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 \u3c .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

Dynamic rainfall-induced landslide susceptibility: A step towards a unified forecasting system

The initial inception of the landslide susceptibility concept defined it as a static property of the landscape, explaining the proneness of certain locations to generate slope failures. Since the spread of data-driven proba- bilistic solutions though, the original susceptibility definition has been challenged to incorporate dynamic ele- ments that would lead the occurrence probability to change both in space and in time. This is the starting point of this work, which combines the traditional strengths of the susceptibility framework together with the strengths typical of landslide early warning systems. Specifically, we model landslide occurrences in the norther sector of Vietnam, using a multi-temporal landslide inventory recently released by NASA. A set of static (terrain) and dynamic (cumulated rainfall) covariates are selected to explain the landslide presence/absence distribution via a Bayesian version of a binomial Generalized Additive Models (GAM). Thanks to the large spatiotemporal domain under consideration, we include a large suite of cross-validation routines, testing the landslide prediction through random sampling, as well as through stratified spatial and temporal sampling. We even extend the model test towards regions far away from the study site, to be used as external validation datasets. The overall per- formance appears to be quite high, with Area Under the Curve (AUC) values in the range of excellent model results, and very few localized exceptions. This model structure may serve as the basis for a new generation of early warning systems. However, the use of The Climate Hazards group Infrared Precipitation with Stations (CHIRPS) for the rainfall component limits the model ability in terms of future prediction. Therefore, we envision subsequent development to take this direction and move towards a unified dynamic landslide forecast. Ultimately, as a proof-of-concept, we have also implemented a potential early warning system in Google Earth Engine

Standing on the shoulder of a giant landslide:A six-year long InSAR look at a slow-moving hillslope in the western Karakoram

In this work, we investigate a slow-moving, large landslide (∼20 km2) in the Chitral district in Northern Pakistan, near several villages. The slow-moving landslide was reported more than four decades ago but has never been examined afterward. Interferometric Synthetic Aperture Radar (InSAR) analyses, using Sentinel-1 data that span a period of six years, allowed us to retrieve the spatio-temporal pattern of hillslope deformation. We combined both ascending and descending orbits to identify vertical and horizontal deformations. Our results showed that the crown is moving relatively fast in comparison to the nearby regions; 30 mm/year and 40 mm/year in downward and eastward directions, respectively. Also, step-like deformations observed over the crown reflect a deep-seated landslide. At the footslope, on the other hand, we captured relatively high deformations but in an upward direction; specifically 30 mm/year and 30 mm/year in upward and eastward directions, respectively. We have discussed the possible roles of meteorologic and anthropogenic factors causing hillslope deformation occurred during the six-year period under consideration. We observed a seasonal deformation patterns that might be mainly interpreted to be governed by the influence of snowmelt due to increasing temperatures during the start of spring. Overall, the same mechanism might be present in many other hillslopes across the whole Hindukush-Himalayan-Karakoram range, where seasonal snowmelt is an active agent. In this context, this research provides a case study shedding a light on the hillslope deformation mechanism at the western edge of the Himalayan range.</p

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

Design, Synthesis, and in Vitro Evaluation of 4-(4-Hydroxyphenyl)piperazine-Based Compounds Targeting Tyrosinase

Melanin biosynthesis is enzymatically regulated by tyrosinase (TYR, EC 1.14.18.1), which is efficiently inhibited by natural and synthetic phenols, demonstrating potential therapeutic application for the treatment of several human diseases. Herein we report the inhibitory effects of a series of (4-(4-hydroxyphenyl)piperazin-1-yl)arylmethanone derivatives, that were designed, synthesised and assayed against TYR from Agaricus bisporus (AbTYR). The best inhibitory activity was predominantly found for compounds bearing selected hydrophobic ortho-substituents on the aroyl moiety (IC50 values in the range of 1.5–4.6 μM). They proved to be more potent than the reference compound kojic acid (IC50=17.8 μM) and displayed competitive mechanism of inhibition of diphenolase activity of AbTYR. Docking simulation predicted their binding mode into the catalytic cavities of AbTYR and the modelled human TYR. In addition, these compounds displayed antioxidant activity combined with no cytotoxicity in MTT tests. Notably, the best inhibitor affected tyrosinase activity in α-MSH-stimulated B16F10 cells, thus demonstrating anti-melanogenic activity

Severe male factor in in vitro fertilization: definition, prevalence, and treatment. An update

Infertility affects 10%-15% of couples worldwide. Of all infertility cases, 20%-70% are due to male factors. In the past, men with severe male factor (SMF) were considered sterile. Nevertheless, the development of intracytoplasmic sperm injection (ICSI) drastically modified this scenario. The advances in assisted reproductive technology (ART), specifically regarding surgical sperm retrieval procedures, allowed the efficacious treatment of these conditions. Yet, before undergoing ICSI, male factor infertility requires careful evaluation of clinical and lifestyle behavior together with medical treatment. Epidemiologically speaking, women whose male partner is azoospermic tend to be younger and with a better ovarian reserve. These couples, in fact, are proposed ART earlier in their life, and for this reason, their ovarian response after stimulation is generally good. Furthermore, in younger couples, azoospermia can be partially compensated by the efficient ovarian response, resulting in an acceptable fertility rate following in vitro fertilization (IVF) techniques. Conversely, when azoospermia is associated with a reduced ovarian reserve and/or advanced maternal age, the treatment becomes more challenging, with a consequent reduction in IVF outcomes. Nonetheless, azoospermia seems to impair neither the euploidy rate at the blastocyst stage nor the implantation of euploid blastocysts. Based on the current knowledge, the assessment of male infertility factors should involve: (1) evaluation - to diagnose and quantify seminologic alterations; (2) potentiality - to determine the real possibilities to improve sperm parameters and/or retrieve spermatozoa; (3) time - to consider the available "treatment window", based on maternal age and ovarian reserve. This review represents an update of the definition, prevalence, causes, and treatment of SMF in a modern ART clinic