Undesirable Responses Research Articles

The protein-nanoparticle interaction (protein corona) and its importance on the therapeutic application of nanoparticles

Nanobiotechnology has provided promising novel diagnostic and therapeutic strategies which capable to create a broad spectrum of nano-based imaging agents and medicines for human administrations. Several studies have demonstrated that the surface of nanomaterials is immediately coated with suspended proteins after contact with plasma or other biological fluids to form protein corona-nanoparticle complexes. Cells react after exposure with these complexes. since, the biological fate and functions of nanomaterials are determined by physiological responses to protein -nanoparticle complexes in this article, we aimed to review some studies about the effects of the protein profiles and physicochemical characteristics of nanoparticles in the biological environment on the formation of protein corona and subsequent the biological responses upon exposure to nanoparticles. Also, some used methods for of protein corona analysis has been reviewed. It has been shown that the biological impacts of protein corona may be both constructive and/or destructive in the biomedical applications of nanomaterials. The protein corona–cell interactions can facilitate targeted delivery and cellular absorption of therapeutic nanomaterials and also, they mitigate the unfavorable cytotoxic effects of nanoparticles. On the other hand, these interactions may cause rapid clearance of nanoparticles from the body as well as the activation of undesirable inflammatory responses. Hence, the study of the formation mechanism and biological effects of protein corona plays an important role in the design of nanoparticles with specific physicochemical properties proportional with their intended biological activity.

Effect of BRAFV600E and TERT Promoter Mutations on Thyroglobulin Response in Patients With Distant-Metastatic Differentiated Thyroid Cancer

ObjectiveTo assess the impact of serine/threonine-protein kinase B-Raf (BRAF) V600E and telomerase reverse transcriptase (TERT) promoter mutations in patients with distant-metastatic differentiated thyroid cancer (DM-DTC) based on thyroglobulin (Tg) response to radioactive iodine (RAI) therapy. MethodsThe BRAFV600E and TERT mutations in primary tumors or metastatic lymph nodes of 114 patients with DM-DTC were retrospectively examined. RAI avidity was evaluated using a posttreatment iodine-131 whole-body scan. The Tg response was dynamically assessed at a median follow-up period of 56.50 months (interquartile range, 28.43-97.98 months). ResultsBRAFV600E was detected in 38.6% of cases, the TERT mutation in 21.1% of cases, and both the BRAFV600E and TERT mutations in 14.9% of cases. Patients with both the mutations tended to be older at diagnosis (P < .001) and less multifocal (P = .011) and have more aggressive histologic subtypes (P = .011) and a higher Ki-67 index (P = .003). Patients with neither mutation tended to be have more RAI avidity than those with either the BRAFV600E mutation alone or both the mutations (P = .001 and .001, respectively). Patients with both the mutations exhibited a more unfavorable Tg response than those without both the mutations and those with the BRAFV600E mutation alone (P = .001 and .013, respectively). The Tg progression-free survival was shorter in patients with the TERT mutation alone than in those with neither mutation (P = .021), and it tended to be shorter when it coexisted with the BRAFV600E mutation (P < .001); however, no significant difference was observed between those with the BRAFV600E mutation alone and those with neither mutation (P = .890). ConclusionThe coexistence of the BRAFV600E and TERT promoter mutations synergistically induce the loss of RAI avidity and leads to an undesirable Tg response in patients with DM-DTC. The TERT promoter mutation appears to affect Tg response more than the BRAFV600E mutation.

Innate Immunity Modulating Impurities and the Immunotoxicity of Nanobiotechnology-Based Drug Products.

Innate immunity can be triggered by the presence of microbial antigens and other contaminants inadvertently introduced during the manufacture and purification of bionanopharmaceutical products. Activation of these innate immune responses, including cytokine secretion, complement, and immune cell activation, can result in unexpected and undesirable host immune responses. These innate modulators can also potentially stimulate the activation of adaptive immune responses, including the formation of anti-drug antibodies which can impact drug effectiveness. To prevent induction of these adverse responses, it is important to detect and quantify levels of these innate immunity modulating impurities (IIMIs) that may be present in drug products. However, while it is universally agreed that removal of IIMIs from drug products is crucial for patient safety and to prevent long-term immunogenicity, there is no single assay capable of directly detecting all potential IIMIs or indirectly quantifying downstream biomarkers. Additionally, there is a lack of agreement as to which of the many analytical assays currently employed should be standardized for general IIMI screening. Herein, we review the available literature to highlight cellular and molecular mechanisms underlying IIMI-mediated inflammation and its relevance to the safety and efficacy of pharmaceutical products. We further discuss methodologies used for direct and indirect IIMI identification and quantification.

Combinatorial in silico and in vivo evaluation of immune response elicitation by the affibody ZHER2

Due to the high affinity for binding to target molecules and also other unique attributes, affibodies have a great potential to be used in immunotherapeutic and diagnostic approaches. However, the possibility of undesirable immune response is still a great concern. In the current study, we investigated the possible antigenicity, allergenicity and cytotoxicity of the HER2-targeting affibody ZHER2. The binding affinity of potential epitopes of the affibody to murine major histocompatibility complex (MHC) molecules was investigated by immunoinformatics tools and docking approaches. The possible interaction of ZHER2 with human leukocyte antigens HLA-DP, HLA-DM, HLA-DQ and HLA-DR was also studied by protein-protein docking. Additionally, the synthesized affibody gene was expressed and the protein was purified for boosted immunization of Balb/c mice. Induced secretion of IFN-γ, IL-2, IL-4 and IL-10, and total serum IgG were assessed in the immunized mice. Furthermore, MTT cell viability test was performed to evaluate the cytotoxicity of ZHER2 in splenocytes of the treated mice. In silico analyses showed the possible induction of the immune response by ZHER2. While the affibody could elicit the secretion of cellular immune cytokines, it could not induce a significant humoral response in the treated mice and did not show any cytotoxic effects on the exposed splenocytes. These findings explain the practicability of ZHER2 for therapeutic and in vivo diagnostic usages, though its ubiquitous application may need more studies.

Engineering β Cell Replacement Therapies for Type 1 Diabetes: Biomaterial Advances and Considerations for Macroscale Constructs.

While significant progress has been made in treatments for type 1 diabetes (T1D) based on exogenous insulin, transplantation of insulin-producing cells (islets or stem cell-derived β cells) remains a promising curative strategy. The current paradigm for T1D cell therapy is clinical islet transplantation (CIT)-the infusion of islets into the liver-although this therapeutic modality comes with its own limitations that deteriorate islet health. Biomaterials can be leveraged to actively address the limitations of CIT, including undesired host inflammatory and immune responses, lack of vascularization, hypoxia, and the absence of native islet extracellular matrix cues. Moreover, in efforts toward a clinically translatable T1D cell therapy, much research now focuses on developing biomaterial platforms at the macroscale, at which implanted platforms can be easily retrieved and monitored. In this review, we discuss how biomaterials have recently been harnessed for macroscale T1D β cell replacement therapies.

Surfactants for Optode Emulsion Stabilization without Sacrificing Selectivity or Binding Constants.

We compare here the effect of surfactants on ion-selective membranes measured via voltammetry and optode emulsions measured optically. Cyclic voltammetry on a thin-film ion-selective membrane is shown to be a useful screening technique for the estimation of effective complex formation constants and selectivity coefficients for different surfactants with various cations. This technique is particularly useful for its ability to identify separate ion-transfer events (free, surfactant complexed, ionophore complexed) for a specific membrane. However, we also caution against the over-reliance on this technique as changes in membrane characteristics are observed following surfactant partitioning. Of the surfactants explored here, a zwitterionic sulfobetaine-based surfactant was found to stabilize sensors without reducing effective binding constants and selectivity, with greatly superior characteristics to other commonly utilized surfactants. Those include Brij-35, F-127, and Triton X-100, all of which showed significant binding to so-called free ions in the membrane, resulting in peak potential shifts of 199 ± 10, 180 ± 24, 278 ± 11 mV, respectively, for potassium following the subtraction of transducing layer effects. This peak shift translated to a much larger undesired free ion response in optode emulsions. The selectivity in emulsion-based systems was also shown to decrease in the presence of nonionic surfactants compared to that containing the zwitterion.

Understanding the effects of prompting immediately after problem behavior occurs during functional communication training.

When reported, the methods for prompting functional communication responses (FCRs) following problem behavior during functional communication training (FCT) vary. Some researchers have prompted the FCR immediately following problem behavior but doing so may inadvertently strengthen problem behavior as the first link in an undesirable response chain. This study investigated the effects of prompting FCRs following problem behavior during FCT with 4 children who exhibited severe problem behavior. Problem behavior remained low and FCR rates were near optimal when prompts were delivered immediately following problem behavior for 2 participants. Delaying prompts following problem behavior was instrumental for FCR acquisition for 1 participant but led to escalation of problem behavior for a 2nd participant. The conditions under which immediate prompts following problem behavior may improve or worsen FCT are discussed.

Long-Term Impact of Single Epilepsy Training on Knowledge, Attitude and Practices: Comparison of Trained and Untrained Rwandan Community Health Workers.

Objectives: To close the epilepsy treatment gap and reduce related stigma, eradication of misconceptions is importantIn 2014, Community Health Workers (CHWs) from Musanze (Northern Rwanda) were trained on different aspects of epilepsy. This study compared knowledge, attitude and practices (KAPs) towards epilepsy of trained CHWs 3 years after training, to untrained CHWs from Rwamagana (Eastern Rwanda). Methods: An epilepsy KAP questionnaire was administered to 96 trained and 103 untrained CHWs. Demographic and intergroup KAP differences were analysed by response frequencies. A multivariate analyses was performed based on desired and undesired response categories. Results: Epilepsy awareness was high in both groups, with better knowledge levels in trained CHWs. Negative attitudes were lowest in trained CHWs, yet 17% still reported misconceptions. Multivariate analysis demonstrated the impact of the training, irrespective of age, gender and educational level. Knowing someone with epilepsy significantly induced more desired attitudes. Conclusion: Despite demographic differences between trained and untrained CHWs, a single epilepsy training resulted in significant improvement of desired KAPs after 3 years. Nation-wide CHW training programs with focus on training-resistant items, e.g., attitudes, are recommended.

Immunosuppressive activity of a cycloartane triterpene glycoside from Beesia calthaefolia by inhibiting T cell proliferation

BC-1 is a cycloartane triterpene glycoside isolated from the whole plant of Beesia calthaefolia. Our recent studies proved that BC-1 inhibited proliferation of splenic lymphocyte and phagocytosis of macrophages, and inhibited the increased production of TNF-α and IL-1β. However, it lacks of study about the immunomodulatory effect of BC-1 on purified T lymphocytes. Therefore, in the present study, we evaluated the suppressive potentials of BC-1 on immune responses in vitro. BC-1 markedly suppressed anti-CD3/CD28 mAbs (mAbs) induced murine T lymphocytes proliferation, the expression levels of CD69 and CD25 of CD3+ T cells. BC-1 could strongly decrease ratio of CD4+/CD8+, decrease the Th1/Th2 cytokines production (IL-2, IFN-γ, IL-4, and IL-10) of CD4+ T-cells. In addition, we studied signal transduction pathways about T-cell activation on puried murine CD4+ T lymphocytes by western-blot assay. The data revealed that BC-1 could inhibit the activation of JNK, ERK and PI3K/AKT signal transduction pathways. These results indicated that BC-1 possesses potential downregulating effect on the immune system and might be developed as an immunosuppressive agent in treatment of CD4+ T cell-mediated inflammatory and undesired immune responses.

Experimental Study on Early Age Characteristics of Lime-GGBS-Treated Gypseous Clays under Wet–Dry Cycles

Gypseous soils are capable of presenting ground construction challenges to civil and geotechnical engineers due to their unpredictable deformation characteristics. These undesirable responses are sometimes caused by environmental changes in moisture content due to temperature variations, fluctuation of underground water table, surface water, and gypsum content. Hence, the adoption of effective and economical means of stabilising gypseous soils is imperative. This study’s focus is on the early age strength and microstructural characteristics of gypseous soils treated with lime and GGBS. Treated and untreated gypseous soils with 5%, 15%, and 25% gypsum content were subjected to wet–dry cycles while investigating unconfined compressive strength (UCS), water absorption, pH, microstructural changes, and swell. The analysis of the results shows that at zero cycle, the UCS of the untreated gypseous soils increases from 0.62 to 0.79 MPa and swell decreases from 69 to 23%, respectively, as gypsum content increases. However, upon subjection to wet–dry cycles, the UCS reduced from 0.16 to 0.08 MPa at the end of the sixth cycle due to dissolution of gypsum within the soil pores which reduced the strength. The result also shows that gypsum content increases water absorption and reduces the pH of the untreated gypseous soils because of the neutral pH of gypsum. Furthermore, lime-GGBS-treated gypseous soils maintained a higher pH after six wet–dry cycles compared to untreated gypseous soils due to the high pH of lime and the increase in calcium content which improved bonding. In addition, microstructural analysis using SEM indicated early age precipitation of cementitious compounds (CSH) for increasing strength of lime-GGBS-treated gypseous soils compared to untreated gypseous soils.

"Smart" Delivery of Monoclonal Antibodies from a Magnetic Responsive Microgel Nanocomposite.

"Smart" drug-delivery systems have significant potential to increase therapeutic efficiency, avoid undesired immune responses, and minimize drug side effects. Herein, we report on an innovative strategy to control the drug release process using two magneto-activated materials operating in the system. One of them, a polyvinyl alcohol (PVA)-diboronate (DB)-interpenetrated (IPN) alginate (Alg) microgel nanocomposite (PVA-DB-IPN-Alg) loaded with magnetic nanoparticles (MNPs), is acting as a drug-delivery system. The drugs or model (bio)molecules are loaded in the PVA-DB-IPN-Alg and then released upon receiving a magnetic signal. Another component of the system is represented with the MNPs functionalized with the glucose oxidase (GOx) enzyme, GOx-MNPs. The immobilized GOx biocatalytically produces H2O2 in the presence of glucose and oxygen, while the PVA-DB-IPN-Alg is decomposed/dissolved by reacting with H2O2. In the absence of a magnet, the biocatalytically produced H2O2 was mostly decomposed by the catalase enzyme present in the solution, thus not reaching the alginate microgel. Upon aggregation of these two types of particles induced by a magnet, the GOx-MNPs produced H2O2in situ increasing locally its concentration, degrading the PVA-DB-IPN, thus opening pores in the alginate hydrogel resulting in a faster release of the entrapped payload. The release of the payload was confirmed in physiological complex environments, exemplified with human serum, demonstrating the stability and functionality of the materials in biological fluids. The release rate was strongly dependent on the concentration of catalase but not dependent on glucose concentration. The magneto-induced release process was confirmed for the small model protein payload, such as bovine serum albumin (BSA), as well as the trastuzumab monoclonal antibody (TmAb). For the latter, the release rate was up to 3.3 times higher in the presence of the magnet than in the absence of it in the human serum. We expect that the drug-delivery concept developed by these materials can find useful applications in the emerging field of "smart" materials in immunotherapy.

Associations between commonly used apparatus and conflict behaviors reported in the ridden horse in Australia

Equestrian equipment is often used to maintain control of horses while riding, training or handling them and therefore to optimize human and horse safety. However, equipment that has been incorrectly selected or inappropriately used may result in horses exhibiting conflict-related behavior. Characterizing associations between apparatus use and unwelcome horse behavior could benefit both horse welfare and human safety by elucidating the ontogeny of undesirable equine responses and promoting the ethical use of equipment. The current study explored associations between commonly used apparatus and the reported behaviors of the ridden horse, using an online survey that attracted 1,101 Australian respondents. Chi-square tests of association revealed thirteen (9.1%) significant relationships between any unwanted behavior and single items of apparatus used during riding. Analysis of combinations of apparatus that impose aversive stimuli (e.g., harsh bits for deceleration, and spurs for acceleration) revealed that 37.19% of combinations of such items were significantly related to unwanted/conflict equine behaviors. Additional analysis demonstrated no significant difference in the unwanted behavior of horses ridden in bitless versus bitted bridles. This study has demonstrated associations between unwanted ridden behaviors and type of apparatus used, particularly when multiple items are used to apply opposing aversive stimuli. Whilst these results do not imply causation, they may be used to better inform equestrians’ choice and ethical use of apparatus.

Mining drug-target and drug-adverse drug reaction databases to identify target-adverse drug reaction relationships.

The level of attrition on drug discovery, particularly at advanced stages, is very high due to unexpected adverse drug reactions (ADRs) caused by drug candidates, and thus, being able to predict undesirable responses when modulating certain protein targets would contribute to the development of safer drugs and have important economic implications. On the one hand, there are a number of databases that compile information of drug–target interactions. On the other hand, there are a number of public resources that compile information on drugs and ADR. It is therefore possible to link target and ADRs using drug entities as connecting elements. Here, we present T-ARDIS (Target—Adverse Reaction Database Integrated Search) database, a resource that provides comprehensive information on proteins and associated ADRs. By combining the information from drug–protein and drug–ADR databases, we statistically identify significant associations between proteins and ADRs. Besides describing the relationship between proteins and ADRs, T-ARDIS provides detailed description about proteins along with the drug and adverse reaction information. Currently T-ARDIS contains over 3000 ADR and 248 targets for a total of more 17 000 pairwise interactions. Each entry can be retrieved through multiple search terms including target Uniprot ID, gene name, adverse effect and drug name. Ultimately, the T-ARDIS database has been created in response to the increasing interest in identifying early in the drug development pipeline potentially problematic protein targets whose modulation could result in ADRs.Database URL: http://www.bioinsilico.org/T-ARDIS

A note on stability and control of sampled-data asynchronous switched systems

High-performance control of switched systems is needed in various applications involving sampled state variables and discrete control signals. However, asynchronous switching phenomenon existing in sampled-data switched systems may introduce undesired response characteristics and even instability. After demonstrating such unfavorable effects, the conditions to check the stability in these systems are provided in this study. Then the control design problem is considered, and an optimal controller design procedure for assorted performance measures is presented for a class of sampled-data switched systems. The performance of the controller is validated through numerical simulations. The proposed control structure is viable in many different applications containing switching phenomena with a discrete control structure.

048 The anti-drug antibody response is associated with amino acid variation within the HLADRB1 peptide-binding groove

Targeted biologic therapies can elicit an undesirable host immune response characterised by the development of anti-drug antibodies (ADA), an important cause of treatment failure. The most widely used biologic across immune-mediated diseases is the TNF inhibitor adalimumab. This genome-wide association study aimed to identify genetic predictors of developing ADA in psoriasis patients on their first course of adalimumab. Within the BSTOP bioresource, 784 psoriasis patients had ADA data 6-36 months after starting adalimumab (discovery cohort), 232 patients had ADA data <6 months after starting adalimumab (early ADA cohort), and 716 patients had only clinical data available (clinical outcome cohort). We genotyped and imputed 10,917,604 SNPs genome-wide and performed HLA imputation. We tested for association between genetic variation and development of ADA (logistic regression), as well as treatment failure (stopping adalimumab due to ineffectiveness [Cox proportional hazards]). We observed a genome-wide association with ADA within the Major Histocompatibility Complex (rs9268628, OR 3.44, 95% CI 2.21-5.36, p=4.93 x10-8) that mapped to the presence of tryptophan at position 9 (OR 0.34, 95% CI 0.25-0.45, p=1.76x10-12) and lysine at position 71 (OR 0.39, 95% CI 0.28-0.55, p=5.77x10-8) within the HLA-DRB1 peptide-binding groove, explaining 20% of ADA heritability. The protective effect of these residues on early ADA development was also observed in the second cohort of 232 patients. Underscoring their clinical relevance, these HLA-DRB1 residues were protective against treatment failure in the third cohort of 716 patients (HR 0.73, 95% CI 0.57-0.94, p=0.013). We suggest that pre-treatment HLA-DRB1 typing could direct clinical decision-making in terms of biologic selection and immunosuppressant co-therapy. Our findings also provide fundamental insight into the mechanisms by which amino acids within MHC Class II subunits play a critical role in selection of drug antigens displayed to the T-cell receptor, thereby determining the immune response to biologics.

To persist or not to persist? The dilemma of goal adjustment in chronic pain.

To persist or not to persist? The dilemma of goal adjustment in chronic pain.

Effect of charged mutation on aggregation of a pentapeptide: Insights from molecular dynamics simulations.

Aggregation of therapeutic monoclonal antibodies (mAbs) can negatively affect their chemistry, manufacturing, and control attributes and lead to undesirable immune responses in patients. Therefore, optimization of lead mAb drug candidates during discovery stages to mitigate aggregation is increasingly becoming an integral part of their developability assessments. The disruption of short sequence motifs called aggregation prone regions (APRs) found in amino acid sequences of mAb candidates can potentially mitigate their aggregation. In this work, we have performed molecular dynamics simulations to study the aggregation of an APR (VLVIY) found in λ light chains of human antibodies and its single point mutant KLVIY. Eighteen different multicopy peptide simulation systems of "VLVIY" and "KLVIY" were constructed by varying their concentrations, temperatures, termini capping, and flanking gate-keeper regions. Within 20 ns of the simulation, peptide "VLVIY" formed an aggregate of 100 peptides at ~0.1M concentration with a 60% reduction in solvent accessible surface area (SASA). Furthermore, analysis of the SASA change, peptide cluster distribution, and water residence time demonstrated how Val ➔ Lys mutation resists aggregation and improves solubility. Presence of Lys slows down aggregation kinetics via charge-charge repulsions and by raising the kinetic barrier to formation of large oligomers. However, the effect of the Val ➔ Lys mutation is dependent on sequence and structural contexts around the APR. This mutation also alters the solvation shell around the peptide by favoring solute-solvent interactions, thereby increasing its solubility. This work has provided a detailed mechanistic explanation of how APR disruption can mitigate aggregation in biotherapeutics and improve their developability.

Effects of motor restrictions on preparatory brain activity

Modifying established motor skills is a challenging endeavor due to proactive interference from undesired old to desired new actions, calling for high levels of cognitive control. Motor restrictions may facilitate the modification of motor skills by rendering undesired responses physically impossible, thus reducing demands to response inhibition. Here we studied behavioral and EEG effects of rule changes to typing in skilled touch-typists. The respective rule change—typing without using the left index finger—was either implemented per instruction only or with an additional motor restriction. In both groups, the rule change elicited delays and more errors in typing, indicating the occurrence of proactive interference. While stimulus-locked ERPs did not exhibit prominent effects of rule change or group, response-locked ERPs revealed that the time courses of preparatory brain activity preceding typing responses depended on the presence of motor restriction. Although further research is necessary to corroborate our findings, they indicate a novel brain correlate that represents changes in inhibitory response preparation induced by short-term motor restrictions.

Dynamic analysis and active control of hard-magnetic soft materials

ABSTRACT The hard-magnetic soft materials which can sustain high residual magnetic flux density gradually attract the attention of researchers because of potential applications in soft robotics and biomedical fields. In this work, we focus on the dynamic response of hard-magnetic soft materials. The dynamic motion equations are derived by the Euler-Lagrange equation. The effects of the aspect radio on the nonlinear vibration of the hard-magnetic soft cuboid under the force and applied magnetic fields in different directions are investigated. The amplitude-frequency curves demonstrate that the aspect ratio also has an influence on the frequency and amplitude of the primary resonance. Moreover, to eliminate undesired vibration responses, the PID controller is applied to the vibration of the hard-magnetic soft materials, and the desired results can be obtained.

Nonlinear vibration of the spiral bevel gear under periodic torque considering multiple elastic deformation evaluations due to different bearing supports

This paper investigates two parameters effect on vibrational responses of the spiral bevel gear. Changing the gear system overall stiffness (GSOS) considering elastic deformation and periodic torques are the two parameters which are represented as the main goals of this study. In order to investigate the effects of shaft stiffness and elastic deformation, two different cases with different support locations are considered. The first case is presented by locating the support close to the gear, and in the latter one, the distance between gear and support is increased. Besides, to study the effect of torque, two main types are considered: constant and periodic excitation torque. To illustrate the dynamic behavior, the governing differential equations are solved numerically according to the Runge–Kutta method. The equations are nonlinear due to backlash and time-varying coefficients as the results of GSOS variation. Vibrational phenomena are illustrated by means of bifurcation diagrams, RMS, and Poincaré maps. Particular vibrational behaviors such as “chaos” and “period-doubling” phenomena are illustrated with details. By investigating the effect of shaft stiffness, results show that when the support is far away from gear, the vibration response increased by 67.5%. Moreover, while the input torque is constant, the support movement does not cause undesirable responses such as chaotic or period-doubling responses. The periodic torque causes undesirable responses such as chaos and bifurcation and period-doubling responses.Article HighlightsWhat is done in the present paper can be mentioned in three main parts:The nonlinear dynamics of the spiral bevel gear pair under two different support situations is investigated in this paper.To scrutinize the dynamic behavior of the spiral bevel gear-pair in a nearly real situation, the input driver torque is periodically variable.The results show that the spiral bevel gear pair may comprise chaotic response with periodic torque excitation if the bearing supports locate far enough from the gears.