Exploration of potential biomarkers for prurigo nodularis based on plasma-metabolome analysis.

Prurigo nodularis (PN) is a chronic and debilitating skin disease with severe itching that negatively impacts patients' quality of life and mental state. However, the treatment options for PN remain limited. Global metabolomics analysis can offer effective information on energy metabolism, pathogenesis and potential diagnostic biomarkers. No study on metabolomic analysis of PN has been reported. To further understand the mechanisms of PN and analyse the plasma metabolite profiles in patients with PN. Targeted-metabolome analysis of 306 metabolites in plasma from 18 patients with PN and 19 healthy controls was performed using Liquid Chromatography-tandem Mass Spectrometer analysis. We identified 31 differential metabolites. Most acylcarnitines, long-chain fatty acids, alpha-aminobutyric acid, hydroxybutyric acid and lactic acid among these metabolites were up-regulated in patients with PN; in contrast, glucaric acid, suberic acid, bile acid derivatives and most amino acids were down-regulated. Positive correlations exist between glucaric acid and itching severity and acylcarnitines and insomnia. Suberic acid and the Investigator's Global Assessment (IGA) scores correlate negatively. Metabolite variation reflects the dysregulation of energy metabolism and chronic systematic inflammation in PN. Several metabolites, such as glucaric acid, suberic acid and acylcarnitines, merit further study as potential biomarkers of disease severity in PN.

New insight into prurigo nodularis: Proadrenomedullin N-terminal 20 peptide mediates mouse mast cell activation via Mrgprb2.

BACKGROUND: Prurigo nodularis (PN) is a chronic inflammatory skin disorder that is characterized by extremely itchy nodules. Proadrenomedullin N-terminal 20 (PAMP) activates mast cell degranulation via Mas-related G protein-coupled receptor X2 (MRGPRX2), which is associated with pruritus in allergic contact dermatitis. However, the mechanisms underlying the action of PAMP and MRGPRX2 in PN remain unclear. OBJECTIVE: To determine the role of PAMP-induced mast cell activation via MRGPRX2 (mouse homologous Mrgprb2) in PN. METHODS: The expression of PAMP and the number of MRGPRX2-expressing mast cells in the skin biopsies of patients with PN, atopic dermatitis (AD), and healthy participants were analyzed using immunohistochemistry and immunofluorescence, respectively. The biphasic response of PAMP9-20 mediated by Mrgprb2 in mouse peritoneal mast cells (PMC) was validated in vitro using qRT-PCR, ELISA, flow cytometry, and siRNA techniques. RESULTS: PAMP expression and the number of MRGPRX2+ mast cells in lesional PN skin, but not in AD, were elevated compared to healthy skin. PAMP9-20 mediates the immediate and delayed phase responses of PMC, such as degranulation, histamine and ß-hexosaminidase release, and secretion of inflammatory factors such as CCL2, TNF-α, and GM-CSF. These effects were inhibited when Mrgprb2 expression was silenced. Silencing Mrgprb2 did not affect the biphasic response of PMC that was induced by IgE-FcεRI activation. CONCLUSIONS: The results show that PAMP mediates mouse mast cell activation via Mrgprb2, which may be involved in the pathogenesis of PN. The PAMP/ Mrgprb2 pathway, independent of classical IgE signaling, could be developed as a candidate drug target for treating PN.

Magneto-ionic Control of Ferrimagnetic Order by Oxygen Gating.

Ferrimagnets are considered an excellent spintronic material candidate which combines ultrafast magnetic dynamics and straightforward electrical detectability. However, efficient routes toward magneto-ionic control of ferrimagnetic order remain elusive. In this study, a solid-state oxygen gating device was designed to control the magnetic properties of the ferrimagnetic CoTb alloy. Experimental results show that applying a small voltage can irreversibly tune a Tb-dominant device to a stable Co-dominant state and decrease the magnetization compensation temperature by 130 K. In addition, a reversible voltage control of the magnetization axis between out-of-plane and in-plane states is observed, which indicates that the migrated oxygen ions can bond to both Tb and Co sublattices. First-principles calculations indicate that voltage can dynamically control the flow-in and flow-out of oxygen ions that bond to the Co sublattice. Our work provides an effective means to manipulate ferrimagnetic order and contributes to the development of ultra-low-power spintronic devices.

RNA sequencing reveals the transcriptome profile of the atopic prurigo nodularis with severe itching.

Prurigo nodularis (PN), characterized by inevitable chronicity and severe pruritus, is most frequently associated with atopy compared with other origins. However, the skin transcriptomic profiling of PN arising from atopic dermatitis (AD), so-called atopic PN (APN), remains unclear. We sought to explore the cutaneous transcriptome of APN with severe pruritus and compare it with classic AD. RNA sequencing was performed on the lesional skin from 13 APN to 11 AD patients with severe pruritus (itch numerical rating scale score ≥ 7) and normal skin from 11 healthy subjects. Quantitative real-time polymerase chain reaction and immunochemistry were used for validation. We detected 1085 and 1984 differentially expressed genes (DEGs) in lesional APN skin and lesional AD skin versus normal skin, respectively. In total, 142 itch/inflammation-related DEGs were identified. Itch/inflammation-related DEGs, such as IL-6, IL-10, IL-13, oncostatin M, and IL-4 receptor, had elevated gene transcript levels in both diseases. The itch/inflammation-related DEGs that increased only in APN were mainly neuroactive molecules, while many inflammatory mediators such as T helper 22-related genes were found to be increased only in AD. Both disorders showed mixed Th1/Th2/Th17 polarisation and impaired skin barrier. In contrast to AD, M1/M2 macrophage activation, tumor necrosis factor production, fibrosis, revascularization and neural dysregulation are unique features of APN. The study findings broaden our understanding of the pathogenesis underlying APN, which provides insights into novel pathogenesis with potential therapeutic implications.

Probabilistic computing with voltage-controlled dynamics in magnetic tunnel junctions.

Probabilistic (p-) computing is a physics-based approach to addressing computational problems which are difficult to solve by conventional von Neumann computers. A key requirement for p-computing is the realization of fast, compact, and energy-efficient probabilistic bits. Stochastic magnetic tunnel junctions (MTJs) with low energy barriers, where the relative dwell time in each state is controlled by current, have been proposed as a candidate to implement p-bits. This approach presents challenges due to the need for precise control of a small energy barrier across large numbers of MTJs, and due to the need for an analog control signal. Here we demonstrate an alternative p-bit design based on perpendicular MTJs that uses the voltage-controlled magnetic anisotropy (VCMA) effect to create the random state of a p-bit on demand. The MTJs are stable (i.e. have large energy barriers) in the absence of voltage, and VCMA-induced dynamics are used to generate random numbers in less than 10 ns/bit. We then show a compact method of implementing p-bits by using VC-MTJs without a bias current. As a demonstration of the feasibility of the proposed p-bits and high quality of the generated random numbers, we solve up to 40 bit integer factorization problems using experimental bit-streams generated by VC-MTJs. Our proposal can impact the development of p-computers, both by supporting a fully spintronic implementation of a p-bit, and alternatively, by enabling true random number generation at low cost for ultralow-power and compact p-computers implemented in complementary metal-oxide semiconductor chips.

Converting industrial waste into a value-added cement material through ambient pressure carbonation.

Converting industrial wastes into value-added building products in an environmental management strategy is a challenging yet vital component of the industrial process. Steel slag (SS), an industrial waste by-product from the steel-making process, is typically disposed of in landfill which consumes land resources and pollutes the environment. This paper explores the possibility of a closed-loop system to convert steel slag into a cement material through carbonation activation, thereby significantly reducing the amount of steel slag waste sent to landfills across Canada. The production of this cementing material can occur next to the steel mill, utilizing steel slag and carbon dioxide collected on-site to fabricate carbon-negative products. To save energy and allow production to be feasible on an industrial scale, ambient pressure (AP) carbonation is developed to reduce carbon emissions while improving their performance. High pressure (HP) carbonation curing and normal hydration (NH) references were also implemented at the same time to justify the application of AP carbonation in reducing CO2 emission. The results of this study found AP carbonation-activated SS compacts have comparable CO2 uptake (about 7.5 tons CO2/100 tons slag) and mechanically compressive strength values as those subjected to HP carbonation, suggesting that AP could be used to replace HP in carbonation curing to ensure a lower energy input. Additionally, AP seemed to possess as effective carbonation as HP. The studies investigated by multiple techniques including X-ray diffractometer (XRD), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FTIR), Raman spectroscopic analysis, and scanning electron microscopy (SEM) aim to identify the microstructure development of carbonated SS paste to assess carbonation results. Developed with life cycle assessment (LCA), environmental impact evaluation shows that AP presents a smaller global warming potential (GWP) value than HP. The comparable CO2 sequestration, satisfactory engineering properties, enhanced microstructure and lesser environmental impact in AP carbonation confirm the feasibility of replacing high pressure with extremely low pressure to cure concrete products. The use of AP carbonation for cement material created using steel slag reduces carbon emissions, energy usage, and natural resource consumption.

Dimensional stability of cement paste and concrete subject to early-age carbonation curing.

Early-age carbonation curing of concrete is receiving more interest in terms of performance improvement and emission reduction. However, the volume change of cement-based products subject to carbonation curing may become a concern because of the potential carbonation shrinkage and its related shrinkage cracking. The purpose of this study was to investigate the dimensional stability of cement paste and concrete subject to the early-age carbonation curing. It was found that the carbonation curing introduced first an initial shrinkage due to water evaporation upon gas injection and then generated an expansion due to CO2 uptake and carbonate precipitation. As carbonation proceeded, the deformation was switched to a secondary shrinkage after expansion. The residual deformation due to carbonation curing was shrinkage in cement paste samples and expansion in concrete samples. This was because the relative expansion due to carbonate precipitation in paste was not large enough to compensate for the shrinkage caused by water loss. However, for concrete samples, the introduction of aggregates reduced the pore spaces in concrete, leading to an expansion owing to the limited precipitation. The results of carbon dioxide uptake, XRD, and SEM analysis confirmed that calcium carbonate formation played a critical role in the relative expansion. The study also showed that cement-based products were more resistant to weathering carbonation after the early-age carbonation curing. After 61-day weathering carbonation exposure, both paste and concrete samples exhibited carbonation shrinkage as a result of carbonation of hydration products. However, the magnitude of shrinkage was much smaller in carbonation curing than in weathering carbonation because of the short period of exposure. Both carbonations did not significantly affect the compressive strength of carbonated products. Carbonation curing likely makes concrete products more dimensionally stable in the long-term service.

Increasing toll-like receptor 2 on astrocytes induced by Schwann cell-derived exosomes promotes recovery by inhibiting CSPGs deposition after spinal cord injury.

BACKGROUND: Traumatic spinal cord injury (SCI) is a severely disabling disease that leads to loss of sensation, motor, and autonomic function. As exosomes have great potential in diagnosis, prognosis, and treatment of SCI because of their ability to easily cross the blood-brain barrier, the function of Schwann cell-derived exosomes (SCDEs) is still largely unknown. METHODS: A T10 spinal cord contusion was established in adult female mice. SCDEs were injected into the tail veins of mice three times a week for 4 weeks after the induction of SCI, and the control group was injected with PBS. High-resolution transmission electron microscope and western blot were used to characterize the SCDEs. Toll-like receptor 2 (TLR2) expression on astrocytes, chondroitin sulfate proteoglycans (CSPGs) deposition and neurological function recovery were measured in the spinal cord tissues of each group by immunofluorescence staining of TLR2, GFAP, CS56, 5-HT, and ß-III-tublin, respectively. TLR2f/f mice were crossed to the GFAP-Cre strain to generate astrocyte specific TLR2 knockout mice (TLR2-/-). Finally, western blot analysis was used to determine the expression of signaling proteins and IKKß inhibitor SC-514 was used to validate the involved signaling pathway. RESULTS: Here, we found that TLR2 increased significantly on astrocytes post-SCI. SCDEs treatment can promote functional recovery and induce the expression of TLR2 on astrocytes accompanied with decreased CSPGs deposition. The specific knockout of TLR2 on astrocytes abolished the decreasing CSPGs deposition and neurological functional recovery post-SCI. In addition, the signaling pathway of NF-κB/PI3K involved in the TLR2 activation was validated by western blot. Furthermore, IKKß inhibitor SC-514 was also used to validate this signaling pathway. CONCLUSION: Thus, our results uncovered that SCDEs can promote functional recovery of mice post-SCI by decreasing the CSPGs deposition via increasing the TLR2 expression on astrocytes through NF-κB/PI3K signaling pathway.

Photopatch testing in Chinese patients: A 5-year experience.

BACKGROUND: In 2015, a Chinese expert consensus on photopatch testing (PPT) was established, based on European consensus methodology. OBJECTIVES: To update current information on the prevalence of photoallergic contact dermatitis (PACD) to 20 photoallergens and their clinical relevance in the Chinese context. METHODS: A retrospective analysis of 2372 patients who performed PPT in a tertiary referral center in China between 2015 and 2019 was completed. A total of 1208 PACD reactions were observed in 897 (37.8%) patients, and 413 reactions were of current or past relevance. RESULTS: The proportion of reactions of current or past relevance was 34.2%. The most frequent photoallergens were chlorpromazine, thimerosal, potassium dichromate, and formaldehyde. The ultraviolet absorbers, benzophenone and Para-aminobenzoic acid, showed opposite gender distribution to PACD. Twenty-five patients (1.9%) developed PACD reactions to a newly added photoallergen preparation - fragrance mix I. Patients with chronic actinic dermatitis, widespread exposed-site or generalized dermatitis, and older age were more likely to have PACD. CONCLUSIONS: This study is the first to profile PACD reactions with clinical relevance in China. The prevalence of PACD to culprit photoallergens was affected by regional peculiarities. Attention needs to be paid to the age, body-site distribution, and known diagnoses of patients for the identification of PACD.

Dual-rotor strategy for organic cocrystals with enhanced near-infrared photothermal conversion.

Organic cocrystal engineering provides a promising route to promote the near-infrared (NIR) light harvesting and photothermal conversion (PTC) abilities of small organic molecules through the rich noncovalent bond interactions of D/A units. Besides, the single-bond rotatable groups known as "rotors" are considered to be conducive to the nonradiative transitions of the excited states of organic molecules. Herein, we propose a single-/double-bond dual-rotor strategy to construct D-A cocrystals for NIR PTC application. The results reveal that the cocrystal exhibits an ultra-broadband absorption from 300 nm to 2000 nm profiting from the strong π-π stacking and charge transfer interactions, and the weakened p-π interaction. More importantly, the PTC efficiency of cocrystals at 1064 nm in the NIR-II region can be largely enhanced by modulating the number of rotor groups and the F-substituents of D/A units. As is revealed by fs-TA spectroscopy, the superior NIR PTC performance can be attributed to the nonradiative decays of excited states induced by the free rotation of the single-bond rotor (-CH3) from the donors and the inactive double-bond rotor ([double bond, length as m-dash]C(C[triple bond, length as m-dash]N)2) being in the active form of [-C(C[triple bond, length as m-dash]N)2] in the excited states from the acceptors. This prototype displays a promising route to extend the functionalization of small organic molecules based on organic cocrystal engineering.

High performance and recyclable Ag/ZnO/PM substrate for the detection of organic pollutants.

A sensitive and recyclable substrate was fabricated through in situ reduction of silver nanoparticles (NPs) on zinc oxide nanorods (NRs). The prepared silver nanoparticles/zinc oxide nanorods/polyamide mesh (Ag/ZnO/PM) substrate exhibited not only excellent surface-enhanced Raman scattering (SERS) performance to R6G with a limit of detection (LOD) of 10-12 M, mainly attributed to the synergistic effect of the suitable size and the nanoscale gaps of the Ag NPs to produce local surface plasmon resonance (LSPR), but also outstanding self-cleaning property via UV irradiation due to its significant photocatalytic property based on the non-equilibrium carriers generated by ZnO and the presence of Schottky junctions between Ag and ZnO. The substrate showed good recycling stability even after five cycles. Furthermore, the successful recyclable application of Ag/ZnO/PM for tetracycline hydrochloride (TC) detection with high sensitivity further suggested that it is a promising candidate for constructing a portable SERS platform to detect organic pollutants.

Molecular mechanisms of pruritus in prurigo nodularis.

Pruritus is the most common symptom of dermatological disorders, and prurigo nodularis (PN) is notorious for intractable and severe itching. Conventional treatments often yield disappointing outcomes, significantly affecting patients' quality of life and psychological well-being. The pathogenesis of PN is associated with a self-sustained "itch-scratch" vicious cycle. Recent investigations of PN-related itch have partially revealed the intricate interactions within the cutaneous neuroimmune network; however, the underlying mechanism remains undetermined. Itch mediators play a key role in pruritus amplification in PN and understanding their action mechanism will undoubtedly lead to the development of novel targeted antipruritic agents. In this review, we describe a series of pruritogens and receptors involved in mediating itching in PN, including cytokines, neuropeptides, extracellular matrix proteins, vasculogenic substances, ion channels, and intracellular signaling pathways. Moreover, we provide a prospective outlook on potential therapies based on existing findings.

Anti-Disturbance Sliding Mode Control of a Novel Variable Stiffness Actuator for the Rehabilitation of Neurologically Disabled Patients.

Lower limb exoskeletons are widely used for rehabilitation training of patients suffering from neurological disorders. To improve the human-robot interaction performance, series elastic actuators (SEAs) with low output impedance have been developed. However, the adaptability and control performance are limited by the constant spring stiffness used in current SEAs. In this study, a novel load-adaptive variable stiffness actuator (LaVSA) is used to design an ankle exoskeleton. To overcome the problems of the LaVSA with a larger mechanical gap and more complex dynamic model, a sliding mode controller based on a disturbance observer is proposed. During the interaction process, due to the passive joints at the load side of the ankle exoskeleton, the dynamic parameters on the load side of the ankle exoskeleton will change continuously. To avoid this problem, the designed controller treats it and the model error as a disturbance and observes it with the disturbance observer (DOB) in real time. The first-order derivative of the disturbance set is treated as a bounded value. Subsequently, the parameter adaptive law is used to find the upper bound of the observation error and make corresponding compensation in the control law. On these bases, a sliding mode controller based on a disturbance observer is designed, and Lyapunov stability analysis is given. Finally, simulation and experimental verification are performed. The wearing experiment shows that the resistance torque suffered by humans under human-robot interaction is lower than 120 Nmm, which confirms that the controller can realize zero-impedance control of the designed ankle exoskeleton.

High-Performance Dielectric Elastomer Nanogenerator for Efficient Energy Harvesting and Sensing via Alternative Current Method.

Soft, low-cost, high-performance generators are highly desirable for harvesting ambient low frequency mechanical energy. Here, a dielectric elastomer nanogenerator (DENG) is reported, which consists of a dielectric elastomer capacitor, an electret electrostatic voltage source, and a charge pump circuit. Under biaxial stretching, DENG can convert tensile mechanical energy into electrical power without any external power supply. Different from traditional DEG with the charge outward transfer in direct current (DC), the DENG works based on shuttle movement of internal charges in an alternating current (AC). Through alternating current (AC) method, the charge density of the DENG can reach 26 mC m-2 per mechanical cycle, as well as energy density of up to 140 mJ g-1 . Due to the all-solid-state structure without air gap, the DENG is capable of working stably under different ambient humidity (20 RH%-100 RH%). To demonstrate the applications, a water wave harvester based on the DENG is constructed. The integrated device powers a sensing communication module for self-powered remote weather monitoring, showing the potential application in ocean wave energy harvesting.

Early Age Carbonation Heat and Products of Tricalcium Silicate Paste Subject to Carbon Dioxide Curing.

This paper presents a study on the carbonation reaction heat and products of tricalcium silicate (C3S) paste exposed to carbon dioxide (CO2) for rapid curing. Reaction heat was measured using a retrofitted micro-calorimeter. The highest heat flow of a C3S paste subject to carbonation curing was 200 times higher than that by hydration, and the cumulative heat released by carbonation was three times higher. The compressive strength of a C3S paste carbonated for 2 h and 24 h was 27.5 MPa and 62.9 MPa, respectively. The 24-h carbonation strength had exceeded the hydration strength at 28 days. The CO2 uptake of a C3S paste carbonated for 2 h and 24 h was 17% and 26%, respectively. The X-ray diffraction (XRD), transmission electron microscope coupled with energy dispersive spectrometer (TEM-EDS), and 29Si magic angle spinning⁻nuclear magnetic resonance (29Si MAS-NMR) results showed that the products of a carbonated C3S paste were amorphous silica (SiO2) and calcite crystal. There was no trace of calcium silicate hydrate (C⁻S⁻H) or other polymorphs of calcium carbonate (CaCO3) detected.