Unveiling the Stereoselectivity and Regioselectivity of the [3+2] Cycloaddition Reaction between N-methyl-C-4-methylphenyl-nitrone and 2-Propynamide from a MEDT Perspective.

[3+2] cycloaddition reactions play a crucial role in synthesizing complex organic molecules and have significant applications in drug discovery and materials science. In this study, the [3+2] cycloaddition (32CA) reactions of N-methyl-C-4-methyl phenyl-nitrone 1 and 2-propynamide 2, which have not been extensively studied before, were investigated using molecular electron density theory (MEDT) at the B3LYP/6-311++G(d,p) level of theory. According to an electron localization function (ELF) study, N-methyl-C-4-methyl phenyl-nitrone 1 is a zwitterionic species with no pseudoradical or carbenoid centers. Conceptual density functional theory (CDFT) indices were used to predict the global electronic flux from the strong nucleophilic N-methyl-C-4-methyl phenylnitrone 1 to the electrophilic 2-propynamide 2 functions. The 32CA reactions proceeded through two pairs of stereo- and regioisomeric reaction pathways to generate four different products: 3, 4, 5, and 6. The reaction pathways were irreversible owing to their exothermic characters: -136.48, -130.08, -130.99, and -140.81 kJ mol-1, respectively. The enthalpy of the 32CA reaction leading to the formation of cycloadduct 6 was lower compared with the other path owing to a slight increase in its polar character, observed through the global electron density transfer (GEDT) during the transition states and along the reaction path. A bonding evolution theory (BET) analysis showed that these 32CA reactions proceed through the coupling of pseudoradical centers, and the formation of new C-C and C-O covalent bonds did not begin in the transition states.

MARCH Proteins Mediate Responses to Antitumor Antibodies.

CD98, which is required for the rapid proliferation of both normal and cancer cells, and MET, the hepatocyte growth factor receptor, are potential targets for therapeutic antitumor Abs. In this study, we report that the antiproliferative activity of a prototype anti-CD98 Ab, UM7F8, is due to Ab-induced membrane-associated ring CH (MARCH) E3 ubiquitin ligase-mediated ubiquitination and downregulation of cell surface CD98. MARCH1-mediated ubiquitination of CD98 is required for UM7F8's capacity to reduce CD98 surface expression and its capacity to inhibit the proliferation of murine T cells. Similarly, CD98 ubiquitination is required for UM7F8's capacity to block the colony-forming ability of murine leukemia-initiating cells. To test the potential generality of the paradigm that MARCH E3 ligases can mediate the antiproliferative response to antitumor Abs, we examined the potential effects of MARCH proteins on responses to emibetuzumab, an anti-MET Ab currently in clinical trials for various cancers. We report that MET surface expression is reduced by MARCH1, 4, or 8-mediated ubiquitination and that emibetuzumab-induced MET ubiquitination contributes to its capacity to downregulate MET and inhibit human tumor cell proliferation. Thus, MARCH E3 ligases can act as cofactors for antitumor Abs that target cell surface proteins, suggesting that the MARCH protein repertoire of cells is a determinant of their response to such Abs.

Nanoliposomes in Cancer Therapy: Marketed Products and Current Clinical Trials.

The drugs used for cancer treatment have many drawbacks, as they damage both tumor and healthy cells and, in addition, they tend to be poorly soluble drugs. Their transport in nanoparticles can solve these problems as these can release the drug into tumor tissues, as well as improve their solubility, bioavailability, and efficacy, reducing their adverse effects. This article focuses on the advantages that nanotechnology can bring to medicine, with special emphasis on nanoliposomes. For this, a review has been made of the nanoliposomal systems marketed for the treatment of cancer, as well as those that are in the research phase, highlighting the clinical trials being carried out. All marketed liposomes studied are intravenously administered, showing a reduced intensity of side-effects compared with the nonliposomal form. Doxorubicin is the active ingredient most frequently employed. Ongoing clinical trials expand the availability of liposomal medicines with new clinical indications. In conclusion, the introduction of drugs in nanoliposomes means an improvement in their efficacy and the quality of life of patients. The future focus of research could be directed to develop multifunctional targeted nanoliposomes using new anticancer drugs, different types of existing drugs, or new standardized methodologies easily translated into industrial scale.

Similarity-Based Virtual Screening to Find Antituberculosis Agents Based on Novel Scaffolds: Design, Syntheses and Pharmacological Assays.

A method to identify molecular scaffolds potentially active against the Mycobacterium tuberculosis complex (MTBC) is developed. A set of structurally heterogeneous agents against MTBC was used to obtain a mathematical model based on topological descriptors. This model was statistically validated through a Leave-n-Out test. It successfully discriminated between active or inactive compounds over 86% in database sets. It was also useful to select new potential antituberculosis compounds in external databases. The selection of new substituted pyrimidines, pyrimidones and triazolo[1,5-a]pyrimidines was particularly interesting because these structures could provide new scaffolds in this field. The seven selected candidates were synthesized and six of them showed activity in vitro.

Optimizing Calibration Procedure to Train a Regression-Based Prediction Model of Actively Generated Lumbar Muscle Moments for Exoskeleton Control.

The risk of low-back pain in manual material handling could potentially be reduced by back-support exoskeletons. Preferably, the level of exoskeleton support relates to the required muscular effort, and therefore should be proportional to the moment generated by trunk muscle activities. To this end, a regression-based prediction model of this moment could be implemented in exoskeleton control. Such a model must be calibrated to each user according to subject-specific musculoskeletal properties and lifting technique variability through several calibration tasks. Given that an extensive calibration limits the practical feasibility of implementing this approach in the workspace, we aimed to optimize the calibration for obtaining appropriate predictive accuracy during work-related tasks, i.e., symmetric lifting from the ground, box stacking, lifting from a shelf, and pulling/pushing. The root-mean-square error (RMSE) of prediction for the extensive calibration was 21.9 nm (9% of peak moment) and increased up to 35.0 nm for limited calibrations. The results suggest that a set of three optimally selected calibration trials suffice to approach the extensive calibration accuracy. An optimal calibration set should cover each extreme of the relevant lifting characteristics, i.e., mass lifted, lifting technique, and lifting velocity. The RMSEs for the optimal calibration sets were below 24.8 nm (10% of peak moment), and not substantially different than that of the extensive calibration.

Mechanical Sensing for Lower Limb Soft Exoskeletons: Recent Progress and Challenges.

Soft exoskeletons hold promise for facilitating monitoring and assistance in case of light impairment and for prolonging independent living. In contrast to rigid material-based exoskeletons, they strongly demand for new approaches of soft sensing and actuation solutions. This chapter overviews soft exoskeletons in contrast to rigid exoskeletons and focuses on the recent advancements on the movement monitoring in lower limb soft exoskeletons. Compliant materials and soft tactile sensing approaches can be utilized to build smart sensorized garments for joint angle measurements (needed for both control and monitoring). However, currently there are still several open challenges derived from the needed close interaction between the human body and the soft exoskeleton itself, especially related to how sensing function and robustness are strongly affected by wearability, which will need to be overcome in the near future.

[Anti-transglutaminase antibody in adults with celiac disease and their relation to the presence and duration of gluten-free diet]. / Anticuerpo anti-transglutaminasa tisular en adultos con enfermedad celíaca y su relación con la presencia y duración de la dieta libre de gluten.

IgA anti-transglutaminase 2 (tTG2) antibody is a relevant marker in celiac disease. The utility of IgA anti-tTG2 determination is well established for the diagnosis, however their use in the follow-up of patients with gluten free diet (GFD) it is not fully established. OBJECTIVE: To determine IgA anti-tTG2 antibody levels in adult Paraguayan celiac disease patients and its relation to the presence and duration of the GFD. MATERIALS AND METHODS: Adult celiac disease patients without (n=23) or with (n=49) GFD were included in this observational, descriptive, cross-sectional study with analytical component. IgA anti-tTG2 antibody serum levels were analyzed by ELISA. RESULTS: All (100%) celiac disease patients without GFD had positive anti-tTG2 IgA. Serum levels of IgA anti-tTG2 were significantly elevated in celiac disease patients without GFD compared to levels in patients with GFD. 35% of patients treated with GFD (diet average duration = 5.7 years) had positive (29%) or indeterminate (6%) levels of IgA anti-tTG2. In terms of GFD duration we observed that while the GFD period increased, antibody levels decreased (r=- 0.2963; p=0.0387). CONCLUSION: IgA anti-tTG2 antibody levels correlated inversely with the GFD duration. However, positive levels of these antibodies persisted in some patients, even several years after the onset of GFD.

Soft Smart Garments for Lower Limb Joint Position Analysis.

Revealing human movement requires lightweight, flexible systems capable of detecting mechanical parameters (like strain and pressure) while being worn comfortably by the user, and not interfering with his/her activity. In this work we address such multifaceted challenge with the development of smart garments for lower limb motion detection, like a textile kneepad and anklet in which soft sensors and readout electronics are embedded for retrieving movement of the specific joint. Stretchable capacitive sensors with a three-electrode configuration are built combining conductive textiles and elastomeric layers, and distributed around knee and ankle. Results show an excellent behavior in the ~30% strain range, hence the correlation between sensors' responses and the optically tracked Euler angles is allowed for basic lower limb movements. Bending during knee flexion/extension is detected, and it is discriminated from any external contact by implementing in real time a low computational algorithm. The smart anklet is designed to address joint motion detection in and off the sagittal plane. Ankle dorsi/plantar flexion, adduction/abduction, and rotation are retrieved. Both knee and ankle smart garments show a high accuracy in movement detection, with a RMSE less than 4° in the worst case.

Molecular Rearrangement of an Aza-Scorpiand Macrocycle Induced by pH: A Computational Study.

Rearrangements and their control are a hot topic in supramolecular chemistry due to the possibilities that these phenomena open in the design of synthetic receptors and molecular machines. Macrocycle aza-scorpiands constitute an interesting system that can reorganize their spatial structure depending on pH variations or the presence of metal cations. In this study, the relative stabilities of these conformations were predicted computationally by semi-empirical and density functional theory approximations, and the reorganization from closed to open conformations was simulated by using the Monte Carlo multiple minimum method.

Influence of Breastfeeding Time on Levels of Organochlorine Pesticides in Human Milk of a Mexican Population.

This study was conducted with the objective of determining whether there is a depuration of organochlorine pesticides in breast milk according to breastfeeding time. In total, 171 samples from mothers that lived in the State of Guerrero, Mexico were analyzed. There was a weak negative relationship between pp'DDE (r = -0.216) and Σ-DDT (r = -0.222) concentrations with the days of lactation. In a comparison analysis, a statistically significant decrease of pp'DDT and pp'DDE levels was observed, as well as the Σ-DDT from the first to the fifth week of lactation. A reduction of 0.188 mg/kg lipid of pp'DDE and 0.181 mg/kg lipid of Σ-DDT per week was obtained. HCB, ß-HCH and op'DDT concentrations were low and had no major fluctuations between subgroups. The low levels found and the observed reduction in time involve less exposure to the infant to these pollutants. Through this methodology changes in levels of certain organochlorine pesticides in various stages of human milk production may be shown.

GPU linear and non-linear Poisson-Boltzmann solver module for DelPhi.

SUMMARY: In this work, we present a CUDA-based GPU implementation of a Poisson-Boltzmann equation solver, in both the linear and non-linear versions, using double precision. A finite difference scheme is adopted and made suitable for the GPU architecture. The resulting code was interfaced with the electrostatics software for biomolecules DelPhi, which is widely used in the computational biology community. The algorithm has been implemented using CUDA and tested over a few representative cases of biological interest. Details of the implementation and performance test results are illustrated. A speedup of ~10 times was achieved both in the linear and non-linear cases. AVAILABILITY AND IMPLEMENTATION: The module is open-source and available at http://www.electrostaticszone.eu/index.php/downloads.

Organochlorine pesticide levels in breast milk in Guerrero, Mexico.

In Mexico, organochlorine pesticides were used in public health and agriculture programs, causing chronic exposure to the population. Human breast milk samples were collected from 171 mothers who were residents from Guerrero, Mexico. Analysis was carried out by gas chromatography. Median concentrations (mg/kg on fat basis) for the following pesticides were: HCB, 0.009; ß-HCH, 0.004; pp'DDE, 0.760; op'DDT, 0.016; pp'DDT, 0.045; and Σ-DDT, 0.833. These values are lower than in other States in Mexico, and in some countries where the use of these pesticides was banned more than 30 years ago. Differences were found in HCB, pp'DDE and pp'DDT concentrations in groups divided according to age (p < 0.05). The older age groups had higher concentrations, except for the comparison between groups 21-23/24-28 years, which were 0.913 and 0.530 mg/kg of pp'DDE, respectively. Given the restrictions on use, a greater decrease in organochlorine pesticide levels in human milk is expected in a few years.

Damage Detection in FRP-Reinforced Concrete Elements.

Fiber-Reinforced Polymer (FRP) composites have emerged as a promising alternative to conventional steel reinforcements in concrete structures owing to their benefits of corrosion resistance, higher strength-to-weight ratio, reduced maintenance cost, extended service life, and superior durability. However, there has been limited research on non-destructive testing (NDT) methods applicable for identifying damage in FRP-reinforced concrete (FRP-RC) elements. This knowledge gap has often limited its application in the construction industry. Engineers and owners often lack confidence in utilizing this relatively new construction material due to the challenge of assessing its condition. Thus, the main objective of this study is to determine the applicability of two of the most common NDT methods: the Ground-Penetrating Radar (GPR) and Phased Array Ultrasonic (PAU) methods for the detection of damage in FRP-RC elements. Three slab specimens with variations in FRP type (glass-, carbon- and basalt-FRP, i.e., GFRP, CFRP, and BFRP, respectively), bar diameter, bar depths, and defect types were investigated to determine the limitations and detection capabilities of these two NDT methods. The results show that GPR could detect damage in GFRP bars and CFRP strands, but PAU was limited to damage detection in CFRP strands. The findings of this study show the applicability of conventional NDT methods to FRP-RC and at the same time identify the areas with a need for further research.

An evaluation of emotion recognition, emotion reactivity, and emotion dysregulation as prospective predictors of 12-month trajectories of non-suicidal self-injury in an adolescent psychiatric inpatient sample.

BACKGROUND: Little is known about trajectories of NSSI. We aimed to identify NSSI trajectories in adolescent psychiatric inpatients and emotional processes that differentiate between trajectories. METHODS: Participants were 180 adolescents (71.7 % female; mean age of 14.89 years, SD = 1.35) from a psychiatric inpatient facility. NSSI was assessed at their index hospitalization, as well as 6, and 12 months after discharge. Emotion recognition, emotion reactivity, and emotion dysregulation were assessed at baseline. Latent class mixture modeling was used to identify different NSSI trajectories and ANOVAs were used to evaluate predictors of the trajectories. RESULTS: Analyses yielded three NSSI trajectories. These included a stable low-frequency class (90.53 % of sample), a stable moderate-frequency class, and a class characterized by high-frequency NSSI at baseline but that largely resolves by 6-month follow-up. After adjustments for multiple comparisons were made, only emotion regulation at baseline differentiated between the trajectories, with greater overall emotion dysregulation and greater emotional non-acceptance (a facet of emotion dysregulation) characterizing the initially high-frequency class and the stable moderate-frequency class more than the stable low-frequency class (ps < .05). Difficulties engaging in goal-directed behavior when distressed characterized the stable moderate-frequency NSSI class more than the stable low-frequency class (p < .05). Limitations The study sample consists predominantly of female and White adolescents and thus may not generalize to other demographic groups. CONCLUSIONS: The current findings suggest that interventions involving emotion regulation with adolescents who engage in NSSI would particularly benefit from a focus on increasing acceptance of emotional experiences.

Antidepressants in the acute treatment of post-traumatic stress disorder in adults: a systematic review and meta-analysis.

Currently, there are few pharmacotherapy options for clinicians treating post-traumatic stress disorder (PTSD), and antidepressants are usually the medication of choice. This meta-analysis aimed to review the efficacy of antidepressants in the acute treatment of PTSD in adults while investigating the contribution of study design and placebo response to the findings of these studies. Randomized, double-blind, placebo-controlled clinical trials that compared antidepressants with placebo for acute treatment of PTSD were selected. Standardized mean difference (SMD) in change in Clinician-Administered PTSD Scale scores were pooled after examining for heterogeneity. A random-effects meta-analysis was performed. Twenty-nine antidepressant-placebo comparisons, involving 4575 subjects, were analyzed. The SMD among all studies was 0.25, a small to medium effect size, lower than that in studies of antidepressants in adult major depressive disorder. The SMDs for low and high mean placebo responses, were 0.27 and 0.22, respectively. The overall SMD for paroxetine studies was in the moderate range (0.43) and that for sertraline studies was in the small range (0.12). Our findings suggest that antidepressants have modest efficacy in alleviating PTSD symptoms. Patient-level meta-analyses are required to further explore the potential clinical relevance of sertraline for PTSD.

A New Hyaluronic Emulgel of Hesperetin for Topical Application-An In Vitro Evaluation.

The present study aimed to formulate and characterize a hesperetin formulation to achieve adequate deposition and retention of hesperetin in the epidermis as a target for some cosmetic/dermatological actions. To derive the final emulgel, various formulations incorporating different proportions of Polysorbate 80 and hyaluronic acid underwent testing through a Box-Behnken experimental design. Nine formulations were created until the targeted emulgel properties were achieved. This systematic approach, following the principles of a design of experiment (DoE) methodology, adheres to a quality-by-design (QbD) paradigm, ensuring a robust and purposeful formulation and highlighting the commitment to a quality-driven design approach. The emulsions were developed using the phase inversion method, optimizing the emulgel with the incorporation of hyaluronic acid. Physically stable optimized emulgels were evaluated for their globule size, surface charge, viscosity, pH, electrical conductivity, and hesperetin content. These assays, along with the temperature swing test, were used to select the optimal formulation. It was characterized by a droplet size, d[4,3], of 4.02 µm, a Z-potential of -27.8 mV, an O/W sign, a pH of 5.2, and a creamy texture and proved to be stable for at least 2 months at room temperature. Additionally, in vitro release kinetics from the selected emulgel exhibited a sustained release profile of hesperetin. Skin assays revealed adequate retention of hesperetin in the human epidermis with minimum permeation. Altogether, these results corroborate the promising future of the proposed emulgel in cosmetic or dermatological use on healthy or diseased skin.

Quasi-passive lower limbs exosuit: an in-depth assessment of fatigue, kinematic and muscular patterns while comparing assistive strategies on an expert subject's gait analysis.

Wearable robots are becoming a valuable solution that helps injured, and elderly people regain mobility and improve clinical outcomes by speeding up the rehabilitation process. The XoSoft exosuit identified several benefits, including improvement of assistance, usability, and acceptance with a soft, modular, bio-mimetic, and quasi-passive exoskeleton. This study compares two assistive configurations: (i) a bilateral hip flexion (HA, hips-assistance) and (ii) a bilateral hip flexion combined with ankle plantarflexion (HAA, hips-ankles-assistance) with the main goal of evaluating compensatory actions and synergetic effects generated by the human- exoskeleton interaction. A complete description of this complex interaction scenario with this actuated exosuit is evaluated during a treadmill walking task, using several indices to quantify the human-robot interaction in terms of muscular activation and fatigue, metabolic expenditure, and kinematic motion patterns. Evidence shows that the HAA biomimetic controller is synergetic with the musculature and performs better concerning the other control strategy. The experimentation demonstrated a metabolic expenditure reduction of 8% of Metabolic Equivalent of Task (MET), effective assistance of the muscular activation of 12.5%, a decrease of the muscular fatigue of 0.6% of the mean frequency, and a significant reduction of the compensatory actions, as discussed in this work. Compensatory effects are present in both assistive configurations, but the HAA modality provides a 47% reduction of compensatory effects when considering muscle activation.

Elbow-sideWINDER (Elbow-side Wearable INDustrial Ergonomic Robot): design, control, and validation of a novel elbow exoskeleton.

Musculoskeletal Disorders associated with the elbow are one of the most common forms of work-related injuries. Exoskeletons have been proposed as an approach to reduce and ideally eliminate these injuries; however, exoskeletons introduce their own problems, especially discomfort due to joint misalignment. The Elbow-sideWINDER with its associated control strategy is a novel elbow exoskeleton to assist elbow flexion/extension during occupational tasks. This study describes the exoskeleton showing how this can minimize discomfort caused by joint misalignment, maximize assistive performance, and provide increased robustness and reliability in real worksites. The proposed medium-level control strategy can provide effective assistive torque using three control units as follows: an arm kinematics estimator, a load estimator, and a friction compensator. The combined hardware/software system of the Elbow-sideWINDER is tested in load-lifting tasks (2 and 7 kg). This experiment focuses on the reduction in the activation level of the biceps brachii and triceps brachii in both arms and the change in the range of motion of the elbow during the task. It is shown that using the Elbow-sideWINDER, the biceps brachii, responsible for the elbow flexion, was significantly less activated (up to 38.8% at 2 kg and 25.7% at 7 kg, on average for both arms). For the triceps brachii, the muscle activation was reduced by up to 37.0% at 2 kg and 35.1% at 7 kg, on average for both arms. When wearing the exoskeleton, the range of motion of the elbow was reduced by up to 13.0° during the task, but it was within a safe range and could be compensated for by other joints such as the waist or knees. There are extremely encouraging results that provide good indicators and important clues for future improvement of the Elbow-sideWINDER and its control strategy.

FRP-Reinforced/Strengthened Concrete: State-of-the-Art Review on Durability and Mechanical Effects.

Fiber-reinforced polymer (FRP) composites have gained increasing recognition and application in the field of civil engineering in recent decades due to their notable mechanical properties and chemical resistance. However, FRP composites may also be affected by harsh environmental conditions (e.g., water, alkaline solutions, saline solutions, elevated temperature) and exhibit mechanical phenomena (e.g., creep rupture, fatigue, shrinkage) that could affect the performance of the FRP reinforced/strengthened concrete (FRP-RSC) elements. This paper presents the current state-of-the-art on the key environmental and mechanical conditions affecting the durability and mechanical properties of the main FRP composites used in reinforced concrete (RC) structures (i.e., Glass/vinyl-ester FRP bars and Carbon/epoxy FRP fabrics for internal and external application, respectively). The most likely sources and their effects on the physical/mechanical properties of FRP composites are highlighted herein. In general, no more than 20% tensile strength was reported in the literature for the different exposures without combined effects. Additionally, some provisions for the serviceability design of FRP-RSC elements (e.g., environmental factors, creep reduction factor) are examined and commented upon to understand the implications of the durability and mechanical properties. Furthermore, the differences in serviceability criteria for FRP and steel RC elements are highlighted. Through familiarity with their behavior and effects on enhancing the long-term performance of RSC elements, it is expected that the results of this study will help in the proper use of FRP materials for concrete structures.

Control of a Back-Support Exoskeleton to Assist Carrying Activities.

Back-support exoskeletons are commonly used in the workplace to reduce low back pain risk for workers performing demanding activities. However, for the assistance of tasks differing from lifting, back-support exoskeletons potential has not been exploited extensively. This work focuses on the use of an active back-support exoskeleton to assist carrying. A control strategy is designed that modulates the exoskeleton torques to comply with the task assistance requirements. In particular, two gait phase detection frameworks are exploited to adapt the exoskeleton assistance according to the legs' motion. The control strategy is assessed through an experimental analysis on ten subjects. Carrying task is performed without and with the exoskeleton assistance. Results prove the potential of the presented control in assisting the task without hindering the gait movement and improving the usability experienced by users. Moreover, the exoskeleton assistance significantly reduces the lumbar load associated with the task, demonstrating its promising use for risk mitigation in the workplace.