD. The paper demonstrates how patients learned to better manage their respiratory condition, the impact of this learning on their daily lives and that of their family carers, and the implications for healthcare practice.


We were struck reading this article by the fact that the authors did not properly address the state-of-the-art of the field in their review and were not addressing all the technologies developed over the past years to address intraoperative tumor diagnostic by MS. As a matter of fact, the authors fail to mention the SpiderMass technology. Therefore, they provide inadequate and not up-to-date citation on this discussed topic. In 2014, PRISM lab  introduced the water-assisted laser desorption/ionization MS (SpiderMass) and filed the patent (PCT/IB2015/057301) [ex vivo molecular profiles of a cohort of biopsies for example. One of the major advantages of the SpiderMass system is its low invasiveness and painless sampling, tissues being reversibly dehydrated. Another advantage and specific characteristic of SpiderMass is the very low fragmentation observed in the spectra and the possible operation in both positive and negative ion modes with good sensitivity. The system was successfully applied for cancer biopsies analysis ex vivo and then was shown for allowing real-time analysis of human skin in vivo as presented for the first time in 2015 at the ASMS conference and then published in 2016 [in vivo analysis and its potential to be used in intraoperative diagnostics. Over the past few years, the system was used to analyze genetically modified macrophage cell lines [ex vivo, allowing for correct classification (97% of specificity) of tumor type and grading [in vivo intraoperative analysis at the surgery room in a veterinary clinic on dog patients [We wish to offer our perspective and expertise concerning the review article entitled ‘mass spectrometry-based intra-operative tumor diagnosis’ written by Lorena Hänel PCT/IB201/057301 [patients . The afo


Occupational diseases are broadly defined as diseases with a specific clinical diagnosis associated with work-related factors. The worldwide burden of work-related diseases and injuries is high, although there are large variations in and between countries . A work-Detecting early signs of work-related diseases could stimulate prevention . Early sConsidering the factor work in clinical care is to increase knowledge of work-related risk factors in diagnoses, selective prevention and treatment in the daily care of patients. The diagnoses of occupational diseases or work-related diseases is often complex due to its multifactorial origin and dependent on work-related, personal  and environmental factors. Work-related risk factors can worsen the prognosis and can hinder returning to work or sustaining at work. Therefore, knowledge about the work-relatedness of diseases is useful for clinicians in order to take timely and actively actions related to risk factors in the workplace; it will optimize the work participation of their patients and prevent worsening of diseases.


The increasing interest for microfluidic devices in medicine and biology has opened the way to new time-lapse microscopy era where the amount of images and their acquisition time will become crucial. In this optic, new data analysis algorithms have to be developed in order to extract novel features of cell behavior and cell–cell interactions. In this brief article, we emphasize the potential strength of a new paradigm arising in the integration of microfluidic devices , time-lapse microscopy analysis, and machine learning approaches. Some snapshots of previous case studies in the context of immunotherapy are included as proof of concepts of the proposed strategies while a visionary description concludes the work foreseeing future research and applicative scenarios. In sucho models . Howevero models , liver  according to cell movements extracted in synthetic videos with the effect to make the ex vivo experiment more robust, to conduct synthetic massive tests, to reduce time-to therapy and patient undesired treatment effects.In this context, one of the most challenging scenarios for OOC devices is represented by cancer-immune cross-talk due to the very complex and not still completely discovered signaling modalities between immune cells and cancer insult or among clustered cancer cells. Some attempts have been presented with the aim to model cancer–immune interaction  through approach  but therapproach ]. In thiapproach . Trajectapproach , automatapproach . After capproach ] can be approach . The stuapproach . Additioapproach . Motilitapproach . Furtherapproach  allow rein vivo and ex vivo like scenarios in favor of reduced invasiveness and deep understanding.The described platform is expected to open new scenarios of cell network modeling such as agent-based system  in order to simulate more advanced organs-on-chip model coupled to artificial intelligence (AI)-based algorithms and neural networks to provide more affordable organs-on-chip models of study. These AI-based OOC may potentially shorten the distances between in silico-based devices. Such a scenario allows enlarging the potentiality of OOCs experiments by increasing the mimicking capability of the platform toward in vivo like environment.Future application scenarios include the possibility to develop a hybrid system in which OOC-based environment interacts with This scenario is made possible counteracting the limitations imposed by the need of very high frame rate and high spatial resolution of the acquired images that lead to undesired effects such as phototoxicity and storage of more than Gigabytes of a single experimental data. Thanks to the exploitation of modern Deep Learning (DL) architecture , future EM and AM designed the manuscript organization and coordinated interactions among authors. All authors contributed to the manuscript preparation and revision.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Nature leads this week with a story about a proposal to fuse space-based astronomy funded by NASA with ground-based astronomy funded by the National Space Foundation (NSF). Science starts the week with a successs story about attempts to slow the spread of foot-and-mouth disease.


In this important paper Dr. Cheung and cols. from New York - USA, presented a modified technique of artificial urinary sphincter (AUS) placement with dorsolateral fibromuscular tissue of bulbo-spongiosus muscle (BSM) preservation.The authors proposed a technique that is associated with low rates of erosion and infection in patients with high risk of complications . BSM, also known as the bulbo-cavernosus muscle, is a paired striated muscle originating from the perineal body and fixed in a median raphe involving the bulbar urethra , 2. BSM The authors concluded that the preservation of dorsolateral fibromuscular tissue of BMS during AUS placement is an effective means to achieve a low risk of erosion with good functional outcomes with low rates of re-operation and excellent long-term continence. The study is retrospective but the description of a 74% success index is amazing and this new technique with BSM preservation is very interesting. This article presents a good overview of the surgical treatment of erectile dysfunction-related Peyronie's disease, covering the best indication of the various possible surgical alternatives. To conclude, we also emphasize that pre-operative counseling about the realistic outcomes of surgery in PD is mandatory to achieve adequate postoperative satisfaction rates.


Cellular aging is characterized by a build-up of oxidatively modified proteins. The steady-state level of oxidized proteins depends on the balance between the rate of protein oxidative damage and the rates of protein degradation and repair. Therefore, the accumulation of oxidized protein with age can be due to increased protein damage, decreased oxidized protein degradation and repair, or the combination of both mechanisms. The proteasomal system is the major intracellular proteolytic pathway implicated in the degradation of oxidized protein, and the peptide methionine sulfoxide reductase catalyzes the reduction of methionine sulfoxide  to methionine within proteins. A short summary on protein oxidative damage and oxidized protein degradation is given, and evidence for a decline of proteasome function with age is presented. Arguments for the implication of peptide methionine sulfoxide reductase in the age-related accumulation of oxidized protein are also discussed.


The late nineteenth century witnessed unprecedented advances in biomedical sciences, with the promotion in particular of physiological experimentation, bacteriological investigation, and chemical research . These finter alia, the shift from traditional materia medica to laboratory- and industry-based research; the establishment of the chemical and biological foundations of pharmacology; the gradual transformation from empirical drug discovery to rational drug design; the development of a wide variety of new drugs, as well as—more recently—the impact of molecular biology; and the re-evaluation of therapeutic strategies and priorities , and sheds more light upon the feedback loops that exist between bench and bedside, which are stereotypical of much pharmaceutical innovation.Al-Humadi et al. in their disease-focused review on the challenges of treating tuberculosis, with a specific emphasis on the decades between World War II and the early twenty-first century. In addition to summarizing the historical sequence of relevant drug development and use, the authors consider issues of drug resistance, drug repurposing, and problems of co-infection as factors influencing the fight against tuberculosis.A different approach is taken by Falzone et al. consider pharmacological treatments for cancer at the beginning of the twenty-first century, against the background of a series of turning points defining modern oncology: radiotherapy; the introduction of broad-based chemotherapy; targeted therapeutics; and the recent adoption of checkpoint inhibition as a novel immunomodulatory anticancer approach. Their review emphasizes the constantly changing and evolving field of drug discovery in the fight against cancer, with a focus on the biopharmaceuticals.Li et al. in their review of drugs for autoimmune inflammatory diseases, in which they describe the therapeutic trajectory from small-molecule compounds to anti-tumor necrosis factor (anti-TNF) biologics. In addition to analyzing the historical development of anti-inflammatory drugs after World War II, the authors consider the promise of novel TNF receptor-targeting entities that have already revolutionized the management of autoimmune diseases such as rheumatoid arthritis.A similar discussion on biopharmaceuticals is presented by Gu and Pei is a shorter perspective on historical aspects of Chinese herbal medicine (CHM) ranging from traditional practice to scientific drug discovery, with a focus on the antimalarial compound artemisinin. The authors suggest that a new understanding of traditional health practices using modern systematic and in silico techniques such as analytical chemistry, systems biology, network pharmacology, and computational modeling could provide promising new interpretations and applications of CHM.The final contribution by The articles included here cover only a small section of this huge subject of post-World War II pharmaceutical innovation. We hope that these papers will stimulate readers to delve further and reflect on the vast and varied relevant literature.Both authors have contributed equally to this work.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Cyprinus carpio), hereafter referred as carp, is one of the most widely cultured fish produced for food globally. It was introduced into Australia for aquaculture in the mid-nineteenth century ] in Australia. McColl et al.  and produce viable offspring which are expected to have a high resistance to CyHV-3 disease  than in aquaculture ponds or under laboratory conditions (Kopf et al., The observation that CyHV-3 can persist in the wild without inducing carp death suggests that the expression of the disease requires environmental co-factors. Notably, the lack of recorded CyHV-3-associated mass carp deaths in Australia may simply reflect a lack of environmental co-factors rather than the absence of the virus. A recent phylogenetic study suggested that ancestors of CyHV-3 may have infected carp populations, long before the initial outbreaks of the disease were first reported (Gao et al., Invasive carp expanded in Australia to their current range and relative abundance decades ago (Shearer and Mulley, All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Despite the increasing trend in catalytic studies dealing with gold-based materials, many questions remain open and the beauty of gold for the catalysis community remains alive. Apparently, the magic of this element resides in its resistance to be completely understood. Simultaneously, this mystery attracts scientists to keep working on it, to keep playing the game of revealing the beautiful secrets behind gold catalysts.Gold nanocatalysts have demonstrated excellent features for environmental catalysis including CO oxidation, clean hydrogen production, VOCs abatement, water purification, and COThe aim of this Research Topic is to celebrate the success of catalysis by gold, the extraordinary versatility of gold nanoparticles as catalytic materials, and the impact of gold-based catalysts for the development of greener and more sustainable societies.Megías-Sayago et al. demonstrated the high efficiency of gold catalysts to conduct oxidations reactions in gas phase  and liquid phase (selective glucose oxidation). Both processes are key reactions with potential applications in the elimination of toxic gases in the former and synthesis of added-value platform chemicals in the latter. In terms of applications, the comprehensive review contribution from Carabineiro showcases the excellent performance of gold-based catalysts for two industrially relevant reactions such as the oxidation of alcohols and the oxidation of alkanes. The influence of the particle size, preparation method, and support is carefully described. Moreover, some mechanistic insights are addressed, opening some room for future catalyst improvement.In this sense, the collection of high-caliber contributions gathered in this special issue reflects the successful story of catalysis by gold and allows one to foresee the future in this field whose horizons are still under continuous expansion. This special issue reflects the versatility of nanogold catalysts in both liquid and gas phase reactions. For instance, the research article by Tabakova's review is an excellent contribution to the field of clean hydrogen production for fuel cell applications. The paper revises the most recent literature on the water gas shift reaction (WGS) and preferential CO oxidation (CO-PrOx)–processes in which gold-based catalysts outstand as highly efficient materials. The review covers multiple aspects that are not standard in review papers such as design of single-atom catalysts, structure-monolithic catalysts, and strategies to design highly stable catalysts, among many other pivotal aspects of gold-based catalysts for redox reactions. Following the topic of the WGS reaction, the team of Prof. Hutchings has made an extraordinary contribution to this special issue with the research paper entitled Enhanced Activity and Stability of Gold/Ceria-Titania for the Low-Temperature Water–Gas Shift Reaction . It is well-known that gold supported on ceria-zirconia is one of the most active low-temperature water–gas shift catalysts reported to date but rapid deactivation occurs under reaction conditions. In this work, ceria-titania is proposed as an alternative support to highly dispersed gold nanoparticles leading to promising results in terms of activity and stability.Molina et al.). An added value of this work is the detailed discussion on how to optimize gold colloid preparation and their deposition to carbon materials that are very different in nature. The change of the continuous phase and its dielectric constant is used to assure the good dispersion of the hydrophilic/hydrophobic carbons and the successful transfer of the preformed small size colloids to their surface.Beyond oxidation reactions, this special also showcases the successful application of gold for reduction processes. The paper from Odriozola's team entitled Carbon Supported Gold Nanoparticles for the Catalytic Reduction of 4-Nitrophenol is a good example of the excellent performance of carbon-supported nanogold particles for organic nitro-compound reduction . This includes, for example, oxidation and reduction reactions in both gas and liquid phase media. The perspective also touches some of the most relevant industrial applications of gold-based catalysts commercialized so far. In addition, this perspective provides a snapshot of the current challenges triggered by nanogold catalyst limitations and also try to pinpoint the future trends expected for these materials.Finally, the perspective paper by Price and co-workers entitled “The successful story of gold based catalysts for Gas and Liquid Phase reactions: brief perspective and beyond” is a nice synthetic piece of work where the fruitful application of gold-based catalysts in multiple processes is carefully addressed (As mentioned above, the spirit of this special issue is to celebrate with the catalysis community the success of one of its most acclaimed metals: gold. Overall, the set of works gathered in this special issue can be considered a fair representation of the versatility of gold-based catalyst to be a champion material in multiple applications. The editorial team hopes that this collection serves as a useful tool for the catalysis society and we hope to ignite passion for the discovery of the beautiful science hidden by this mysterious element.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


This data is useful to compare the oil prices impact on the leading oil trading countries and also compare a set of countries affected most by oil prices’ fluctuations, oil-exporting countries or oil-importing countries. Since this data covers the period of latest oil-crisis, so the impact of oil-crisis could also be analysed.This data presented in this article is specifically employed from the Asian region based on the top position in the list of oil exporting and oil-importing countries around the world. Asia as the biggest continent on the earth had high consumption of energy [1]. Here we employed the daily prices of crude oil and seven oil trading countries, out of which three are oil exporting  and four are oil-importing countries , from the time period of 1-09-2009 to 31-08-2018. The data is collected from an authentic database Bloomberg. This data is related to the research paper “Volatility spillover impact of world oil prices on leading Asian energy exporting and importing economies' stock returns. Energy, 188 (2019), 116002,  Energy 2The data covers the daily stock prices of three oil-exporting and four oil-importing countries, and then return of these prices are employed. The returns are calculated by taking the natural logarithm of closing prices divided by lagged closing prices.At first the graphical pictures of prices and returns are presented  to analyDescriptive analysis was performed to present a real picture about the important trends of the oil trading countries . The details of the descriptive analysis for the data are presented in Ethics approval is not applicable.The authors of the study have given their consent for the data to be used and published in this scientific article.Data generated or analysed during the study are available in the published paper which is highlighted in the aforementioned text. Moreover, raw data is linked with this data article in the (1)- Financial support from Fujian Major Social Science Planning Fund Program under grant no. FJ2017Z006.(2)- Fujian Natural Science Foundation Project under grant no. 2017J01518.There are two kind of funding supports with this data article.All of the authors have contributed equally to the design of theoretical model, to analyzing and discussing the data and to writing the data article. All of the authors read and approved this data article.


After the diagnosis of transsexualism is confirmed therapy commences with psychotherapeutic preparation for the conversion, and after conversion, long-term patient rehabilitation is maintained for at least two years. The indication for surgery is chronic discomfort caused by discord with the patient's natural gender, intense dislike of developing secondary sex characteristics and the onset of puberty. The surgical conversion of transsexuals is the main step in the complex care of these problematic patients . This suWe present a step-by-step male to female transsexual surgery.Surgical gender reassignment of male transsexuals resulted in replicas of female genitalia which enabled coitus with orgasm . With th


A 30-year-old male with history of repaired hypospadias and anal atresia was referred for magnetic resonance imaging (MRI) of the pelvis  because of ongoing chronic prostatitis-like complaints for three months. MRI revealed a large thick-walled cystic lesion in the midline between the prostate and the (deformed) sacrum, communicating with the prostatic urethra at the level of the verumontanum via a thin neck  are cystic intraprostatic lesions located dorsocranially in the midline with communication to the prostatic urethra at the level of the verumontanum. They are embryologic remnants of the Müllerian duct system and are associated with genito-urinary abnormalities including hypospadias, intersex disorders, cryptorchidism and renal agenesis . PUCs ar


The urban-rural dichotomy underpins the common approach in studying environmental conditions influencing older adults’ lives characterized by post-Second World War urban migration in both Italy and the United States (US). However, the traditional opposition urban-rural dichotomy is inadequate to study how the environmental characteristics of a geographical area can account for the heterogeneous profile of its populations and its age distribution. This study aims to overcome the traditional mobility theories as an explanatory dichotomy for understanding the distribution of the age structure of a given population. The extent of a supportive network, and the connection between the place of residence to the proximity of other residential centres can be seen as potential resources for understanding the attractiveness of certain areas for older adults. A large harmonized set of demographic and socio-economic data were collected from the Italian National Institute of Statistics (ISTAT) and the American Community Survey (ACS). An analysis at the Italian municipality- and US county-level finds the population over 75 years old are overrepresented in rural areas of both countries as would be expected by available employment opportunities, but considerable heterogeneity among both urban and rural areas exist. In particular, rural more than urban settings are based on an informal support network that is argued to rely on human proximity to produce successful aging in the community. The variation in population of older adults in rural areas, therefore, might have implications on how to achieve age-friendly communities, aside from population’s traditional mobility theories and formal support network.


Depression is a common mental disorder worldwide, and also a leading cause of disability and global burden of disease. The risk factors of depression are multi-facets; however, past studies have focused more on individual factors than ecological factors. This study aims to use a health map framework with multi-level analysis to analyze the effects of environmental factors on the incidence of depression of older adults in Taiwan. We connected 3 national datasets, including the National Health Interview Survey (NHIS), Age-friendly Dataset at city-level, and the National Health Insurance Research Databases (NHRID), to examine the relationship between environmental factors and the incidence of depression in Taiwan. The dependent variable was the new cases of depression in older adults during 2010-2016. The study variables were environment factors including 5 build environments and 8 social environments. A total of 6494 valid participants aged 50 and over were recruited from the 2009 NHIS and were followed up to 2016. There were 292 (4.5%) new incident cases of depression during 2010-2016. Results of multi-level analysis showed that only one built environment (no. of heritage sites) was associated with the incidence of depression. No social factors was found significantly in the study. It seems that factors of individual-level appear more important than that of ecological-level as the determinants of depression. Results of this study could provide an exploratory information for future research regarding the relationships between depression and environments.


In the last 10 years there has been increasing interest in the role of calcitonin gene-related peptide (CGRP) in primary headaches. Tension-type headache is one of the most common and important types of primary headaches, and ongoing nociception from myofascial tissues may play an important role in the pathophysiology of this disorder. CGRP sensory fibers are preferentially located in the walls of arteries, and nerve fibers containing CGRP accompany small blood vessels in human cranial muscles. It is well established that nociception may lead to release of CGRP from sensory nerve endings and from central terminals of sensory afferents into the spinal cord. It has also been shown that density of CGRP fibers around arteries is increased in persistently inflamed muscle. These findings indicate that ongoing activity in sensory neurons in the cranial muscles may be reflected in changes of plasma levels of neuropeptides in patients with chronic tension-type headache. To explore the possible role of CGRP in tension-type headache, plasma levels of CGRP were measured in patients with chronic tension-type headache. This study showed that plasma levels of CGRP are normal in patients and unrelated to headache state. However, the findings of normal plasma levels of CGRP do not exclude the possibility that abnormalities of this neuropeptide at the neuronal or peripheral  levels play a role in the pathophysiology of tension-type headache. Investigation of CGRP in other compartments with new sensitive methods of analysis is necessary to clarify its role in tension-type headache.


Please be advised that since publication of the original article  the authPlease see below for the correct (up-to-date) version of the figure:The authors apologize for this error.


The engineering design of microbioreactors (MBRs) and Organ-on-Chips (OoCs) has advanced considerably in recent years ,2. The tIn bioprocess development, the main aim of the use of MBRs is to accelerate the development work of new bioprocesses with microorganisms or mammalian cells as production organisms . The culThe aim of OoC devices is to facilitate the study of organ cell assemblies in vitro under conditions that recreate in vivo conditions of the organ in the body for recapitulating time-related cellular behavior ,5. An OoThis special issue addresses these diverse aspects of MBR design in nine expert contributions where a variety of cells and tissues are used with various aims and ambitions.The fundamental design challenges in MBRs are highlighted in two review contributions ,7. The sSeldon and Fuller  further The use of MBRs as tools for investigating tumor models is highlighted in two research studies ,9. KuhlbToh and colleagues  have devInvestigating effects of drug compounds on organ cells in in vitro microfluidic models has been mentioned recurrently to fill the need in the pharma industry for more efficient drug testing. In a study by Christoffersson and colleagues , a 3D moFreyer and colleagues  demonstrIn another MBR setup, Wrzesinski and Fey  carry ouAspects of fluid dynamics in MBRs are addressed by Tajsoleiman et al. . Due to Another important aspect of MBR design is oxygen distribution. Fernandez et al.  demonstrAll together, these nine contributions reflect state-of-the-art aspects of MBR design and highlight the inherent potential and strengths of the concept of MBRs for organ cell studies.


Digital communication technologies expand opportunities for social interactions and as a result have the potential to either amplify or dampen the coupling of social interactions with well-being in daily life. We use data from the 100-day Personal Understanding of Life and Social Experiences project  to examine variation in the sensitivity of older adults’ daily reports of well-being to the quality of social interactions with their five closest social partners across digital  and analogue (in person/by phone) interactions. Digital interactions were more common among less-close social partners. Multilevel random coefficient models showed days with more digital interactions than normal to be characterized by a) lower well-being and b) less sensitivity in well-being to the quality of social interactions with close social partners on that day. The implications of our findings are discussed within a life-span perspective of social relationships and well-being.


Kynurenic acid (KYNA) is a bioactive compound that is produced along the kynurenine pathway (KP) during tryptophan degradation. In a few decades, KYNA shifted from being regarded a poorly characterized by-product of the KP to being considered a main player in many aspects of mammalian physiology, including the control of glutamatergic and cholinergic synaptic transmission, and the coordination of immunomodulation. The renewed attention being paid to the study of KYNA homeostasis is justified by the discovery of selective and potent inhibitors of kynurenine aminotransferase II, which is considered the main enzyme responsible for KYNA synthesis in the mammalian brain. Since abnormally high KYNA levels in the central nervous system have been associated with schizophrenia and cognitive impairment, these inhibitors promise the development of novel anti-psychotic and pro-cognitive drugs. Here, we summarize the currently available structural information on human and rodent kynurenine aminotransferases (KATs) as the result of global efforts aimed at describing the full complement of mammalian isozymes. These studies highlight peculiar features of KATs that can be exploited for the development of isozyme-specific inhibitors. Together with the optimization of biochemical assays to measure individual KAT activities in complex samples, this wealth of knowledge will continue to foster the identification and rational design of brain penetrant small molecules to attenuate KYNA synthesis, i.e., molecules capable of lowering KYNA levels without exposing the brain to the harmful withdrawal of KYNA-dependent neuroprotective actions. N-methyl-D-aspartate receptor (NMDAR). In addition, KYNA non-competitively antagonizes the α7-nicotinic acetylcholine receptor (α7nAChR) . Research interests in the KP find a unifying rationale in the ever-increasing demonstrations that the majority of the compounds formed along the pathway play a role in modulating fundamental aspects of biology  the absolute availability of tryptophan and/or L-kynurenine (KYN), (ii) the competition that exists between the kynurenine monooxygenase/kynureninase-dependent branches of the catabolic KP cascade   , in complex with the amino group donor/substrate kynurenine, or with the amino group acceptor/co-substrate oxaloacetate   . This rekat1 gene variant isolated from spontaneously hypertensive rats (SHR) is characterized by a missense mutation that leads to a Glu-to-Gly amino acid substitution at the C-terminal side of the sliding α-helix in the KAT I N-terminal arm (Kwok et al., The structural information on KATs summarized here strengthens the initially hypothesized fundamental role of a discrete region of the N-terminal arm of KATs in controlling substrate/inhibitor access into and binding inside the active site (Rossi et al., The analysis of KYNA synthesis from an integrated structural biology/neuropharmacology standpoint will drive the lead optimization process aimed at further improving the pharmacodynamics, bioavailability and specificity of action for the most potent hKAT II inhibitors developed thus far, as a prerequisite to their safe use in pathological situations characterized by abnormally elevated brain KYNA levels. However, due to the potential adverse effects associated with the irreversible inhibition of KATs, the future challenge for the field is the identification and/or the structure-based design of molecules capable of reversibly associating with specific KAT targets (Nematollahi et al., heme demolition, and XA deficiency has been associated with direct oxidative damage to insect midgut epithelial cells (Lima et al., Anopheles gambiae 3-hydroxykynurenine transaminase (Rossi et al., Plasmodium male gametogenesis, which takes place in the mosquito upon a parasite-infected blood meal (Billker et al., in vivo analyses, it has been proposed that KAT II could be the main determinant of XA synthesis in the CNS (Sathyasaikumar et al., At the same time, by revealing the determinants of substrate specificity in specific KAT isozymes, a combined structural biology/biochemistry approach could provide new small molecule tools to better characterize the interplay between the alternative branches of the KP in physiological conditions and in human diseases. A paradigmatic example of the applicability of such an approach is its recent use to study the roles of XA in the CNS. In light of the pro-apoptotic and neurotoxic potential associated with 3-HK (Okuda et al., All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Given the high current prevalence of dementia and expected increases in the coming years, it is increasingly important to understand and address the process of transitioning from driving to non-driving among older drivers with dementia and the potential role of self-regulation . The purpose of this Alzheimer’s Association-funded study was to examine differences in self-regulation between older drivers with and without dementia. Fifty-two active drivers age 65 or older , completed a validated self-regulation questionnaire and standardized assessment of cognition, vision, and psychomotor skills. The dementia group reported some awareness of cognitive challenges (lower driving-related abilities to remember things and concentrate on multiple things at a time than the comparison group). Similarly, the dementia group performed significantly worse on memory tasks and complex reaction time in the objective assessment. Both groups were confident they could drive safely where they needed to go. However, the dementia group reported being less comfortable driving in several situations . Despite lower driving comfort among the dementia group, there were few differences in self-regulation between the groups. The only statistically significant difference was that more of the dementia group had reduced their driving in the past year. There were no differences in self-regulation between groups for any of the specific driving situations for which the dementia group reported feeling less comfortable. Full study results will be presented along with implications for programs and future research.


Bactrocera dorsalis) infestations. The data was collected from the experiment. Fifty chili varieties (Capsicum spp.) were planted in the screen house and subjected to antixenosis and antibiosis tests. The antixenosis test was evaluated using choice and no-choice methods. The data observed was the number of oviposition punctures by fruit fly on the chili fruits. The antibiosis test was conducted on chili fruits using the Fitness Index method. The data observed were the percentage of pupa (%), the weight of pupa (mg), duration of larva-pupa (day), and duration of pupa-imago (day).This article contains the data on chili antixenosis and antibiosis to fruit fly ( The antixenosis response of chili to fruit fly (An antibiosis experiment was set up according to Hennessey et al.


In the original article, there was an error regarding the cost of medically unexplained symptoms (MUS).A correction has been made to the Abstract:“Medically unexplained symptoms (MUS) are common in both primary and secondary health care. It is gradually being acknowledged that there needs to be a variety of interventions for patients with MUS to meet the needs of different groups of patients with such chronic long-term symptoms. The proposed intervention described herewith is called The BodyMind Approach (TBMA) and promotes learning for self-management through establishing a dynamic and continuous process of emotional self-regulation. The problem is the mismatch between the patient's mind-set and profile and current interventions. This theoretical article, based on practice-based evidence, takes forward the idea that different approaches  are required for people with MUS. The mind-set and characteristics of patients with MUS are reflected upon to shape the rationale and design of this novel approach. Improving services for this population in primary care is crucial to prevent the iterative spiraling downward of frequent general practitioner (GP) visits, hospital appointments, and accident and emergency attendance (A&E), all of which are common for these patients. The approach derives from embodied psychotherapy (authentic movement in dance movement psychotherapy) and adult models of learning for self-management. It has been developed from research and practice-based evidence. In this article the problem of MUS in primary care is introduced and the importance of the reluctance of patients to accept a psychological/mental health referral in the first instance is drawn out. A description of the theoretical underpinnings and philosophy of the proposed alternative to current interventions is then presented related to the design, delivery, facilitation, and educational content of the program. The unique intervention is also described to give the reader a flavor.”Additionally, a correction has been made to the Introduction, paragraph one:“Medically unexplained symptoms (MUS) are a thorny issue in primary care. Despite the differing nomenclature, the recent DSM-5 terms it as somatic symptom disorder (SSD) but is yet to achieve general usage. Many general practitioners (GPs) appear to reliably recognize MUS without the need for standardized assessments (Rasmussen et al., The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.