Autonomous Healable Elastomers with High Elongation, Stiffness, and Fatigue Resistance.

Although self-healing elastomers have been developed in a great breakthrough, it is still a challenge to develop one kind of material that can respond to the fracture instantly even though this characteristic plays an essential role in emergency circumstances. Herein, we adopt free radical polymerization to construct one polymer network equipped with two weak interactions (dipole-dipole interaction and hydrogen bonding). The elastomer we synthesized has a high self-healing efficiency (100%) and a very short healing time (3 min) in an air atmosphere, and it can also self-heal in seawater, showing an ideal healing efficiency of >80%. Additionally, on account of its high elongation (>1000%) and antifatigue capacity (no rupture after loading-unloading 2000 times), the elastomer can be utilized in a wide range of applications, including e-skin and soft robot fields.

Design of Robust Self-Healing Silicone Elastomers Based on Multiple H-Bonding and Dynamic Covalent Bond.

A room-temperature self-healing silicone elastomer was prepared based on the synergistic effect of multiple H-bonding and dynamic covalent bond. The multiple bonds constructed by inserting thiourea into the polyurea network can inhibit the crystallization of hard urea H-bonds segments and activate the diffusion movement of polymer chains. Dynamic imine endows materials with a strong connection for the fracture interface by imine metathesis. The effect of thiourea on urea H-bonds was confirmed by the Fourier transform infrared spectrum, which showed obvious changes of H-bond density according to peak revolution of C═O and N-H. Differential scanning calorimetry demonstrated the transition from the crystalline to amorphous state after the introduction of thiourea. Tensile tests and scratch-healing tests showed that this design method can improve the self-healing property without sacrificing the mechanical strength. Finally, the optimized self-healing process was analyzed from the perspectives of the contact process, the interpenetration diffusion of the polymer chain, and rebuilding of crosslinking points between the two interfaces, which would build an avenue for constructing a fast, self-healing, and tough material.

Bioinspired Thermoplastic Elastomer with Flexible, Self-Healing Capabilities.

The self-healing property of biological tissues gives humans inspiration to endow artificial synthetic materials with self-healing functions. Herein, we report a thermoplastic elastomer that can be self-repaired in a short time, which uses dual dynamic bonds (hydrogen bonds and disulfide bonds) coupled to realize its self-healing function through the rapid conversion of dynamic hydrogen bonds between the hard and soft segments, as well as the dynamic bonding and dissociation of disulfide bonds. Furthermore, the maximum tensile strength and strain of the elastomer can reach 17.4 MPa and 3780%, respectively, and the maximum self-healing rate is close to 100% (temperature: 90 °C, time: 5 h). The arrays' arrangement and reversibility of hydrogen bonds endow the elastomer with high toughness and self-healing properties and thus solve the problem that ordinary polymers cannot self-heal.

Time course of diffusion tensor imaging metrics in the chronic spinal cord compression rat model.

BACKGROUND: Diffusion tensor imaging (DTI) provides information about water molecule diffusion in spinal cord. PURPOSE: This study was aimed to investigate DTI changes in the different stages of compressive spinal cord induced by water-absorbing material implantation. MATERIAL AND METHODS: The spinal cord compression was administered over the fourth cervical vertebral level in rat. Rat models were divided into five subgroups according to compression stages: sham group, group A: three-day compression rat models; group B: 12-day compression rat models; group C: 20-day compression rat models; group D: 60-day compression rat models. DTI including fractional anisotropy (FA) and apparent diffusion coefficient (ADC) in the compressive spinal cord were collected. The relationship between the Basso, Beattie, and Bresnahan (BBB) scores and DTI metrics was further explored. RESULTS: Compared with the sham group, BBB scoring of rat model showed a decreased tendency from group A ( P < 0.05) to group B ( P < 0.05). Then the motor function of rat model hindlimbs was recovered in some degree from group C ( P < 0.05) to group D ( P < 0.05) but had significant motor defects when compared with the normal level ( P < 0.05). The DTI metrics results revealed that chronic spinal cord compression resulted in lower FA value and higher ADC value at the compressive spinal cord level assessed at all four time-points ( P < 0.05). DTI metrics also showed a close correlation with motor function ( P < 0.05). CONCLUSION: DTI is an optimal pre-clinical imaging tool to reflect locomotor performance and pathological status of compressive spinal cord epicenter in chronic spinal cord compression rat model.

In Situ 3D Monitoring of Geometric Signatures in the Powder-Bed-Fusion Additive Manufacturing Process via Vision Sensing Methods.

Lack of monitoring of the in situ process signatures is one of the challenges that has been restricting the improvement of Powder-Bed-Fusion Additive Manufacturing (PBF AM). Among various process signatures.

Risk of papillary thyroid carcinoma and nodular goiter associated with exposure to semi-volatile organic compounds: A multi-pollutant assessment based on machine learning algorithms.

BACKGROUND: Exposure to semi-volatile organic compounds (SVOCs) may link to thyroid nodule risk, but studies of mixed-SVOCs exposure effects are lacking. Traditional analytical methods are inadequate for dealing with mixed exposures, while machine learning (ML) seems to be a good way to fill the gaps in the field of environmental epidemiology research. OBJECTIVES: Different ML algorithms were used to explore the relationship between mixed-SVOCs exposure and thyroid nodule. METHODS: A 1:1:1 age- and gender-matched case-control study was conducted in which 96 serum SVOCs were measured in 50 papillary thyroid carcinoma (PTC), 50 nodular goiters (NG), and 50 controls. Different ML techniques such as Random Forest, AdaBoost were selected based on their predictive power, and variables were selected based on their weights in the models. Weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR) were used to assess the mixed effects of the SVOCs exposure on thyroid nodule. RESULTS: Forty-three of 96 SVOCs with detection rate >80 % were included in the analysis. ML algorithms showed a consistent selection of SVOCs associated with thyroid nodule. Fluazifop-butyl and fenpropathrin are positively associated with PTC and NG in single compound models (all P < 0.05). WQS model shows that exposure to mixed-SVOCs was associated with an increased risk of PTC and NG, with the mixture dominated by fenpropathrin, followed by fluazifop-butyl and propham. In the BKMR model, mixtures showed a significant positive association with thyroid nodule risk at high exposure levels, and fluazifop-butyl showed positive effects associated with PTC and NG. CONCLUSION: This study confirms the feasibility of ML methods for variable selection in high-dimensional complex data and showed that mixed exposure to SVOCs was associated with increased risk of PTC and NG. The observed association was primarily driven by fluazifop-butyl and fenpropathrin. The findings warranted further investigation.

Assessment of circulating proteins in thyroid cancer: Proteome-wide Mendelian randomization and colocalization analysis.

The causality between circulating proteins and thyroid cancer (TC) remains unclear. We employed five large-scale circulating proteomic genome-wide association studies (GWASs) with up to 100,000 participants and a TC meta-GWAS (nCase = 3,418, nControl = 292,703) to conduct proteome-wide Mendelian randomization (MR) and Bayesian colocalization analysis. Protein and gene expressions were validated in thyroid tissue. Through MR analysis, we identified 26 circulating proteins with a putative causal relationship with TCs, among which NANS protein passed multiple corrections (P BH = 3.28e-5, 0.05/1,525). These proteins were involved in amino acids and organic acid synthesis pathways. Colocalization analysis further identified six proteins associated with TCs (VCAM1, LGMN, NPTX1, PLEKHA7, TNFAIP3, and BMP1). Tissue validation confirmed BMP1, LGMN, and PLEKHA7's differential expression between normal and TC tissues. We found limited evidence for linking circulating proteins and the risk of TCs. Our study highlighted the contribution of proteins, particularly those involved in amino acid metabolism, to TCs.

Cross-sectional and Longitudinal Associations Between Metal Mixtures and Serum C3, C4: Result from the Manganese­exposed Workers Healthy Cohort.

Exposure to metal mixtures compromises the immune system, with the complement system connecting innate and adaptive immunity. Herein, we sought to explore the relationships between blood cell metal mixtures and the third and fourth components of serum complement (C3, C4). A total of 538 participants were recruited in November 2017, and 289 participants were followed up in November 2021. We conducted a cross-sectional analysis at baseline and a longitudinal analysis over 4 years. Least Absolute Shrinkage and Selection Operator (LASSO) was employed to identify the primary metals related to serum C3, C4; generalized linear model (GLM) was further used to evaluate the cross-sectional associations of the selected metals and serum C3, C4. Furthermore, participants were categorized into three groups according to the percentage change in metal concentrations over 4 years. GLM was performed to assess the associations between changes in metal concentrations and changes in serum C3, C4 levels. At baseline, each 1-unit increase in log10-transformed in magnesium, manganese, copper, rubidium, and lead was significantly associated with a change in serum C3 of 0.226 (95% CI: 0.146, 0.307), 0.055 (95% CI: 0.022, 0.088), 0.113 (95% CI: 0.019, 0.206), - 0.173 (95% CI: - 0.262, - 0.083), and - 0.020 (95% CI: - 0.039, - 0.001), respectively. Longitudinally, decreased copper concentrations were negatively associated with an increment in serum C3 levels, while decreased lead concentrations were positively associated with an increment in serum C3 levels. However, no metal was found to be primarily associated with serum C4 in LASSO, so we did not further explore the relationship between them. Our research indicates that copper and lead may affect complement system homeostasis by influencing serum C3 levels. Further investigation is necessary to elucidate the underlying mechanisms.

In Situ 4D Printing of Polyelectrolyte/Magnetic Composites for Sutureless Gastric Perforation Sealing.

In situ bioprinting has emerged as one of the most promising techniques for the sutureless tissue sealing of internal organs. However, most existing in situ bioprinting methods are limited by the complex and confined printing space inside the organs, harsh curing conditions for printable bioinks, and poor ability to suturelessly seal injured parts. The combination of in situ bioprinting and 4D printing is a promising technique for tissue repair. Herein, the in situ 4D printing of polyelectrolyte/magnetic composites by gastroscopy for sutureless internal tissue sealing is reported. Using gastric perforation as an example, a gelatin/sodium alginate/magnetic bioink is developed, which can be precisely located by a gastroscope with the assistance of an external magnetic field, solidified in gastric fluid, and firmly adhered to tissue surfaces. The solidified bioink along the defect can be attracted by an external magnetic field, resulting in sutureless sealing. A demonstration using a porcine stomach with an artificial perforation confirms the feasibility of sutureless sealing using 4D printing. Moreover, an in vivo investigation on gastric perforation in a rat model identifies the biocompatibility by H&E and CD68+ staining. This study provides a new orientation and concept for functionality-modified in situ 4D bioprinting.

Metformin promotes Schwann cell remyelination, preserves neural tissue and improves functional recovery after spinal cord injury.

Patients with a spinal cord injury (SCI) usually suffer lifelong disability as a result. Considering this, SCI treatment and pathology study are urgently needed. Metformin, a widely used hypoglycemic drug, has been indicated for its important role in central nervous system diseases. This study aimed to investigate the potential effect of metformin on remyelination after SCI. In the present study, we established a cervical contusion SCI model and metformin treatment was applied after SCI. Biomechanical parameters and behavioral assessment were used to evaluate the severity of injury and the improvement of functional recovery after SCI, respectively. The immunofluorescence and western blot were performed at the terminal time point. Our results showed that treating with metformin after SCI improved functional recovery by reducing the white matter loss and promoting Schwann cell remyelination, and the Nrg1/ErbB signaling pathway may be involved in promoting remyelination mediated by oligodendrocytes and Schwann cells. In addition, the area of spared tissues was significantly increased in the metformin group. However, metformin had no significant effects on the glial scar and inflammation after SCI. In summary, these findings indicated that the role of metformin in Schwann cell remyelination after SCI was probably related to the regulation of the Nrg1/ErbB pathway. It is, therefore, possible to suggest that metformin may be a potential therapy for SCI.

Large-Scale, Abrasion-Resistant, and Solvent-Free Superhydrophobic Objects Fabricated by a Selective Laser Sintering 3D Printing Strategy.

Manufacturing abrasion-resistant superhydrophobic matters is challenging due to the fragile feature of the introduced micro-/nanoscale surface roughness. Besides the long-term durability, large scale at meter level, and 3D complex structures are of great importance for the superhydrophobic objects used across diverse industries. Here it is shown that abrasion-resistant, half-a-meter scaled superhydrophobic objects can be one-step realized by the selective laser sintering (SLS) 3D printing technology using hydrophobic-fumed-silica (HFS)/polymer composite grains. The HFS grains serve as the hydrophobic guests while the sintered polymeric network provides the mechanical strength, leading to low-adhesion, intrinsic superhydrophobic objects with desired 3D structures. It is found that as-printed structures remained anti-wetting capabilities even after undergoing different abrasion tests, including knife cutting test, rude file grinding test, 1000 cycles of sandpaper friction test, tape test and quicksand impacting test, illustrating their abrasion-resistant superhydrophobic stability. This strategy is applied to manufacture a shell of the unmanned aerial vehicle and an abrasion-resistant superhydrophobic shoe, showing the industrial customization of large-scale superhydrophobic objects. The findings thus provide insight for designing intrinsic superhydrophobic objects via the SLS 3D printing strategy that might find use in drag-reduce, anti-fouling, or other industrial fields in harsh operating environments.

A stretchable and healable elastomer with shape memory capability based on multiple hydrogen bonds.

Although a wide range of self-healing materials have been reported by researchers, it is still a challenge to endow exceptional mechanical properties and shape memory characteristics simultaneously in a single material. Inspired by the structure of natural silk, herein, we have adopted a simple synthetic method to prepare a kind of elastomer (HM-PUs) with stiff, healable and shape memory capabilities assisted by multiple hydrogen bonds. The self-healing elastomer exhibits a maximum tensile strength of 39 MPa, toughness of 111.65 MJ m-3 and self-healing efficiency of 96%. Moreover, the recuperative efficiency of shape memory could reach 100%. The fundamental study of HM-PUs will facilitate the development of flexible electronics and medical materials.

Spontaneous water-on-water spreading of polyelectrolyte membranes inspired by skin formation.

Stable interfaces between immiscible solvents are crucial for chemical synthesis and assembly, but interfaces between miscible solvents have been less explored. Here the authors report the spontaneous water-on-water spreading and self-assembly of polyelectrolyte membranes. An aqueous mixture solution containing poly(ethyleneimine) and poly(sodium 4-styrenesulfonate) spreads efficiently on acidic water, leading to the formation of hierarchically porous membranes. The reduced surface tension of the polyelectrolyte mixture solution drives the surface spreading, while the interfacial polyelectrolytes complexation triggered by the low pH of water mitigates water-in-water mixing. The synergy of surface tension and pH-dependent complexation represents a generic mechanism governing interfaces between miscible solvents for materials engineering, without the need for surfactants or sophisticated equipment. As a proof-of-concept, porous polyelectrolyte hybrid membranes are prepared by surface spreading, exhibiting exceptional solar thermal evaporation performance (2.8 kg/m2h) under 1-sun irradiation.

High Expression of TIMELESS Predicts Poor Prognosis: A Potential Therapeutic Target for Skin Cutaneous Melanoma.

Background: Skin cutaneous melanoma (SKCM) is the most lethal skin cancer with an increasing incidence worldwide. The poor prognosis of SKCM urgently requires us to discover prognostic biomarkers for accurate therapy. As a regulator of DNA replication, TIMELESS (TIM) has been found to be highly expressed in various malignancies but rarely reported in SKCM. The objective of this study was to evaluate the relationship between TIM and SKCM tumorigenesis and prognosis. Methods: We obtained RNA sequencing data from TCGA and GTEx to analyze TIM expression and differentially expressed genes (DEGs). Subsequently, GO/KEGG, GSEA, immune cell infiltration analysis, and protein-protein interaction (PPI) network were used to perform the functional enrichment analysis of TIM-related DEGs. Moreover, the receiver operating characteristic (ROC) curves, Cox regression analysis, Kaplan-Meier (K-M) analysis, and nomograms were applied to figure out the clinical significance of TIM in SKCM. In addition, we investigated the relationship between TIM promoter methylation and SKCM prognosis through the UALCAN database. Finally, the immunohistochemical (IHC) results of normal skin and SKCM were analyzed to determine expression differences. Results: TIM was significantly elevated in various malignancies, including SKCM, and high expression of TIM was associated with poor prognosis. Moreover, a total of 402 DEGs were identified between the two distinct TIM expression groups, and functional annotation showed enrichment with positive regulation of cell cycle and classic oncogenic pathways in the high TIM expression phenotype, while keratinization pathways were negatively regulated and enriched. Further analysis showed that TIM was correlated with infiltration of multiple immune cells. Finally, IHC validated the differential expression of TIM in SKCM. Conclusion: TIM might play a pivotal role in tumorigenesis of SKCM and is closely related to its prognosis.

Enhanced Strength and Hardness of AS41 Magnesium Alloy Fabricated by Selective Laser Melting.

AS41 magnesium alloy possesses outstanding performance features such as light weight, high strength to toughness ratio and excellent heat resistance due to the addition of Si element, while traditional casting methods are prone to inducing large grain size and coarse Mg2Si phase. In this study, we first reported utilizing the selective laser melting (SLM) technique, fabricating AS41 samples and exploring the effect of laser energy densities on the metallurgical quality by characterizing and investigating the microstructure and mechanical properties. Results showed that the optimal laser energy density range was 60 to 100 J/mm3. Average grain size of only 2.9 µm was obtained with weak texture strength of 1.65 in {0001} orientation. Meanwhile, many dispersed secondary ß-Mg17Al12 and Mg2Si phases were distributed inside the α-Mg matrix. It was confirmed that the SLM process introduced more grain recrystallization, inducing giant high-angle grain boundaries (HAGBs) and hindering the movement of dislocations, therefore forming dislocation strengthening while achieving grain refinement strengthening. Finally, three times the ultimate tensile strength of 313.7 MPa and higher microhardness of 96.4 HV than those of the as-cast state were obtained, verifying that the combined effect of grain refinement, solid solution strengthening and precipitation strengthening was responsible for the increased strength. This work provides new insight and a new approach to preparing AS41 magnesium alloy.

Study on Risk Factors of Primary Non-traumatic OVCF in Chinese Elderly and a Novel Prediction Model.

OBJECTIVE: Prevention of fragility fractures is one of the public health priorities worldwide, whilst the incidence of osteoporotic vertebral compression fractures (OVCF) continues to rise and lacks the corresponding accurate prediction model. This study aimed to screen potential causes and risk factors for primary non-traumatic osteoporotic vertebral compression fractures (NTOVCF) in the elderly by characterizing a patient population with NTOVCF and comparing it with a population of osteoporotic patients. METHODS: Between January 2013 and January 2022, 208 elderly patients with unequivocal evidence of bone fragility manifested as painful NTOVCF were enrolled, and compared with 220 patients with osteoporosis and no fractures. The demographic data, bone turnover markers, blood routine, serum biochemical values, and radiological findings were investigated. Differences between the fracture and non-fracture groups were analyzed, and variables significant in univariate analysis and correlation analysis were included in the logistic analysis to build the risk prediction model for osteoporotic vertebral fractures. Univariate analysis using student's t-tests for continuous variables or a chi-squared test for categorical variables was conducted to identify risk factors. RESULTS: No significant differences were revealed regarding age, gender, BMI, smoking, alcohol consumption, blood glucose, propeptide of type I procollagen (P1NP), and N-terminal middle segment osteocalcin (N-MID) (P > 0.05). Parathyroid Hormone (PTH), 25(OH)D, serum albumin (ALB), hemoglobin (HB), bone mineral density (BMD), and cross-sectional area (CSA) of the paraspinal muscle in the fracture group were significantly lower than those in the control group; however, b-C-terminal telopeptide of type I collagen (ß-CTX), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), non-prostatic acid phosphatase (NACP), and fatty degeneration ratio (FDR) were significantly higher than those in the control group (P < 0.05). Logistic regression analysis showed that ALB, HB, CSA, and BMD were negatively correlated with NTOVCF, while ß-CTX, HDL-C, NACP, and FDR were positively correlated with NTOVCF. CONCLUSION: Decreased physical activity, anemia, hypoproteinemia, imbalances in bone metabolism, abnormal lipid metabolism, and degenerative and decreased muscle mass, were all risk factors for OVCF in the elderly, spontaneous fractures may be the consequence of cumulative declines in multiple physiological systems over the lifespan. Based on this risk model, timely detection of patients with high OVCF risk and implementation of targeted preventive measures is expected to improve the effect of fracture prevention.

Recent Advances on High-Performance Polyaryletherketone Materials for Additive Manufacturing.

Polyaryletherketone (PAEK) is emerging as an important high-performance polymer material in additive manufacturing (AM) benefiting from its excellent mechanical properties, good biocompatibility, and high-temperature stability. The distinct advantages of AM facilitate the rapid development of PAEK products with complex customized structures and functionalities, thereby enhancing their applications in various fields. Herein, the recent advances on AM of high-performance PAEKs are comprehensively reviewed, concerning the materials properties, AM processes, mechanical properties, and potential applications of additively manufactured PAEKs. To begin, an introduction to fundamentals of AM and PAEKs, as well as the advantages of AM of PAEKs is provided. Discussions are then presented on the material properties, AM processes, processing-matter coupling mechanism, thermal conductivity, crystallization characteristics, and microstructures of AM-processed PAEKs. Thereafter, the mechanical properties and anisotropy of additively manufactured PAEKs are discussed in depth. Their representative applications in biomedical, aerospace, electronics, and other fields are systematically presented. Finally, current challenges and possible solutions are discussed for the future development of high-performance AM polymers.

Research Status and Prospect of Additive Manufactured Nickel-Titanium Shape Memory Alloys.

Nickel-titanium alloys have been widely used in biomedical, aerospace and other fields due to their shape memory effect, superelastic effect, as well as biocompatible and elasto-thermal properties. Additive manufacturing (AM) technology can form complex and fine structures, which greatly expands the application range of Ni-Ti alloy. In this study, the development trend of additive manufactured Ni-Ti alloy was analyzed. Subsequently, the most widely used selective laser melting (SLM) process for forming Ni-Ti alloy was summarized. Especially, the relationship between Ni-Ti alloy materials, SLM processing parameters, microstructure and properties of Ni-Ti alloy formed by SLM was revealed. The research status of Ni-Ti alloy formed by wire arc additive manufacturing (WAAM), electron beam melting (EBM), directional energy dedication (DED), selective laser sintering (SLS) and other AM processes was briefly described, and its mechanical properties were emphatically expounded. Finally, several suggestions concerning Ni-Ti alloy material preparation, structure design, forming technology and forming equipment in the future were put forward in order to accelerate the engineering application process of additive manufactured Ni-Ti alloy. This study provides a useful reference for scientific research and engineering application of additive manufactured Ni-Ti alloys.

Fused Deposition Modeling of Poly (lactic acid)/Macadamia Composites-Thermal, Mechanical Properties and Scaffolds.

In this work Macadamia nutshell (MS) was used as filler in fused deposition modeling (FDM) of Poly (lactic acid) (PLA) composites filaments. Composites containing MS both treated and untreated with alkali and silane were investigated by means of Fourier transform infrared spectroscopy (FTIR), X-Ray diffraction (XRD), Thermogravimetry (TG), scanning electron microscopy (SEM). The results showed that the treated MS composites had better thermal stability. Furthermore, compression tests were carried out. The PLA with 10 wt% treated MS composite was found possessing the best mechanical properties which was almost equivalent to that of the pure PLA. Finally, porous scaffolds of PLA/10 wt% treated MS were fabricated. The scaffolds exhibited various porosities in range of 30-65%, interconnected holes in size of 0.3-0.5 mm, micro pores with dimension of 0.1-1 µm and 37.92-244.46 MPa of elastic modulus. Those values indicated that the FDM of PLA/MS composites have the potential to be used as weight lighter and structural parts.

4D Printing Strain Self-Sensing and Temperature Self-Sensing Integrated Sensor-Actuator with Bioinspired Gradient Gaps.

Integrated sensor-actuators with exciting functionalities, such as action self-sensing, position self-sensing, posture self-sensing, or active sensing, are promising for applications in biomedical device, human-machine interaction, intelligent self-protection devices, and humanoid robots. Despite recent progress, it remains challenging to achieve a macroscopical integrated sensor-actuator in a material system with microstructures. To address this critical challenge, a 4D printing bioinspired microstructure strategy is reported to design a high-performance integrated sensor-actuator capable of simultaneous actuation and sensation. Decoupled thermal stimulation and strain sensation is achieved by combining nanocarbon black/polylactic acid composites with bioinspired gradient microgap structures. As a result, printed integrated sensor-actuators can actively touch objects triggered by thermal stimulation and self-sense the touching state through the resistance change. It is anticipated that the basic design principle underlying this behavior can be used to develop integrated sensor-actuators of various shapes and functionalities to meet desirable applications.