Identifying Umami Peptides Specific to the T1R1/T1R3 Receptor via Phage Display.

Umami peptides are small molecular weight oligopeptides that play a role in umami taste attributes. However, the identification of umami peptides is easily limited by environmental conditions, and the abundant source and high chromatographic separation efficiency remain difficult. Herein, we report a robust strategy based on a phage random linear heptapeptide library that targets the T1R1-Venus flytrap domain (T1R1-VFT). Two candidate peptides (MTLERPW and MNLHLSF) were readily identified with high affinity for T1R1-VFT binding (KD of MW-7 and MF-7 were 790 and 630 nM, respectively). The two peptides exhibited umami taste and significantly enhanced the umami intensity when added to the monosodium glutamate solution. Overall, this strategy shows that umami peptides could be developed via phage display technology for the first time. The phage display platform has a promising application to discover other taste peptides with affinity for taste receptors of interest and has more room for improvement in the future.

Specific Clearance of Lipopolysaccharide from Blood Based on Peptide Bottlebrush Polymer for Sepsis Therapy.

Lipopolysaccharide (LPS) is the primary bacterial toxin that is vital to the pathogenesis and progression of sepsis associated with extremely high morbidity and mortality worldwide. However, specific clearance of LPS from circulating blood is highly challenging because of the structural complexity and its variation between/within bacterial species. Herein, a robust strategy based on phage display screening and hemocompatible peptide bottlebrush polymer design for specific clearance of targeted LPS from circulating blood is proposed. Using LPS extracted from Escherichia coli as an example, a novel peptide (HWKAVNWLKPWT) with high affinity (KD < 1.0 nм), specificity, and neutralization activity (95.9 ± 0.1%) against the targeted LPS is discovered via iterative affinity selection coupled with endotoxin detoxification screening. A hemocompatible bottlebrush polymer bearing the short peptide [poly(PEGMEA-co-PEP-1)] exhibits high LPS selectivity to reduce circulating LPS level from 2.63 ± 0.01 to 0.78 ± 0.05 EU mL-1 in sepsis rabbits via extracorporeal hemoperfusion (LPS clearance ratio > 70%), reversing the LPS-induced leukocytopenia and multiple organ damages significantly. This work provides a universal paradigm for developing a highly selective hemoadsorbent library fully covering the LPS family, which is promising to create a new era of precision medicine in sepsis therapy.

Impacts of respiratory fluctuations on cerebral circulation: a machine-learning-integrated 0-1D multiscale hemodynamic model.

Objective. This study aims to accurately identify the effects of respiration on the hemodynamics of the human cardiovascular system, especially the cerebral circulation.Approach: we have developed a machine learning (ML)-integrated zero-one-dimensional (0-1D) multiscale hemodynamic model combining a lumped-parameter 0D model for the peripheral vascular bed and a one-dimensional (1D) hemodynamic model for the vascular network.In vivomeasurement data of 21 patients were retrieved and partitioned into 8000 data samples in which respiratory fluctuation (RF) of intrathoracic pressure (ITP) was fitted by the Fourier series. ML-based classification and regression algorithms were used to examine the influencing factors and variation trends of the key parameters in the ITP equations and the mean arterial pressure. These parameters were employed as the initial conditions of the 0-1D model to calculate the radial artery blood pressure and the vertebral artery blood flow volume (VAFV).Main results: during stable spontaneous respiration, the VAFV can be augmented at the inhalation endpoints by approximately 0.1 ml s-1for infants and 0.5 ml s-1for adolescents or adults, compared to those without RF effects. It is verified that deep respiration can further increase the ranges up to 0.25 ml s-1and 1 ml s-1, respectively.Significance. This study reveals that reasonable adjustment of respiratory patterns, i.e. in deep breathing, enhances the VAFV and promotes cerebral circulation.

Durability and corrosion behaviors of superhydrophobic amorphous coatings: a contrastive investigation.

Superhydrophobic surfaces can be derived from roughening hydrophobic materials. However, the superhydrophobic surfaces with various micro/nano morphologies present variations of chemical and mechanical durability, which limits their practical applications. Very little actually is known about comparing durability and corrosion resistance of concave and convex superhydrophobic surface structures systematically. In this paper, two kinds of superhydrophobic AlNiTi amorphous coatings with concave and convex surfaces were obtained by chemical etching and hydrothermal methods, respectively. Benefiting from nanoscale sheet structure, the convex superhydrophobic coating displays higher water-repellence (contact angle = 157.6°), better self-cleaning performance and corrosion resistance. The corrosion current density of the convex superhydrophobic surface is approximately one order of magnitude smaller than the concave superhydrophobic surface. Besides, the long-term chemical stability and mechanical durability of both superhydrophobic surfaces were also investigated. The formation and damage mechanisms of these two kinds of superhydrophobic surfaces were proposed. It is hoped that these investigations could provide clear guidance for the real-world applications of superhydrophobic amorphous coatings.

A Decreased Absolute Number of Treg Cells in Patients with Active Rheumatoid Arthritis is Associated with Elevated Serum Osteopontin Levels with Disease Progression.

INTRODUCTION: Rheumatoid arthritis (RA) is a chronic and refractory autoimmune disease characterized by synovial inflammation with unknown aetiology. Immune system dysfunction mediated by CD4+ T lymphocytes, which is regulated by the cytokine osteopontin (OPN), plays an important role in the pathogenesis of RA. METHODS: In this study, the levels of peripheral CD4+ T subsets and serum OPN in patients with active RA were measured and analysed to determine the possible pathogenesis of RA and to provide potential therapeutic targets. RESULTS: Serum OPN levels in both patients with active RA and patients with refractory RA were higher than those in healthy controls (HCs). Compared with HCs, the absolute numbers of Th2 cells increased in patients with active RA, while the absolute counts of Th1 and Treg cells decreased. There was no significant difference in CD4+ T subset levels between new-onset and refractory patients. As the condition persisted or deteriorated, a gradual increase in the levels of OPN and gradual declines in the absolute counts of Th1 and Treg cells were observed in patients with active RA. The fewest Th1 and Treg cells and the highest OPN levels were observed in patients with high disease activity. The serum OPN level was only significantly negatively correlated with the absolute counts of Treg cells in the CD4+ T lymphocyte subsets. CONCLUSIONS: Fewer Treg cells with the increase in disease activity may be related to the increased OPN concentration, which may provide new ideas and directions for the targeted immunoregulatory treatment of RA.

Phage display derived peptides for Alzheimer's disease therapy and diagnosis.

Alzheimer's disease (AD) is an incurable and fatal progressive neurodegenerative disorder associated with memory and cognition impairment. AD is one of the top medical care concerns across the world with a projected economic burden of $2 trillion by 2030. To date, however, there remains no effective disease-modifying therapy available. It is more important than ever to reveal novel therapeutic approaches. Peptide-based biotherapeutics has been a great potential strategy attributed to their distinct and superior biochemical characteristics, such as reproducible chemical synthesis and modification, rapid cell and tissue permeability, and fast blood clearance. Phage display, one of today's most powerful platforms, allows selection and identification of suitable peptide drug candidates with high affinities and specificity toward target, demonstrating the potential to overcome challenges and limitations in AD diagnosis/treatment. We aim to provide the first comprehensive review to summarize the status in this research direction. The biological overview of phage display is described, including basic biology of the phage vectors and construction principle of phage library, biopanning procedure, mirror image phage display, and various binding affinity evaluation approaches. Further, the applications of phage display in AD therapy, targeted drug delivery, and early detection are presented. Finally, we discuss the current challenges and offer a future outlook for further advancing the potential application of phage display on AD and other neurodegenerative diseases.

Effect of ultrasonic surface deep rolling combined with oxygen boost diffusion treatment on fatigue properties of pure titanium.

Ultrasonic surface deep rolling (USDR), oxygen boost diffusion (OBD), and their combination (USDR-OBD) were all used to improve the surface hardening of pure titanium. The microstructure, microhardness, and fatigue life of pure titanium treated by USDR, OBD, and USDR-OBD methods were analyzed. USDR treatment induced a severe deformation area, while OBD treatment produced a brittle oxygen diffusion zone. The USDR-OBD treated samples approached the highest hardness in comparison with other treated samples. The fatigue lives of USDR treated samples were improved, which was due to the high compressive residual stress and refined grains. However, the fatigue lives of both OBD treated samples and USDR-OBD treated samples were decreased due to premature crack initiation and rapid propagation in the oxygen diffusion zone. Finally, the fatigue fracture mechanisms of different samples were proposed.

Wear-Resistant TiC Strengthening CoCrNi-Based High-Entropy Alloy Composite.

In order to improve the wear resistance of CoCrNi alloy, TiC was introduced into the alloy and wear-resistant CoCrNi/(TiC)x composites were designed. The effects of TiC contents on the microstructure, mechanical properties, and wear resistance of CoCrNi matrix were investigated, respectively. It was found that the TiC produced dissolution and precipitation process in CoCrNi alloy, and a large number of needled and blocky TiC particles were precipitated in the composites. The compressive yield strength of CoCrNi/(TiC)x composites increased with the increasing TiC content. Compared with the CoCrNi alloy, the yield strength of CoCrNi/(TiC)x composites increased from 108 to 1371 MPa, and the corresponding strengthening mechanism contributed to the second phase strengthening. The wear resistance of CoCrNi/(TiC)x composites was also greatly improved due to the strengthening of TiC. Compared with the CoCrNi alloy, the specific wear rate of CoCrNi/(TiC)1.0 alloy was reduced by about 77%. The wear resistance of CoCrNi/(TiC)x composites was enhanced with the increasing content of TiC addition.

A Novel Cu(II)-Binding Peptide Identified by Phage Display Inhibits Cu2+-Mediated Aß Aggregation.

Copper (Cu) has been implicated in the progression of Alzheimer's disease (AD), and aggregation of Cu and amyloid ß peptide (Aß) are considered key pathological features of AD. Metal chelators are considered to be potential therapeutic agents for AD because of their capacity to reduce metal ion-induced Aß aggregation through the regulation of metal ion distribution. Here, we used phage display technology to screen, synthesize, and evaluate a novel Cu(II)-binding peptide that specifically blocked Cu-triggered Aß aggregation. The Cu(II)-binding peptide (S-A-Q-I-A-P-H, PCu) identified from the phage display heptapeptide library was used to explore the mechanism of PCu inhibition of Cu2+-mediated Aß aggregation and Aß production. In vitro experiments revealed that PCu directly inhibited Cu2+-mediated Aß aggregation and regulated copper levels to reduce biological toxicity. Furthermore, PCu reduced the production of Aß by inhibiting Cu2+-induced BACE1 expression and improving Cu(II)-mediated cell oxidative damage. Cell culture experiments further demonstrated that PCu had relatively low toxicity. This Cu(II)-binding peptide that we have identified using phage display technology provides a potential therapeutic approach to prevent or treat AD.

Formation and Properties of Superhydrophobic Al Coatings on Steel.

Thermal sprayed aluminum coatings are widely scalable to corrosion protection of the offshore steel structure. However, the corrosion rate of the Al coating increases considerably due to the severe marine environment. It has remained a challenge to improve the corrosion resistance and protective ability of Al coatings. The superhydrophobic surface provides a potential way to improve the corrosion resistance of metal materials. Hence, the development of superhydrophobic Al coatings with superior corrosion resistance is of great interest. In this work, the feasibility of the preparation of superhydrophobic Al coatings on a steel substrate was explored. First, Al coatings were prepared onto the steel substrate by the arc-spraying process, followed by ultrasonic etching with 0.1 M NaOH solution, and afterward passivated using 1% fluorosilanes. The effects of the etching time on morphology, contact angle, and corrosion resistance of the Al coatings were evaluated. The schematic model of the fluorosilane passivation process on the Al coating surface was provided. The micro/nanoscale surface structure of the low-surface-energy fluorosilanes promotes the wetting angle of 153.4° and a rolling angle to 6.6°, denoting the superhydrophobic properties. The superhydrophobic Al coating surface displays excellent self-cleaning performance due to its weak adhesion to water droplets. The corrosion current density of the superhydrophobic Al coating (1.36 × 10-8 A cm-2) is 2 orders of magnitude lower than that of the as-sprayed Al coating (1.18 × 10-6 A cm-2). Similarly, the charge-transfer resistance is found to be 12 times larger for the superhydrophobic Al coating and the corresponding corrosion inhibition efficiency reaches 98.9%. The superhydrophobic Al coating displays superior corrosion resistance and promising applications in a marine corrosion environment.

Personalized 0D-1D multiscale hemodynamic modeling and wave dynamics analysis of cerebral circulation for an elderly patient with dementia.

Senile dementia is associated with pronounced alterations in cerebral circulation. A fundamental understanding of intracranial hemodynamics and wave dynamics is essential for assessing dementia risk. Recent findings suggest that higher carotid artery wave intensity (WI) can predict future cognitive impairments in the elderly. However, wave power (WP) is more advantageous for assessing the risk of cognitive impairment and dementia because of its conservative form, which allows quantification of detailed WP distribution among the entire cerebrovascular network. Unfortunately, intracranial hemodynamics and wave dynamics in elderly patients with dementia remain poorly understood due to ethical issues and technical challenges. In this paper, we proposed a novel and easily achievable personalized methodology for the 0D-1D model of cerebral circulation using widely available clinical data on transcranial Doppler ultrasonography velocity, cerebral artery anatomy from magnetic resonance imaging, and brachial artery pressure. Using the proposed model, we simulated the cerebral blood flows and compared the wave dynamics between a healthy elderly subject and one living with dementia. Moreover, we performed a variance-based global sensitivity analysis to quantify the model-predicted WI and WP sensitivity to the uncertainties of model inputs. This provided more precise information for model personalization and further insights into the wave dynamics of cerebral circulation. In conclusion, the proposed personalized model framework provides a practical approach for patient-specific modeling and WI/WP analysis of cerebral circulation through noninvasive clinical data. The wave dynamics features of higher WI and lower WP in cerebral arteries may be an invaluable biomarker for assessing dementia risk.

Insights into influences of sucrose amendment on nitrification and denitrification in sewage sludge composting.

Sucrose amendment could promote ammonia assimilation and reduce nitrogen loss in sewage sludge (SS) composting, but the effects of sucrose amendment on nitrification and denitrification are still unknown that were firstly researched in present paper. Result showed that sucrose amendment reduced 33.0% of N2O emission by changing the physicochemical indexes, nitrogen forms, related bacteria and functional genes. In the sucrose treatment, the higher nitrifying bacteria community, amoA and nxrA genes abundance were, the lower hao, narG、nirS、nirK and norB genes abundance were. Based on the correlation analysis, the number of nitrifying bacteria was significantly positively correlated with NO3- and nxrA abundance, indicating that sucrose amendment promoted the growth of nitrifying bacteria, the contents of NO3- and the activity of nitrite oxidation. Moreover, contents of NO2- were positively correlated with N2O emission, narG, nirS and norB abundance, indicating that denitrification was the main path of N2O generated.

Brain Targeting and Aß Binding Bifunctional Nanoparticles Inhibit Amyloid Protein Aggregation in APP/PS1 Transgenic Mice.

Alzheimer's disease (AD) is an insidious and progressive neurodegenerative disease with few disease-modifying treatments. A variety of peptide/protein drugs have neuroprotective effects, which brings new hope for the treatment of AD. However, the application of these drugs is limited because of their low specificity and difficulty in crossing the blood-brain barrier. Herein, using the phage display technology, we identified the Aß oligomer binding peptide (KH) and the brain targeting peptide (IS). We combined these peptides to develop a bifunctional nanoparticle (IS@NP/KH) for the delivery of Aß1-42 oligomer binding peptide into the brain. Intranasal administration of IS@NP/KH significantly attenuated the cognitive and behavioral deficits and reduced the Aß deposition in the brain of an AD animal model (APPswe/PS 1d9 double-transgenic mice). Our results suggest that intranasal IS@NP/KH administration could be a novel therapeutic strategy for the treatment of AD.

Highly Strong and Solvent-Resistant Cellulose Nanocrystal Photonic Films for Optical Coatings.

Cellulose nanocrystals (CNCs) are powerful photonic building blocks for the fabrication of biosourced colored films. A combination of the advantages of self-assembled CNCs and multiple templating agents offers access to the development of novel physicochemical sensors, structural coatings, and optic devices. However, due to the inherent brittleness and water instability of CNC-derived materials, their further applications are widely questionable and restrictive. Here, a soft polymer of poly(vinyl alcohol) (PVA) was introduced into the rigid CNC system to balance molecular interactions, whereafter two hard/soft nanocomposites were fastened through a cross-linking reaction of glutaraldehyde (GA), resulting in a highly flexible, water-stable, and chiral nematic CNC composite film through an evaporation-induced self-assembly technique. For a 1.5 wt % GA-cross-linked 70 wt % CNC loading film, its treatment with harsh hydrophilic exposure (soaking in a strong acid, strong base, and seawater) and various organic solvents show exceptional solvent-resistant abilities. Furthermore, the film can even withstand a weight of 167 g cm-2 without failure, which is a highly stiff and durable character. Importantly, the film remains a highly ordered chiral nematic organization, being able to act as a highly transparent substrate for selective reflection of left-handed circularly polarized light, preparing fully covered and patterned full-color coatings on various substrates. Our work paves the way for applications in low-cost, durable, and photonic cellulosic coatings.

Improving sewage sludge compost process and quality by carbon sources addition.

In present study, the effects of carbon sources on compost process and quality were evaluated in the lab-scale sewage sludge (SS) composting. The composting experiments were performed for 32 days in 5 L reactors. The results showed that carbon sources could change the nitrogen conversion and improve the compost quality. Especially, the readily degradable carbon source could promote organic matter degradation, improve nitrogen conversion process and accelerate compost maturation. The addition of glucose and sucrose could increase dissolved organic carbon, CO2 emission, dehydrogenase activity, nitrification and germination index during the SS composting. That's because glucose and sucrose could be quickly used by microbes as energy and carbon source substance to increase activity of microbes and ammonia assimilation. What's more, the NH3 emission was reduced by 26.9% and 32.1% in glucose and sucrose treatments, respectively. Therefore, the addition of readily degradable carbon source could reduce NH3 emission and improve compost maturity in the SS composting.

Impact of ductus arteriosus constriction and restrictive foramen ovale on global hemodynamics for term fetuses with d-TGA.

The ductus arteriosus (DA) constriction and restrictive foramen ovale (FO) are known as the leading cause of compromise and death of fetuses with dextro-transposition of the great arteries (d-TGA). Although the d-TGA fetal hemodynamics is of great importance in making diagnosis and management of the congenital heart defect, it remains poorly understood, particularly in terms of abnormal DA and FO. In this study, we developed a closed-loop 0-1D multiscale model of the fetal cardiovascular system (CVS) specified for the d-TGA circulation and conducted a systematic study of the impact of the DA constriction and restrictive FO on fetal hemodynamics. We found that the DA constriction led to a pronounced increase in the pulmonary artery pressure, pulmonary and mitral valve (PV and MV) regurgitation as well as left heart volume; the restrictive FO was responsible for reducing MV E/A ratio, ie, the ratio of peak early filling and late diastolic filling velocities, and PV peak systolic flow (PSV) but could increase both aortic valve (AV) PSV and aortic isthmus systolic index (ISI). Moreover, the amount of blood flowing through the DA was observed equivalent to that through the FO; the influence of DA constriction on the cerebral and placental perfusions are larger than that of the FO. Our results demonstrate that the proposed fetal cardiovascular model may be a useful tool for studying the underlying mechanisms associated with d-TGA fetal circulation and providing insights into its complex physiology and pathology.

Selection of a d-Enantiomeric Peptide Specifically Binding to PHF6 for Inhibiting Tau Aggregation in Transgenic Mice.

Tauopathies refer to a group of neurodegenerative disorders caused by the accumulation of insoluble hyperphosphorylated Tau protein in the brain. The inhibition and interruption of Tau aggregation are considered important strategies to ameliorate the neurodegenerative process. Previous work has shown that hexapeptide 306VQIVYK311 (PHF6) located in the repeat domain 3 of Tau protein drives Tau aggregation and itself forms a ß-sheet structure similar to those of Tau-oligomers and neurofibrillary tangles (NFTs). In this study, a mirror image phage display technology was used to screen protease-resistant and low-immunogenic d-enantiomeric peptides for their capacity to inhibit Tau aggregation. Following the preparation of d-enantiomeric PHF6 fibrils and M13 phage peptide library biopanning, 7 sets of high specificity peptides were obtained. Through ELISA and competition inhibition assays, we chose a highly specific peptide p-NH with the sequence N-I-T-M-N-S-R-R-R-R-N-H. The molecular docking results showed that p-NH interacted with PHF6 fibrils mainly through van der Waals forces and hydrogen bonding and could inhibit PHF6 aggregation in a d-configuration and concentration-dependent manner. In vitro, p-NH prohibited the formation of PHF6 fibrils and was able to enter into mouse neuroblastoma N2a cells (N2a cells) to inhibit Tau hyperphosphorylation and aggregation. Intranasal administration of p-NH reduced NFTs and improved the cognitive ability of TauP301S transgenic mice. These findings represent a straightforward methodology to find therapeutic peptides with potential applications in tauopathies.

Influence of spent mushroom substrate and molasses amendment on nitrogen loss and humification in sewage sludge composting.

The present study included lab-scale sewage sludge (SS) composting amended by molasses and spent mushroom substrate (SMS) in 5 L composting reactor system. The influence of molasses and SMS amendment on nitrogen loss and humification of SS composting was evaluated. The results showed that SMS amendment, especially combination with molasses raised composting temperature, increased CO2 volatilization, promoted organic matter degradation, improve germination index and humification process. The addition of SMS and molasses contain carbohydrates used as carbon source and energy substance by microorganisms could increase microbial activity and ammonia assimilation. In the SMS + molasses treatments, NH3 volatilization was reduced by 33.1%-37.3% and N2O volatilization was only 17.8%-25.4% of that in the control treatment, furthermore, the nitrogen loss rate was reduced by 27.2%-32.2%. Consequently, the addition of SMS and molasses improved the compost maturity and reduced nitrogen loss in the SS composting process.

Optimal Design Methodology of Tapered Waveguide Transducers for Thickness Monitoring.

For the purpose of providing transducers for long-term monitoring of wall thinning of critical pressure equipment in corrosion or high temperature environments, the optimal design methodology for tapered waveguide units was proposed in the present study. Firstly, the feasibility of the quasi-fundamental shear horizontal (SH0*) wave propagating in the tapered waveguide units was analyzed via numerical simulations, and the transmitting limitations of the non-dispersive SH0* wave were researched. Secondly, several tapered waveguide transducers with varying cross-sections to transmit pure SH0* wave were designed according to the numerical results. Experimental investigations were carried out, and the results were compared with waveguide transducers with a prismatic cross-section. It was found that the tapered waveguide units can transmit non-dispersive shear horizontal waves and suppress the wave attenuation at the same time. The experimental results agreed very well with the numerical simulations. Finally, high-temperature experiments were carried out, and the reliability of thickness measuring by the tapered waveguide transducers was validated. The errors between the measured and the true thicknesses were small. This work paves a solid foundation for the optimal design of tapered waveguide transducers for thickness monitoring of equipment in harsh environments.

Autonomous Exploration and Map Construction of a Mobile Robot Based on the TGHM Algorithm.

An a priori map is often unavailable for a mobile robot in a new environment. In a large-scale environment, relying on manual guidance to construct an environment map will result in a huge workload. Hence, an autonomous exploration algorithm is necessary for the mobile robot to complete the exploration actively. This study proposes an autonomous exploration and mapping method based on an incremental caching topology-grid hybrid map (TGHM). Such an algorithm can accomplish the exploration task with high efficiency and high coverage of the established map. The TGHM is a fusion of a topology map, containing the information gain and motion cost for exploration, and a grid map, representing the established map for navigation and localization. At the beginning of one exploration round, the method of candidate target point generation based on geometry rules are applied to extract the candidates quickly. Then, a TGHM is established, and the information gain is evaluated for each candidate topology node on it. Finally, the node with the best evaluation value is selected as the next target point and the topology map is updated after each motion towards it as the end of this round. Simulations and experiments were performed to benchmark the proposed algorithm in robot autonomous exploration and map construction.