Water Sorption and Structural Properties of Human Airway Mucus in Health and Muco-Obstructive Diseases.

Muco-obstructive diseases change airway mucus properties, impairing mucociliary transport and increasing the likelihood of infections. To investigate the sorption properties and nanostructures of mucus in health and disease, we investigated mucus samples from patients and cell cultures (cc) from healthy, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF) airways. Atomic force microscopy (AFM) revealed mucin monomers with typical barbell structures, where the globule to spacer volume ratio was the highest for CF mucin. Accordingly, synchrotron small-angle X-ray scattering (SAXS) revealed more pronounced scattering from CF mucin globules and suggested shorter carbohydrate side chains in CF mucin and longer side chains in COPD mucin. Quartz crystal microbalance with dissipation (QCM-D) analysis presented water sorption isotherms of the three types of human airway mucus, where, at high relative humidity, COPD mucus had the highest water content compared to cc-CF and healthy airway mucus (HAM). The higher hydration of the COPD mucus is consistent with the observation of longer side chains of the COPD mucins. At low humidity, no dehydration-induced glass transition was observed in healthy and diseased mucus, suggesting mucus remained in a rubbery state. However, in dialyzed cc-HAM, a sorption-desorption hysteresis (typically observed in the glassy state) appeared, suggesting that small molecules present in mucus suppress the glass transition.

Strategies to promote contraception use by female volunteers in Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease (API ADAD) Colombia trial.

BACKGROUND/AIMS: Including women of childbearing age in a clinical trial makes it necessary to consider two factors from a bioethical perspective: first, the lack of knowledge about the potential teratogenic effects of an investigational product, and also, the principle of justice not to exclude any population from the benefits of research. The most common way to address this issue is by requiring volunteers to use contraceptives before, during, and a few weeks after the clinical trial. This work presents all the strategies used to promote contraception use and prevent pregnancy during the Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease (API ADAD) Colombia clinical trial. Two characteristics of this trial make it of special interest for closely monitoring contraception use. One is that the trial lasted more than 7 years, and the other is that participants could be carriers of the E280A PSEN1 mutation, leading to a mild cognitive impairment as early as their late 30s. METHODS: An individual medical evaluation to select the contraception method that best fits the volunteer was carried out during the screening visit, remitting to the gynecologist when necessary. All non-surgical contraception methods were supplied by the sponsor. Staff were trained on contraception counseling, correctly dispensing contraceptive drugs to volunteers, and identifying, reporting, and following up on pregnancies. Two comprehensive educational campaigns on contraception use were performed, and the intervention included all volunteers. In addition, volunteers were asked on an annual survey to evaluate the dispensing procedure. Finally, the effectiveness of these strategies was retrospectively evaluated, comparing by extrapolation the number of pregnancies presented throughout the trial with the General Fertility Rate in Colombia. RESULTS: A total of 159 female volunteers were recruited. All strategies were implemented as planned, even during the COVID-19 contingency. Ten pregnancies occurred during the evaluation period (2015-2021). Two were planned; the rest were associated with a potential therapeutic failure or incorrect use of contraceptive methods for a contraceptive failure of 0.49% per year. Sixty percent of pregnancies led to an abortion, either miscarriage or therapeutic abortion. However, there was not enough data to associate the pregnancy outcome with the administration of the investigational product. Finally, we observed a lower fertility rate in women participating in the trial compared to the Colombian population. CONCLUSION: The lower rates of contraceptive failure and the decrease in the incidence of pregnancies in women participating in the trial compared to the Colombian population across the 7 years of evaluation suggest that the strategies used in API ADAD Colombia were adequate and effective in addressing contraception use.

Monoolein-Based Wireless Capacitive Sensor for Probing Skin Hydration.

Capacitive humidity sensors typically consist of interdigitated electrodes coated with a dielectric layer sensitive to varying relative humidity levels. Previous studies have investigated different polymeric materials that exhibit changes in conductivity in response to water vapor to design capacitive humidity sensors. However, lipid films like monoolein have not yet been integrated with humidity sensors, nor has the potential use of capacitive sensors for skin hydration measurements been fully explored. This study explores the application of monoolein-coated wireless capacitive sensors for assessing relative humidity and skin hydration, utilizing the sensitive dielectric properties of the monoolein-water system. This sensitivity hinges on the water absorption and release from the surrounding environment. Tested across various humidity levels and temperatures, these novel double functional sensors feature interdigitated electrodes covered with monoolein and show promising potential for wireless detection of skin hydration. The water uptake and rheological behavior of monoolein in response to humidity were evaluated using a quartz crystal microbalance with dissipation monitoring. The findings from these experiments suggest that the capacitance of the system is primarily influenced by the amount of water in the monoolein system, with the lyotropic or physical state of monoolein playing a secondary role. A proof-of-principle demonstration compared the sensor's performance under varying conditions to that of other commercially available skin hydration meters, affirming its effectiveness, reliability, and commercial viability.

Portable Prussian Blue-Based Sensor for Bacterial Detection in Urine.

Bacterial infections can affect the skin, lungs, blood, and brain, and are among the leading causes of mortality globally. Early infection detection is critical in diagnosis and treatment but is a time- and work-consuming process taking several days, creating a hitherto unmet need to develop simple, rapid, and accurate methods for bacterial detection at the point of care. The most frequent type of bacterial infection is infection of the urinary tract. Here, we present a wireless-enabled, portable, potentiometric sensor for E. coli. E. coli was chosen as a model bacterium since it is the most common cause of urinary tract infections. The sensing principle is based on reduction of Prussian blue by the metabolic activity of the bacteria, detected by monitoring the potential of the sensor, transferring the sensor signal via Bluetooth, and recording the output on a laptop or a mobile phone. In sensing of bacteria in an artificial urine medium, E. coli was detected in ~4 h (237 ± 19 min; n = 4) and in less than 0.5 h (21 ± 7 min, n = 3) using initial E. coli concentrations of ~103 and 105 cells mL-1, respectively, which is under or on the limit for classification of a urinary tract infection. Detection of E. coli was also demonstrated in authentic urine samples with bacteria concentration as low as 104 cells mL-1, with a similar response recorded between urine samples collected from different volunteers as well as from morning and afternoon urine samples.

Altered Cortical Palmitoylation Induces Widespread Molecular Disturbances in Parkinson's Disease.

The relationship between Parkinson's disease (PD), the second-most common neurodegenerative disease after Alzheimer's disease, and palmitoylation, a post-translational lipid modification, is not well understood. In this study, to better understand the role of protein palmitoylation in PD and the pathways altered in this disease, we analyzed the differential palmitoyl proteome (palmitome) in the cerebral cortex of PD patients compared to controls (n = 4 per group). Data-mining of the cortical palmitome from PD patients and controls allowed us to: (i) detect a set of 150 proteins with altered palmitoylation in PD subjects in comparison with controls; (ii) describe the biological pathways and targets predicted to be altered by these palmitoylation changes; and (iii) depict the overlap between the differential palmitome identified in our study with protein interactomes of the PD-linked proteins α-synuclein, LRRK2, DJ-1, PINK1, GBA and UCHL1. In summary, we partially characterized the altered palmitome in the cortex of PD patients, which is predicted to impact cytoskeleton, mitochondrial and fibrinogen functions, as well as cell survival. Our study suggests that protein palmitoylation could have a role in the pathophysiology of PD, and that comprehensive palmitoyl-proteomics offers a powerful approach for elucidating novel cellular pathways modulated in this neurodegenerative disease.

Highly Stable Passive Wireless Sensor for Protease Activity Based on Fatty Acid-Coupled Gelatin Composite Films.

Proteases are often used as biomarkers of many pathologies as well as of microbial contamination and infection. Therefore, extensive efforts are devoted to the development of protease sensors. Some applications would benefit from wireless monitoring of proteolytic activity at minimal cost, e.g., sensors embedded in care products like wound dressings and diapers to track wound and urinary infections. Passive (batteryless) and chipless transponders stand out among wireless sensing technologies when low cost is a requirement. Here, we developed and extensively characterized a composite material that is biodegradable but still highly stable in aqueous media, whose proteolytic degradation could be used in these wireless transponders as a transduction mechanism of proteolytic activity. This composite material consisted of a cross-linked gelatin network with incorporated caprylic acid. The digestion of the composite when exposed to proteases results in a change of its resistivity, a quantity that can be wirelessly monitored by coupling the composite to an inductor-capacitor resonator, i.e., an antenna. We experimentally proved this wireless sensor concept by monitoring the presence of a variety of proteases in aqueous media. Moreover, we also showed that detection time follows a relationship with protease concentration, which enables quantification possibilities for practical applications.

Effect of Relative Humidity on the Viscoelasticity of Thin Organic Films Studied by Contact Thermal Noise AFM.

Material scientists are in need of experimental techniques that facilitate a quantitative mechanical characterization of mesoscale materials and, therefore, their rational design. An example is that of thin organic films, as their performance often relates to their ability to withstand use without damage. The mechanical characterization of thin films has benefited from the emergence of the atomic force microscope (AFM). In this regard, it is of relevance that most soft materials are not elastic but viscoelastic instead. While most AFM operation modes and analysis procedures are suitable for elasticity studies, the use of AFM for quantitative viscoelastic characterizations is still a challenge. This is now an emerging topic due to recent developments in contact resonance AFM. The aim of this work was to further explore the potential of this technique by investigating its sensitivity to viscoelastic changes induced by environmental parameters, specifically humidity. Here, we show that by means of this experimental approach, it was possible to quantitatively monitor the influence of humidity on the viscoelasticity of two different thin and hydrophobic polyurethane coatings representative of those typically used to protect materials from processes like weathering and wear. The technique was sensitive even to the transition between the antiplasticizing and plasticizing effects of ambient humidity. Moreover, we showed that this was possible without the need of externally exciting the AFM cantilever or the sample, i.e., just by monitoring the Brownian motion of cantilevers, which significantly facilitates the implementation of this technique in any AFM setup.

Massive ordering and alignment of cylindrical micro-objects by photovoltaic optoelectronic tweezers.

Optical tools for manipulation and trapping of micro- and nano-objects are a fundamental issue for many applications in nano- and biotechnology. This work reports on the use of one such method, known as photovoltaic optoelectronics tweezers, to orientate and organize cylindrical microcrystals, specifically elongated zeolite L, on the surface of Fe-doped LiNbO3 crystal plates. Patterns of aligned zeolites have been achieved through the forces and torques generated by the bulk photovoltaic effect. The alignment patterns with zeolites parallel or perpendicular to the substrate surface are highly dependent on the features of light distribution and crystal configuration. Moreover, dielectrophoretic chains of zeolites with lengths up to 100 µm have often been observed. The experimental results of zeolite trapping and alignment have been discussed and compared together with theoretical simulations of the evanescent photovoltaic electric field and the dielectrophoretic potential. They demonstrate the remarkable capabilities of the optoelectronic photovoltaic method to orientate and pattern anisotropic microcrystals. The combined action of patterning and alignment offers a unique tool to prepare functional nanostructures with potential applications in a variety of fields such as nonlinear optics or plasmonics.

Less Data Same Information for Event-Based Sensors: A Bioinspired Filtering and Data Reduction Algorithm.

Sensors provide data which need to be processed after acquisition to remove noise and extract relevant information. When the sensor is a network node and acquired data are to be transmitted to other nodes (e.g., through Ethernet), the amount of generated data from multiple nodes can overload the communication channel. The reduction of generated data implies the possibility of lower hardware requirements and less power consumption for the hardware devices. This work proposes a filtering algorithm (LDSI-Less Data Same Information) which reduces the generated data from event-based sensors without loss of relevant information. It is a bioinspired filter, i.e., event data are processed using a structure resembling biological neuronal information processing. The filter is fully configurable, from a "transparent mode" to a very restrictive mode. Based on an analysis of configuration parameters, three main configurations are given: weak, medium and restrictive. Using data from a DVS event camera, results for a similarity detection algorithm show that event data can be reduced up to 30% while maintaining the same similarity index when compared to unfiltered data. Data reduction can reach 85% with a penalty of 15% in similarity index compared to the original data. An object tracking algorithm was also used to compare results of the proposed filter with other existing filter. The LDSI filter provides less error ( 4 . 86 ± 1 . 87 ) when compared to the background activity filter ( 5 . 01 ± 1 . 93 ). The algorithm was tested under a PC using pre-recorded datasets, and its FPGA implementation was also carried out. A Xilinx Virtex6 FPGA received data from a 128 × 128 DVS camera, applied the LDSI algorithm, created a AER dataflow and sent the data to the PC for data analysis and visualization. The FPGA could run at 177 MHz clock speed with a low resource usage (671 LUT and 40 Block RAM for the whole system), showing real time operation capabilities and very low resource usage. The results show that, using an adequate filter parameter tuning, the relevant information from the scene is kept while fewer events are generated (i.e., fewer generated data).

Study of the expression of cathepsins in histological material from pancreatic lesions.

BACKGROUND AND AIMS: To assess the expression levels of cathepsins in malignant and premalignant lesions. METHODS: We retrospectively included patients who underwent pancreatic surgery on pancreatic solid or cystic masses. The expression of cathepsin H, L, B and S was determined in both types of samples. Lesions were divided into three categories: malignant (pancreatic adenocarcinoma and malignant mucinous neoplasms), premalignant (mucinous neoplasms) and benign (other lesions). RESULTS: Thirty-one surgical resection samples were studied. The expression of cathepsins was significantly higher in malignant lesions than in premalignant and benign lesions (H 75%, 27%, 37% p = 0.05; L 92%, 36%, 37% p = 0.011; B 83%, 36%, 62% p = 0.069; S 92%, 36%, 25% p = 0.004, respectively). CONCLUSIONS: Cathepsins are overexpressed in histological samples of malignant lesions compared to premalignant and benign lesions. However, the expression of cathepsins is similar in both premalignant and benign lesions.

Electrical Conduction Mechanisms in Ethyl Cellulose Films under DC and AC Electric Fields.

This work reports the dielectric behavior of the biopolymer ethyl cellulose (EC) observed from transient currents experiments under the action of a direct current (DC) electric field (~107 V/m) under vacuum conditions. The viscoelastic response of the EC was evaluated using dynamic mechanical analysis (DMA), observing a mechanical relaxation related to glass transition of around ~402 K. Furthermore, we propose a mathematical framework that describes the transient current in EC using a fractional differential equation, whose solution involves the Mittag-Leffler function. The fractional order, between 0 and 1, is related to the energy dissipation rate and the molecular mobility of the polymer. Subsequently, the conduction mechanisms are considered, on the one hand, the phenomena that occur through the polymer-electrode interface and, on the other hand, those which manifest themselves in the bulk material. Finally, alternating current (AC) conductivity measurements above the glass transition temperature (~402 K) and in a frequency domain from 20 Hz to 2 MHz were carried out, observing electrical conduction described by the segmental movements of the polymeric chains. Its electrical properties also position EC as a potential candidate for electrical, electronics, and mechatronics applications.

Effect of lung volume preservation during spontaneous breathing trial on successful extubation in patients receiving mechanical ventilation: protocol for a multicenter clinical trial.

BACKGROUND: In standard weaning from mechanical ventilation, a successful spontaneous breathing test (SBT) consisting of 30 min 8 cmH2O pressure-support ventilation (PSV8) without positive end-expiratory pressure (PEEP) is followed by extubation with continuous suctioning; however, these practices might promote derecruitment. Evidence supports the feasibility and safety of extubation without suctioning. Ultrasound can assess lung aeration and respiratory muscles. We hypothesize that weaning aiming to preserve lung volume can yield higher rates of successful extubation. METHODS: This multicenter superiority trial will randomly assign eligible patients to receive either standard weaning [SBT: 30-min PSV8 without PEEP followed by extubation with continuous suctioning] or lung-volume-preservation weaning [SBT: 30-min PSV8 + 5 cmH2O PEEP followed by extubation with positive pressure without suctioning]. We will compare the rates of successful extubation and reintubation, ICU and hospital stays, and ultrasound measurements of the volume of aerated lung (modified lung ultrasound score), diaphragm and intercostal muscle thickness, and thickening fraction before and after successful or failed SBT. Patients will be followed for 90 days after randomization. DISCUSSION: We aim to recruit a large sample of representative patients (N = 1600). Our study cannot elucidate the specific effects of PEEP during SBT and of positive pressure during extubation; the results will show the joint effects derived from the synergy of these two factors. Although universal ultrasound monitoring of lungs, diaphragm, and intercostal muscles throughout weaning is unfeasible, if derecruitment is a major cause of weaning failure, ultrasound may help clinicians decide about extubation in high-risk and borderline patients. TRIAL REGISTRATION: The Research Ethics Committee (CEIm) of the Fundació Unió Catalana d'Hospitals approved the study (CEI 22/67 and 23/26). Registered at ClinicalTrials.gov in August 2023. Identifier: NCT05526053.

Dibenzo[1,2,5]thiadiazepines are non-competitive GABAA receptor antagonists.

A new process for obtaining dibenzo[c,f][1,2,5]thiadiazepines (DBTDs) and their effects on GABA(A) receptors of guinea pig myenteric neurons are described. Synthesis of DBTD derivatives began with two commercial aromatic compounds. An azide group was obtained after two sequential reactions, and the central ring was closed via a nitrene to obtain the tricyclic sulfonamides (DBTDs). Whole-cell recordings showed that DBTDs application did not affect the holding current but inhibited the currents induced by GABA (I(GABA)), which are mediated by GABA(A) receptors. These DBTDs effects reached their maximum 3 min after application and were: (i) reversible, (ii) concentration-dependent (with a rank order of potency of 2c = 2d > 2b), (iii) mediated by a non-competitive antagonism, and (iv) only observed when applied extracellularly. Picrotoxin (which binds in the channel mouth) and DBTDs effects were not modified when both substances were simultaneous applied. Our results indicate that DBTD acted on the extracellular domain of GABA(A) channels but independent of the picrotoxin, benzodiazepine, and GABA binding sites. DBTDs used here could be the initial model for synthesizing new GABA(A) receptor inhibitors with a potential to be used as antidotes for positive modulators of these receptors or to induce experimental epilepsy.

Thermomechanical Characterization and Modeling of NiTi Shape Memory Alloy Coil Spring.

Today, shape memory alloys (SMAs) have important applications in several fields of science and engineering. This work reports the thermomechanical behavior of NiTi SMA coil springs. The thermomechanical characterization is approached starting from mechanical loading-unloading tests under different electric current intensities, from 0 to 2.5 A. In addition, the material is studied using dynamic mechanical analysis (DMA), which is used to evaluate the complex elastic modulus E* = E' - iE″, obtaining a viscoelastic response under isochronal conditions. This work further evaluates the damping capacity of NiTi SMA using tan δ, showing a maximum around 70 °C. These results are interpreted under the framework of fractional calculus, using the Fractional Zener Model (FZM). The fractional orders, between 0 and 1, reflect the atomic mobility of the NiTi SMA in the martensite (low-temperature) and austenite (high-temperature) phases. The present work compares the results obtained from using the FZM with a proposed phenomenological model, which requires few parameters for the description of the temperature-dependent storage modulus E'.

Locating critical events in AFM force measurements by means of one-dimensional convolutional neural networks.

Atomic Force Microscopy (AFM) force measurements are a powerful tool for the nano-scale characterization of surface properties. However, the analysis of force measurements requires several processing steps. One is locating different type of events e.g., contact point, adhesions and indentations. At present, there is a lack of algorithms that can automate this process in a reliable way for different types of samples. Moreover, because of their stochastic nature, the acquisition and analysis of a high number of force measurements is typically required. This can result in these experiments becoming an overwhelming task if their analysis is not automated. Here, we propose a Machine Learning approach, the use of one-dimensional convolutional neural networks, to locate specific events within AFM force measurements. Specifically, we focus on locating the contact point, a critical step for the accurate quantification of mechanical properties as well as long-range interactions. We validate this approach on force measurements obtained both on hard and soft surfaces. This approach, which could be easily used to also locate other events e.g., indentations and adhesions, has the potential to significantly facilitate and automate the analysis of AFM force measurements and, therefore, the use of this technique by a wider community.

Massive Cavitation by Pneumocystis jirovecii in an Immunocompromised Patient.

Since the development of antiretroviral therapy (ART) and antibiotic prophylaxis, the incidence of opportunistic infections in human immunodeficiency virus-acquired immunodeficiency syndrome (HIV-AIDS) has been drastically reduced. However, third-world countries remain a fertile ground for medication nonadherence and inappropriate patient follow-up. Here, we present the case of a 42-year-old male with a history of HIV who presented with worsening shortness of breath and atypical chest pain. A chest X-ray and chest computed tomography scan revealed a left parahilar cavitation measuring 86 mm in diameter. A percutaneous lung biopsy revealed Pneumocystis jirovecii. Appropriate antibiotics were started, and the patient's clinical status significantly improved. This case illustrates the devastating consequences of uncontrolled HIV-AIDS. ART and prophylactic antibiotics remain the cornerstone of treatment to ameliorate progressive lung damage in patients.

Recurrent Steven-Johnson/Toxic Epidermal Necrolysis Overlap Syndrome.

Steven-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening mucocutaneous reactions that are predominantly drug-induced. Treatment varies depending on the severity, but even with accurate medical management, the mortality rate can be up to 50% in severe cases. Recurrent episodes with different agents are uncommon, but they have been reported in the literature. We present a case of a 30-year-old female presenting with recurrent SJS/TEN overlap syndrome complicated by sepsis after phenytoin use. Records revealed a previous episode after carbamazepine use one month prior to the current presentation and a first episode 23 years ago with an unknown medication. The offending agent was discontinued, the appropriate treatment was given, and the patient's clinical status significantly improved. This case highlights the life-threatening manifestation of a mucocutaneous reaction. Prompt clinical assessment is paramount for patient survival.

MUC5B mucin films under mechanical confinement: A combined neutron reflectometry and atomic force microscopy study.

HYPOTHESIS: Among other functions, mucins hydrate and protect biological interfaces from mechanical challenges. Mucins also attract interest as biocompatible coatings with excellent lubrication performance. Therefore, it is of high interest to understand the structural response of mucin films to mechanical challenges. We hypothesized that this could be done with Neutron Reflectometry using a novel sample environment where mechanical confinement is achieved by inflating a membrane against the films. EXPERIMENTS: Oral MUC5B mucin films were investigated by Force Microscopy/Spectroscopy and Neutron Reflectometry both at solid-liquid interfaces and under mechanical confinement. FINDINGS: NR indicated that MUC5B films were almost completely compressed and dehydrated when confined at 1 bar. This was supported by Force Microscopy/Spectroscopy investigations. Force Spectroscopy also indicated that MUC5B films could withstand mechanical confinement by means of steric interactions for pressures lower than âˆ¼ 0.5 bar i.e., mucins could protect interfaces from mechanical challenges of this magnitude while keeping them hydrated. To investigate mucin films under these pressures by means of the employed sample environment for NR, further technological developments are needed. The most critical would be identifying or developing more flexible membranes that would still meet certain requirements like chemical homogeneity and very low roughness.