Exploring Structural Requirements for Sigma-1 Receptor Linear Ligands: Experimental and Computational Approaches.

Sigma-1 receptor (S1R) is involved in a large array of biological functions due to its ability to interact with various proteins and ion channels. Crystal structures of human S1R revealed the trimeric organization for which each protomer comprises the ligand binding pocket. This study applied a multistep computational procedure to develop a pharmacophore model obtained from molecular dynamics simulations of available cocrystal structures of well-known S1R ligands. Apart from the well-established positive ionizable and hydrophobic features, the obtained model included an additional specific hydrophobic feature and different excluded volumes, thus increasing the selectivity of the model as well as a more detailed determination of the distance between two essential features. The obtained pharmacophore model passed the validation test by receiver operating characteristic (ROC) curve analysis of active and inactive S1R ligands. Finally, the pharmacophoric performance was experimentally investigated through the synthesis and binding assay of new 4-phenylpiperazine-based compounds. The most active new ligand 2-(3-methyl-1-piperidyl)-1-(4-phenylpiperazin-1-yl)ethanone (3) showed an S1R affinity close to the reference compound haloperidol (Ki values of 4.8 and 2.6 nM, respectively). The proposed pharmacophore model can represent a useful tool to design and discover new potent S1R ligands.

Anatomical Registration of Implanted Sensors Improves Accuracy of Trunk Tilt Estimates with a Networked Neuroprosthesis.

For individuals with spinal cord injuries (SCIs) above the midthoracic level, a common complication is the partial or complete loss of trunk stability in the seated position. Functional neuromuscular stimulation (FNS) can restore seated posture and other motor functions after paralysis by applying small electrical currents to the peripheral motor nerves. In particular, the Networked Neuroprosthesis (NNP) is a fully implanted, modular FNS system that is also capable of capturing information from embedded accelerometers for measuring trunk tilt for feedback control of stimulation. The NNP modules containing the accelerometers are located in the body based on surgical constraints. As such, their exact orientations are generally unknown and cannot be easily assessed. In this study, a method for estimating trunk tilt that employed the Gram-Schmidt method to reorient acceleration signals to the anatomical axes of the body was developed and deployed in individuals with SCI using the implanted NNP system. An anatomically realistic model of a human trunk and five accelerometer sensors was developed to verify the accuracy of the reorientation algorithm. Correlation coefficients and root mean square errors (RMSEs) were calculated to compare target trunk tilt estimates and tilt estimates derived from simulated accelerometer signals under a variety of conditions. Simulated trunk tilt estimates with correlation coefficients above 0.92 and RMSEs below 5° were achieved. The algorithm was then applied to accelerometer signals from implanted sensors installed in three NNP recipients. Error analysis was performed by comparing the correlation coefficients and RMSEs derived from trunk tilt estimates calculated from implanted sensor signals to those calculated via motion capture data, which served as the gold standard. NNP-derived trunk tilt estimates exhibited correlation coefficients between 0.80 and 0.95 and RMSEs below 13° for both pitch and roll in most cases. These findings suggest that the algorithm is effective at estimating trunk tilt with the implanted sensors of the NNP system, which implies that the method may be appropriate for extracting feedback signals for control systems for seated stability with NNP technology for individuals who have reduced control of their trunk due to paralysis.

Leveraging the 3-Chloro-4-fluorophenyl Motif to Identify Inhibitors of Tyrosinase from Agaricus bisporus.

Tyrosinase (EC 1.14.18.1) is implicated in melanin production in various organisms. There is a growing body of evidence suggesting that the overproduction of melanin might be related to several skin pigmentation disorders as well as neurodegenerative processes in Parkinson's disease. Based on this consideration, the development of tyrosinase inhibitors represents a new challenge to identify new agents in pharmaceutical and cosmetic applications. With the goal of identifying tyrosinase inhibitors from a synthetic source, we employed a cheap and facile preliminary assay using tyrosinase from Agaricus bisporus (AbTYR). We have previously demonstrated that the 4-fluorobenzyl moiety might be effective in interactions with the catalytic site of AbTYR; moreover, the additional chlorine atom exerted beneficial effects in enhancing inhibitory activity. Therefore, we planned the synthesis of new small compounds in which we incorporated the 3-chloro-4-fluorophenyl fragment into distinct chemotypes that revealed the ability to establish profitable contact with the AbTYR catalytic site. Our results confirmed that the presence of this fragment is an important structural feature to improve the AbTYR inhibition in these new chemotypes as well. Furthermore, docking analysis supported the best activity of the selected studied compounds, possessing higher potency when compared with reference compounds.

Anti-Aggregative and Protective Effects of Vicenin-2 on Heat and Oxidative Stress-Induced Damage on Protein Structures.

Vicenin-2, a flavonoid categorized as a flavones subclass, exhibits a distinctive and uncommon C-glycosidic linkage. Emerging evidence challenges the notion that deglycosylation is not a prerequisite for the absorption of C-glycosyl flavonoid in the small intestine. Capitalizing on this experimental insight and considering its biological attributes, we conducted different assays to test the anti-aggregative and antioxidant capabilities of vicenin-2 on human serum albumin under stressful conditions. Within the concentration range of 0.1-25.0 µM, vicenin-2 effectively thwarted the heat-induced HSA fibrillation and aggregation of HSA. Furthermore, in this study, we have observed that vicenin-2 demonstrated protective effects against superoxide anion and hydroxyl radicals, but it did not provide defense against active chlorine. To elucidate the underlying mechanisms, behind this biological activity, various spectroscopy techniques were employed. UV-visible spectroscopy revealed an interaction between HSA and vicenin-2. This interaction involves the cinnamoyl system found in vicenin-2, with a peak of absorbance observed at around 338 nm. Further evidence of the interaction comes from circular dichroism spectrum, which shows that the formation of bimolecular complex causes a reduction in α-helix structures. Fluorescence and displacement investigations indicated modifications near Trp214, identifying Sudlow's site I, similarly to the primary binding site. Molecular modeling revealed that vicenin-2, in nonplanar conformation, generated hydrophobic interactions, Pi-pi stacking, and hydrogen bonds inside Sudlow's site I. These findings expand our understanding of how flavonoids bind to HSA, demonstrating the potential of the complex to counteract fibrillation and oxidative stress.

Motorless cadence control of standard and low duty cycle-patterned neural stimulation intensity extends muscle-driven cycling output after paralysis.

BACKGROUND: Stimulation-driven exercise is often limited by rapid fatigue of the activated muscles. Selective neural stimulation patterns that decrease activated fiber overlap and/or duty cycle improve cycling exercise duration and intensity. However, unequal outputs from independently activated fiber populations may cause large discrepancies in power production and crank angle velocity among pedal revolutions. Enforcing a constant cadence through feedback control of stimulus levels may address this issue and further improve endurance by targeting a submaximal but higher than steady-state exercise intensity. METHODS: Seven participants with paralysis cycled using standard cadence-controlled stimulation (S-Cont). Four of those participants also cycled with a low duty cycle (carousel) cadence-controlled stimulation scheme (C-Cont). S-Cont and C-Cont patterns were compared with conventional maximal stimulation (S-Max). Outcome measures include total work (W), end power (Pend), power fluctuation (PFI), charge accumulation (Q) and efficiency (η). Physiological measurements of muscle oxygenation (SmO2) and heart rate were also collected with select participants. RESULTS: At least one cadence-controlled stimulation pattern (S-Cont or C-Cont) improved Pend over S-Max in all participants and increased W in three participants. Both controlled patterns increased Q and η and reduced PFI compared with S-Max and prior open-loop studies. S-Cont stimulation also delayed declines in SmO2 and increased heart rate in one participant compared with S-Max. CONCLUSIONS: Cadence-controlled selective stimulation improves cycling endurance and increases efficiency over conventional stimulation by incorporating fiber groups only as needed to maintain a desired exercise intensity. Closed-loop carousel stimulation also successfully reduces power fluctuations relative to previous open-loop efforts, which will enable neuroprosthesis recipients to better take advantage of duty cycle reducing patterns.

Selective neural stimulation methods improve cycling exercise performance after spinal cord injury: a case series.

BACKGROUND: Exercise after paralysis can help prevent secondary health complications, but achieving adequate exercise volumes and intensities is difficult with loss of motor control. Existing electrical stimulation-driven cycling systems involve the paralyzed musculature but result in rapid force decline and muscle fatigue, limiting their effectiveness. This study explores the effects of selective stimulation patterns delivered through multi-contact nerve cuff electrodes on functional exercise output, with the goal of increasing work performed and power maintained within each bout of exercise. METHODS: Three people with spinal cord injury and implanted stimulation systems performed cycling trials using conventional (S-Max), low overlap (S-Low), low duty cycle (C-Max), and/or combined low overlap and low duty cycle (C-Low) stimulation patterns. Outcome measures include total work (W), end power (Pend), power fluctuation indices (PFI), charge accumulation (Q), and efficiency (η). Mann-Whitney tests were used for statistical comparisons of W and Pend between a selective pattern and S-Max. Welch's ANOVAs were used to evaluate differences in PFIs among all patterns tested within a participant (n ≥ 90 per stimulation condition). RESULTS: At least one selective pattern significantly (p < 0.05) increased W and Pend over S-Max in each participant. All selective patterns also reduced Q and increased η compared with S-Max for all participants. C-Max significantly (p < 0.01) increased PFI, indicating a decrease in ride smoothness with low duty cycle patterns. CONCLUSIONS: Selective stimulation patterns can increase work performed and power sustained by paralyzed muscles prior to fatigue with increased stimulation efficiency. While still effective, low duty cycle patterns can cause inconsistent power outputs each pedal stroke, but this can be managed by utilizing optimized stimulation levels. Increasing work and sustained power each exercise session has the potential to ultimately improve the physiological benefits of stimulation-driven exercise.

Is your mind set? - how are intra- and interpersonal competences dealt with in medical education? A multi-professional qualitative study.

BACKGROUND: Professional intrapersonal and interpersonal competences (IICs) form an important part of medical expertise but are given little attention during clinical training. In other professional fields such as psychotherapy, education and aviation, training in IICs is an integral part of education and practice. In medicine, IICs tend to actually decline during studies. To date it is unclear why IICs are given less attention in medicine, despite evidence for their importance in the treatment process. In view of this, the study examined the role of IICs in the treatment process, the current situation of IIC training in medicine and, most importantly, the reasons for the comparatively low focus on IICs in the clinical training of medical students. METHODS: Semi-structured interviews were carried out with 21 experts from a variety of medical specialties and non-medical professions that provide a training with a stronger focus on IIC development. The interviews were evaluated using grounded theory. RESULTS: The experts confirmed the idea that IICs are an equally important component in the treatment process, along with medical knowledge and technical skills. They also described large differences between the IICs possessed by physicians but noted a general developmental need. The key shortcoming was perceived to be a deep-seated defensiveness towards learning from mistakes and deficits e.g. through reflection and feedback. The interaction of different factors that seem to be reasons for this defensiveness and perpetuate it were identified: lack of support in dealing with insecurities in the face of responsibility; the notion of medicine as a science with the categories of right and wrong answers; and a range of pressures arising from the setting, such as hierarchical, economic and competition pressures. CONCLUSION: Our study showed, that the defensive attitude towards learning from mistakes and deficits especially in the field of IICs appears to be a subtle but powerful obstacle for implementing IICs in medical training, in contrast to other professional fields. This obstacle is sustained by various underlying barrier factors. We therefore propose that changes should be made within a cultural transformation targeting this defensive mindset and culture and its presumed reasons.

Long-Term Performance and User Satisfaction With Implanted Neuroprostheses for Upright Mobility After Paraplegia: 2- to 14-Year Follow-Up.

OBJECTIVE: To quantify the long-term (>2y) effects of lower extremity (LE) neuroprostheses (NPs) for standing, transfers, stepping, and seated stability after spinal cord injury. DESIGN: Single-subject design case series with participants acting as their own concurrent controls, including retrospective data review. SETTING: Hospital-based clinical biomechanics laboratory with experienced (>20y in the field) research biomedical engineers, a physical therapist, and medical monitoring review. PARTICIPANTS: Long-term (6.2±2.7y) at-home users (N=22; 19 men, 3 women) of implanted NPs for trunk and LE function with chronic (14.4±7.1y) spinal cord injury resulting in full or partial paralysis. INTERVENTIONS: Technical and clinical performance measurements, along with user satisfaction surveys. MAIN OUTCOME MEASURES: Knee extension moment, maximum standing time, body weight supported by lower extremities, 3 functional standing tasks, 2 satisfaction surveys, NP usage, and stability of implanted components. RESULTS: Stimulated knee extension strength and functional capabilities were maintained, with 94% of implant recipients reporting being very or moderately satisfied with their system. More than half (60%) of the participants were still using their implanted NPs for exercise and function for >10min/d on nearly half or more of the days monitored; however, maximum standing times and percentage body weight through LEs decreased slightly over the follow-up interval. Stimulus thresholds were uniformly stable. Six-year survival rates for the first-generation implanted pulse generator (IPG) and epimysial electrodes were close to 90%, whereas those for the second-generation IPG along with the intramuscular and nerve cuff electrodes were >98%. CONCLUSIONS: Objective and subjective measures of the technical and clinical performances of implanted LE NPs generally remained consistent for 22 participants after an average of 6 years of unsupervised use at home. These findings suggest that implanted LE NPs can provide lasting benefits that recipients value.

Automatic application of neural stimulation during wheelchair propulsion after SCI enhances recovery of upright sitting from destabilizing events.

BACKGROUND: The leading cause of injury for manual wheelchair users are tips and falls caused by unexpected destabilizing events encountered during everyday activities. The purpose of this study was to determine the feasibility of automatically restoring seated stability to manual wheelchair users with spinal cord injury (SCI) via a threshold-based system to activate the hip and trunk muscles with electrical stimulation during potentially destabilizing events. METHODS: We detected and classified potentially destabilizing sudden stops and turns with a wheelchair-mounted wireless inertial measurement unit (IMU), and then applied neural stimulation to activate the appropriate muscles to resist trunk movement and restore seated stability. After modeling and preliminary testing to determine the appropriate inertial signatures to discriminate between events and reliably trigger stimulation, the system was implemented and evaluated in real-time on manual wheelchair users with SCI. Three participants completed simulated collision events and four participants completed simulated rapid turns. Data were analyzed as a series of individual case studies with subjects acting as their own controls with and without the system active. RESULTS: The controller achieved 93% accuracy in detecting collisions and right turns, and 100% accuracy in left turn detection. Two of the three subjects who participated in collision testing with stimulation experienced significantly decreased maximum anterior-posterior trunk angles (p < 0.05). Similar results were obtained with implanted and surface stimulation systems. CONCLUSIONS: This study demonstrates the feasibility of a neural stimulation control system based on simple inertial measurements to improve trunk stability and overall safety of people with spinal cord injuries during manual wheelchair propulsion. Further studies are required to determine clinical utility in real world situations and generalizability to the broader SCI or other population of manual or powered wheelchair users. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01474148 . Registered 11/08/2011 retrospectively registered.

Setting the pace: insights and advancements gained while preparing for an FES bike race.

The reduction in physical activity following a spinal cord injury often leads to a decline in mental and physical health. Developing an exercise program that is effective and enjoyable is paramount for this population. Although functional electrical stimulation (FES) stationary cycling has been utilized in rehabilitation settings, implementing an overground cycling program for those with spinal cord injuries has greater technical challenges. Recently our laboratory team focused on training five individuals with compete spinal cord injuries utilizing an implanted pulse generator for an overground FES bike race in CYBATHLON 2016 held in Zurich, Switzerland. The advancements in muscle strength and endurance and ultimately cycling power our pilots made during this training period not only helped propel our competing pilot to win gold at the CYBATHLON 2016, but allowed our pilots to ride their bikes outside within their communities. Such a positive outcome has encouraged us to put effort into developing more widespread use of FES overground cycling as a rehabilitative tool for those with spinal cord injuries. This commentary will describe our approach to the CYBATHLON 2016 including technological advancements, bike design and the training program.

Reactive stepping with functional neuromuscular stimulation in response to forward-directed perturbations.

BACKGROUND: Implanted motor system neuroprostheses can be effective at increasing personal mobility of persons paralyzed by spinal cord injuries. However, currently available neural stimulation systems for standing employ patterns of constant activation and are unreactive to changing postural demands. METHODS: In this work, we developed a closed-loop controller for detecting forward-directed body disturbances and initiating a stabilizing step in a person with spinal cord injury. Forward-directed pulls at the waist were detected with three body-mounted triaxial accelerometers. A finite state machine was designed and tested to trigger a postural response and apply stimulation to appropriate muscles so as to produce a protective step when the simplified jerk signal exceeded predetermined thresholds. RESULTS: The controller effectively initiated steps for all perturbations with magnitude between 10 and 17.5 s body weight, and initiated a postural response with occasional steps at 5% body weight. For perturbations at 15 and 17.5% body weight, the dynamic responses of the subject exhibited very similar component time periods when compared with able-bodied subjects undergoing similar postural perturbations. Additionally, the reactive step occurred faster for stronger perturbations than for weaker ones (p < .005, unequal varience t-test.) CONCLUSIONS: This research marks progress towards a controller which can improve the safety and independence of persons with spinal cord injury using implanted neuroprostheses for standing.

A neuroprosthesis for control of seated balance after spinal cord injury.

BACKGROUND: A major desire of individuals with spinal cord injury (SCI) is the ability to maintain a stable trunk while in a seated position. Such stability is invaluable during many activities of daily living (ADL) such as regular work in the home and office environments, wheelchair propulsion and driving a vehicle. Functional neuromuscular stimulation (FNS) has the ability to restore function to paralyzed muscles by application of measured low-level currents to the nerves serving those muscles. METHODS: A feedback control system for maintaining seated balance under external perturbations was designed and tested in individuals with thoracic and cervical level spinal cord injuries. The control system relied on a signal related to the tilt of the trunk from the vertical position (which varied between 1.0 ≡ erect posture and 0.0 ≡ most forward flexed posture) derived from a sensor fixed to the sternum to activate the user's own hip and trunk extensor muscles via an implanted neuroprosthesis. A proportional-derivative controller modulated stimulation between trunk tilt values indicating deviation from the erect posture and maximum desired forward flexion. Tests were carried out with external perturbation forces set at 35%, 40% and 45% body-weight (BW) and maximal forward trunk tilt flexion thresholds set at 0.85, 0.75 and 0.70. RESULTS: Preliminary tests in a case series of five subjects show that the controller could maintain trunk stability in the sagittal plane for perturbations up to 45% of body weight and for flexion thresholds as low as 0.7. The mean settling time varied across subjects from 0.5(±0.4) and 2.0 (±1.1) seconds. Mean response time of the feedback control system varied from 393(±38) ms and 536(±84) ms across the cohort. CONCLUSIONS: The results show the high potential for robust control of seated balance against nominal perturbations in individuals with spinal cord injury and indicates that trunk control with FNS is a promising intervention for individuals with SCI.

Effects of stimulating hip and trunk muscles on seated stability, posture, and reach after spinal cord injury.

OBJECTIVE: To determine the stimulated strength of the paralyzed gluteal and paraspinal muscles and their effects on the seated function of individuals with paralysis. DESIGN: Case series with subjects acting as their own concurrent controls. SETTING: Hospital-based clinical biomechanics laboratory. PARTICIPANTS: Users (N=8) of implanted neuroprostheses for lower extremity function with low-cervical or thoracic level injuries. INTERVENTIONS: Dynamometry and digital motion capture both with and without stimulation to the hip and trunk muscles. MAIN OUTCOME MEASURES: Isometric trunk extension moment at 0°, 15°, and 30° of flexion; seated stability in terms of simulated isokinetic rowing; pelvic tilt, shoulder height, loaded and unloaded bimanual reaching to different heights, and subjective ratings of difficulty during unsupported sitting. RESULTS: Stimulation produced significant increases in mean trunk extension moment (9.2±9.5Nm, P<.001) and rowing force (27.4±23.1N, P<.012) over baseline volitional values. Similarly, stimulation induced positive changes in average pelvic tilt (16.7±15.7°) and shoulder height (2.2±2.5cm) during quiet sitting and bimanual reaching, and increased mean reach distance (5.5±6.6cm) over all subjects, target heights, and loading conditions. Subjects consistently rated tasks with stimulation easier than voluntary effort alone. CONCLUSIONS: In spite of considerable intersubject variability, stabilizing the paralyzed trunk with electrical stimulation can positively impact seated posture, extend forward reach, and allow exertion of larger forces on objects in the environment.

Effects of intramuscular trunk stimulation on manual wheelchair propulsion mechanics in 6 subjects with spinal cord injury.

OBJECTIVE: To quantify the effects of stabilizing the paralyzed trunk and pelvis with electrical stimulation on manual wheelchair propulsion. DESIGN: Single-subject design case series with subjects acting as their own concurrent controls. SETTING: Hospital-based clinical biomechanics laboratory. PARTICIPANTS: Individuals (N=6; 4 men, 2 women; mean age ± SD, 46 ± 10.8y) who were long-time users (6.1 ± 3.9y) of implanted neuroprostheses for lower extremity function and had chronic (8.6 ± 2.8y) midcervical- or thoracic-level injuries (C6-T10). INTERVENTIONS: Continuous low-level stimulation to the hip (gluteus maximus, posterior adductor, or hamstrings) and trunk extensor (lumbar erector spinae and/or quadratus lumborum) muscles with implanted intramuscular electrodes. MAIN OUTCOME MEASURES: Pushrim kinetics (peak resultant force, fraction effective force), kinematics (cadence, stroke length, maximum forward lean), and peak shoulder moment at preferred speed over 10-m level surface; speed, pushrim kinetics, and subjective ratings of effort for level 100-m sprints and up a 30.5-m ramp of approximately 5% grade. RESULTS: Three of 5 subjects demonstrated reduced peak resultant pushrim forces (P≤.014) and improved efficiency (P≤.048) with stimulation during self-paced level propulsion. Peak sagittal shoulder moment remained unchanged in 3 subjects and increased in 2 others (P<.001). Maximal forward trunk lean also increased by 19% to 26% (P<.001) with stimulation in these 3 subjects. Stroke lengths were unchanged by stimulation in all subjects, and 2 showed extremely small (5%) but statistically significant increases in cadence (P≤.021). Performance measures for sprints and inclines were generally unchanged with stimulation; however, subjects consistently rated propulsion with stimulation to be easier for both surfaces. CONCLUSIONS: Stabilizing the pelvis and trunk with low levels of continuous electrical stimulation to the lumbar trunk and hip extensors can positively impact the mechanics of manual wheelchair propulsion and reduce both perceived and physical measures of effort.

Mindset and Reflection-How to Sustainably Improve Intra- and Interpersonal Competences in Medical Education.

Intra- and interpersonal competences (IICs) are essential for medical expertise. However, the effects of current medical curricula seem to not be sustainable enough, even though poorly trained IICs have negative effects on medical practice. A defensive attitude towards openly addressing personal-professional challenges seems to hinder a sustainable implementation of IICs training. Therefore, this study asks about the changeability of IICs and target factors of their implementation in medical education. The aim was to detect factors for the sustainable implementation of IICs in medical education from medical and non-medical perspectives. For this purpose, a total of 21 experts were interviewed. The interview material was analysed according to grounded theory principles to generate core categories to answer the research questions. As a first result, analysis revealed that IICs are changeable and developable, not in all, but in many students. It also showed four central prerequisites for successful implementation: the longitudinal integration of reflection and feedback in medical education and practice; a clear framework and individual path of education; the students' mindset to develop themselves on a personal level; as well as the superiors' mindset to openly deal with personal challenges in low hierarchies. Contrasting Carol Dweck's mindset concept with our findings supports our theory that the development of a mindset which allows an open approach to personal deficits and challenges seems to be of central importance for both students and teachers. Two key factors in this process might be teaching about the impact of mindsets on learning and the willingness of superiors to openly address their personal challenges. To improve IICs in medical professionals, it seems helpful to pay more attention to the development of mindsets. Educating teachers and superiors about targeting factors could be a feasible direction for sustainable implementation.

Stabilizing leaning postures with feedback controlled functional neuromuscular stimulation after trunk paralysis.

Spinal cord injury (SCI) can cause paralysis of trunk and hip musculature that negatively impacts seated balance and ability to lean away from an upright posture and interact fully with the environment. Constant levels of electrical stimulation of peripheral nerves can activate typically paralyzed muscles and aid in maintaining a single upright seated posture. However, in the absence of a feedback controller, such seated postures and leaning motions are inherently unstable and unable to respond to perturbations. Three individuals with motor complete SCI who had previously received a neuroprosthesis capable of activating the hip and trunk musculature volunteered for this study. Subject-specific muscle synergies were identified through system identification of the lumbar moments produced via neural stimulation. Synergy-based calculations determined the real-time stimulation parameters required to assume leaning postures. When combined with a proportional, integral, derivative (PID) feedback controller and an accelerometer to infer trunk orientation, all individuals were able to assume non-erect postures of 30-40° flexion and 15° lateral bending. Leaning postures increased forward reaching capabilities by 10.2, 46.7, and 16 cm respectively for each subject when compared with no stimulation. Additionally, the leaning controllers were able to resist perturbations of up to 90 N, and all subjects perceived the leaning postures as moderately to very stable. Implementation of leaning controllers for neuroprostheses have the potential of expanding workspaces, increasing independence, and facilitating activities of daily living for individuals with paralysis.

Computational methods to analyze and predict the binding mode of inhibitors targeting both human and mushroom tyrosinase.

Tyrosinase, a copper-containing enzyme critical in melanin biosynthesis, is a key drug target for hyperpigmentation and melanoma in humans. Testing the inhibitory effects of compounds using tyrosinase from Agaricus bisporus (AbTYR) has been a common practice to identify potential therapeutics from synthetic and natural sources. However, structural diversity among human tyrosinase (hTYR) and AbTYR presents a challenge in developing drugs that are therapeutically effective. In this study, we combined retrospective and computational analyses with experimental data to provide insights into the development of new inhibitors targeting both hTYR and AbTYR. We observed contrasting effects of Thiamidol™ and our 4-(4-hydroxyphenyl)piperazin-1-yl-derivative (6) on both enzymes; based on this finding, we aimed to investigate their binding modes in hTYR and AbTYR to identify residues that significantly improve affinity. All the information led to the discovery of compound [4-(4-hydroxyphenyl)piperazin-1-yl](2-methoxyphenyl)methanone (MehT-3, 7), which showed comparable activity on AbTYR (IC50 = 3.52 µM) and hTYR (IC50 = 5.4 µM). Based on these achievements we propose the exploitation of our computational results to provide relevant structural information for the development of newer dual-targeting molecules, which could be preliminarily tested on AbTYR as a rapid and inexpensive screening procedure before being tested on hTYR.

Discovery and computational studies of piperidine/piperazine-based compounds endowed with sigma receptor affinity.

Herein, we describe our efforts to identify sigma receptor 1 (S1R) ligands through a screening campaign on our in-house collection of piperidine/piperazine-based compounds. Our investigations led to the discovery of the potent compound 2-[4-(benzyl)-1-piperidin-1-yl]-1-4-(4-phenylpiperazin-1-yl)ethanone (1) with high affinity toward S1R (Ki value of 3.2 nM) that was comparable to reference compound haloperidol (Ki value of 2.5 nM). Functional assay revealed that compound 1 acted as S1R agonist. To decipher the binding mode of this promising S1R ligand as a starting point for further structure-based optimization, we analysed the docking pose by using a S1R-structure derived from cocrystal structures of potent ligands in complex with target protein. The computational study was enriched with molecular dynamic simulations that revealed the crucial amino acid residues that interacted with the most interesting compound 1.

Sudden stop detection and automatic seating support with neural stimulation during manual wheelchair propulsion.

Objective: Wheelchair safety is of great importance since falls from wheelchairs are prevalent and often have devastating consequences. We developed an automatic system to detect destabilizing events during wheelchair propulsion under real-world conditions and trigger neural stimulation to stiffen the trunk to maintain seated postures of users with paralysis.Design: Cross-over interventionSetting: Laboratory and community settingsParticipants: Three able-bodied subjects and three individuals with SCI with previously implanted neurostimulation systemsInterventions: An algorithm to detect wheelchair sudden stops was developed. This was used to randomly trigger trunk extensor stimulation during sudden stops eventsOutcome Measures: Algorithm success and false positive rates were determined. SCI users rated each condition on a seven-point Usability Rating Scale to indicate safety.Results: The system detected sudden stops with a success rate of over 93% in community settings. When used to trigger trunk neurostimulation to ensure stability, the implant recipients consistently reported feeling safer (P<.05 for 2/3 subjects) with the system while encountering sudden stops as indicated by a 1-3 point change in safety rating.Conclusion: These preliminary results suggest that this system could monitor wheelchair activity and only apply stabilizing neurostimulation when appropriate to maintain posture. Larger scale, unsupervised and longer-term trials at home and in the community are indicated. This system could be generalized and applied to individuals without an implanted stimulation by utilizing surface stimulation, or by actuating a mechanical restraint when necessary, thus allowing unrestricted trunk movements and only restraining the user when necessary to ensure safety.Trial Registration: NCT01474148.

Facilitation of dependent transfers with functional neuromuscular stimulation: a computer simulation study.

A two-part simulation process was developed to investigate the facilitation of vertical patient lifts with functional neuromuscular stimulation (FNS) in individuals with spinal cord injury (SCI). First, external lifting forces representing caregiver assistance were applied to a 3D musculoskeletal model representing the patient and optimized to enforce a specific lifting trajectory during a forward dynamic simulation. The process was repeated with and without the activation of the knee, hip, and trunk extensor muscles of the patient model to represent contractions of the paralyzed muscles generated via FNS. Secondly, the spinal compression experienced by a caregiver at the L5/S1 joint while generating these external lifting forces was estimated using a second musculoskeletal model representing the caregiver. Simulation without muscle activation predicted spinal compression in the caregiver model approximately 1.3 × the National Institute for Occupational Safety and Health (NIOSH) recommended "Action Limit." Comparatively, simulations with two unique patterns of muscle activation both predicted caregiver spinal compressions below NIOSH recommendations. These simulation results support the hypothesis that FNS activation of a patient's otherwise paralyzed muscles would lower the force output required of a caregiver during a dependent transfer, thus lowering the spinal compression and risk of injury experienced by a caregiver.