Ferroptosis: emerging roles in lung cancer and potential implications in biological compounds.

Lung cancer has high metastasis and drug resistance. The prognosis of lung cancer patients is poor and the patients' survival chances are easily neglected. Ferroptosis is a programmed cell death proposed in 2012, which differs from apoptosis, necrosis and autophagy. Ferroptosis is a novel type of regulated cell death which is driven by iron-dependent lipid peroxidation and subsequent plasma membrane ruptures. It has broad prospects in the field of tumor disease treatment. At present, multiple studies have shown that biological compounds can induce ferroptosis in lung cancer cells, which exhibits significant anti-cancer effects, and they have the advantages in high safety, minimal side effects, and less possibility to drug resistance. In this review, we summarize the biological compounds used for the treatment of lung cancer by focusing on ferroptosis and its mechanism. In addition, we systematically review the current research status of combining nanotechnology with biological compounds for tumor treatment, shed new light for targeting ferroptosis pathways and applying biological compounds-based therapies.

Distilling dynamical knowledge from stochastic reaction networks.

Stochastic reaction networks are widely used in the modeling of stochastic systems across diverse domains such as biology, chemistry, physics, and ecology. However, the comprehension of the dynamic behaviors inherent in stochastic reaction networks is a formidable undertaking, primarily due to the exponential growth in the number of possible states or trajectories as the state space dimension increases. In this study, we introduce a knowledge distillation method based on reinforcement learning principles, aimed at compressing the dynamical knowledge encoded in stochastic reaction networks into a singular neural network construct. The trained neural network possesses the capability to accurately predict the state conditional joint probability distribution that corresponds to the given query contexts, when prompted with rate parameters, initial conditions, and time values. This obviates the need to track the dynamical process, enabling the direct estimation of normalized state and trajectory probabilities, without necessitating the integration over the complete state space. By applying our method to representative examples, we have observed a high degree of accuracy in both multimodal and high-dimensional systems. Additionally, the trained neural network can serve as a foundational model for developing efficient algorithms for parameter inference and trajectory ensemble generation. These results collectively underscore the efficacy of our approach as a universal means of distilling knowledge from stochastic reaction networks. Importantly, our methodology also spotlights the potential utility in harnessing a singular, pretrained, large-scale model to encapsulate the solution space underpinning a wide spectrum of stochastic dynamical systems.

Assumption-free analysis for amplification-based quantitative nucleic acid detection.

The accurate detection and quantification of biological species that are rarely present but potentially devastating is of paramount importance for the life sciences, biosecurity, food safety, and environmental monitoring. Consequently, there has been significant interest in the sensitive and accurate detection of nucleic acids, leveraging both chemical and biological methods. Among these, quantitative polymerase chain reaction (qPCR) is regarded as the gold standard due to its sensitivity and precision in identifying specific nucleic acid targets. Despite the widespread adoption of qPCR for nucleic acid detection, the analysis of qPCR data typically depends on the use of calibrated standard curves and a threshold method to interpret signal measurements. In this study, we use a stochastic simulation to show the limitations of the threshold method due to its assumptions on amplification kinetics. We propose a new approach for the absolute quantification of nucleic acids that overcomes these limitations by reconstructing the efficiency profile across amplification cycles and using cumulative amplification folds to build a standard curve, thus avoiding the constant efficiency assumption. Our method, validated through experiments with nucleic acid amplification in the presence of potent inhibitors, demonstrates improved accuracy in quantifying nucleic acids, avoiding the systematic errors of the threshold method. This innovation enhances the reliability of nucleic acid quantification, especially where traditional methods struggle with kinetic variability.

Modulating pancreatic cancer microenvironment: The efficacy of Huachansu in mouse models via TGF-ß/Smad pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Huachansu (HCS) is a traditional Chinese medicine obtained from the dried skin glands of Bufo gargarizans and clinical uses of HCS have been approved in China to treat malignant tumors. The traditional Chinese medicine theory states that HCS relieves patients with cancer by promoting blood circulation to remove blood stasis. Clinical observation found that local injection of HCS given to pancreatic cancer patients can significantly inhibit tumor progression and assist in enhancing the efficacy of chemotherapy. However, the material basis and underlying mechanism have not yet been elucidated. AIM OF THE STUDY: To investigate the therapeutic potential of HCS for the treatment of pancreatic cancer in in situ transplanted tumor nude mouse model. Furthermore, this study sought to elucidate the molecular mechanisms underlying its efficacy and assess the impact of HCS on the microenvironment of pancreatic cancer. To identify the antitumor effect of HCS in in situ transplanted tumor nude mouse model and determine the Chemopreventive mechanism of HCS on tumor microenvironment (TME). METHODS: Using the orthotopic transplantation nude mouse model with fluorescently labeled pancreatic cancer cell lines SW1990 and pancreatic stellate cells (PSCs), we examined the effect of HCS on the pancreatic ductal adenocarcinoma (PDAC) microenvironment based on the transforming growth factor ß (TGF-ß)/Smad pathway. The expression of TGF-ß, smad2, smad3, smad4, collagen type-1 genes and proteins in nude mouse model were detected by qRT-PCR and Western blot. RESULTS: HCS significantly reduced tumor growth rate, increased the survival rate, and ameliorated the histopathological changes in the pancreas. It was found that HCS concentration-dependently reduced the expression of TGF-ß1 and collagen type-1 genes and proteins, decreased the expression of Smad2 and Smad3 genes, and downregulated the phosphorylation level of Smad2/3. Additionally, the gene and protein expression of Smad4 were promoted by HCS. Further, the promoting effect gradually enhanced with the rise of HCS concentration. CONCLUSIONS: The results demonstrated HCS could regulate the activity of the TGF-ß/Smad pathway in PDAC, improved the microenvironment of PDAC and delayed tumor progression. This study not only indicated that the protective mechanism of HCS on PDAC might be attributed partly to the inhibition of cytokine production and the TGF-ß/Smad pathway, but also provided evidence for HCS as a potential medicine for PDAC treatment.

RETRACTED: Liu et al. The Effect of Intrinsic Mechanical Properties on Reducing the Friction-Induced Ripples of Hard-Filler-Modified HDPE. Polymers 2023, 15, 268.

The Polymers Editorial Office retracts the article "The Effect of Intrinsic Mechanical Properties on Reducing the Friction-Induced Ripples of Hard-Filler-Modified HDPE" [...].

Intralesional Axitinib Injection Mitigates Hypertrophic Scar by Inhibiting Angiogenesis Pathway: A Preliminary Study in a Rabbit Ear Model.

Objective: High levels of VEGF and excessive angiogenesis contribute significantly to hypertrophic scar (HS) formation. Our study aimed to preliminarily investigate the effect of axitinib, a selective VEGF receptor tyrosine kinase inhibitor, on angiogenesis of HS and to explore its possible mechanism in a rabbit ear model. Methods: Ten male New Zealand white rabbits were used to establish HS models and then randomised to the control and axitinib groups. The scar tissues in the two groups were injected with axitinib or normal saline, and they were evaluated after one month of treatment. Macroscopic scar thickness, vascularity and pliability, as well as histopathological analysis including HE staining and Masson staining and scar elevation index (SEI) between two groups were compared. Immunohistochemical staining of CD31 in two groups was conducted to assess the degree of angiogenesis in HS tissue. The protein expression of protein kinase B (AKT) and ribosomal protein S6 kinase (p70S6K) and their phosphorylation levels in both groups were examined by Western blot analysis. Results: The macroscopic and histological observation showed intralesional axitinib injection significantly reduced scar thickness, vascularity and pliability of HS in the rabbit ear model. The value of SEI in HE assessment was also significantly declined in the axitinib group. Furthermore, immunohistochemical analysis revealed that axitinib suppressed the expression of CD31 in HS tissue, and the mean IOD for blood vessels was significantly lower in the axitinib-treated group. Additionally, axitinib effectively attenuated the protein expression of p70S6K, p-AKT and p-p70S6K by Western blot analysis. Conclusion: Our study suggests that intralesional injection of axitinib can effectively attenuate HS by reducing angiogenesis in the rabbit ear model, and this inhibitory effect may be mediated by suppression of AKT/p70S6K signaling pathway. It indicates that axitinib may be a promising option for the treatment of HS in the future.

Error-Controlled Coarse-Graining Dynamics with Mean-Field Randomization.

In order to comprehend the stochastic behavior of biological systems, it is essential to accurately infer the dynamics of chemical reaction networks. However, computation of the likelihood remains a bottleneck. In this study, we propose the mean-field randomization procedure as a means of efficiently generating error-controlled coarse-graining dynamics. The error is measured by mutual information between the generated trajectories and the coarse-graining procedure. We demonstrate that the exact dynamics can be recovered by resampling, which eliminates the correlation between the dynamics and the procedure. We developed three algorithms to efficiently generate exact or coarse-graining trajectories within a specified error range. By subjecting our algorithms to testing on chemical reaction systems of varying complexities and scales, we observe that they outperform existing state-of-the-art algorithms, and the efficiency of coarse-graining trajectory generation is only weakly dependent on system scales.

The Effect of Intrinsic Mechanical Properties on Reducing the Friction-Induced Ripples of Hard-Filler-Modified HDPE.

Ripple deformations induced by friction on polymeric materials have negative effects on the entire stability of operating machineries. These deformations are formed as a response to contacting mechanics, caused by the intrinsic mechanical properties. High-density polyethylene (HDPE) with varying silicon nitride (Si3N4) contents is used to investigate different ripple deformation responses by conducting single-asperity scratch tests. The relationship between the intrinsic mechanical properties and the ripple deformations caused by filler modifications is analyzed in this paper. The results show the coupling of the inherent mechanical properties, and the stick-slip motion of HDPE creates ripple deformations during scratching. The addition of the Si3N4 filler changes the frictional response; the filler weakens the ripples and almost smoothens the scratch, particularly at 4 wt.%, but the continued increase in the Si3N4 content produces noticeable ripples and fluctuations. These notable differences can be attributed to the yield and post-yield responses; the high yield stress and strain-hardening at 4 wt.% provide good friction resistance and stress distribution, thus a smooth scratch is observed. In contrast, increasing the filler content weakens both the yield and post-yield responses, leading to deformation. The results herein reveal the mechanism behind the initial ripple deformation, thus providing fundamental insights into universally derived friction-induced ripples.

Cinobufacini Inhibits the Development of Pancreatic Cancer Cells through the TGFß/Smads Pathway of Pancreatic Stellate Cells.

This study aimed to test cinobufacini therapeutic potential for pancreatic cancer, verify its potential molecular mechanism, and evaluate the cinobufacini impact on pancreatic cancer microenvironment. First, the effect of cinobufacini-treated pancreatic stellate cells (PSCs) supernatant on the value-added ability of pancreatic cancer (PCCs) was tested. The results show that cinobufacini can effectively reduce the ability of PSCs supernatant to promote the value-added PCCs. Further results show that cinobufacini can effectively reduce the concentration of TGFß in the supernatant of PSCs. Subsequently, the impact of cinobufacini on the transcription and translation levels of key genes in the TGFß/Smads pathway was examined. The results showed that the impact of cinobufacini on the transcription levels of Smad2, Smad3, and Smad7 was in a concentration-dependent manner, while the transcriptional activity of collagen I mRNA was decreased with the increase of cinobufacini concentration. The results of protein expression showed that cinobufacini could upregulate the expression of inhibitory protein Smad7, inhibit the phosphorylation level of p-Smad2/3, and then suppress the expression of type I collagen (collagen I). On the one hand, this study shows that cinobufacini can inhibit the promotion of PSCs on the proliferation of PCCs. On the other hand, cinobufacini can upregulate the expression of the inhibitory molecule, Smad7, through the TGFß/Smads pathway and reduce the phosphorylation level of p-Smad2/3, thereby inhibiting the expression of collagen I and pancreatic fibrosis. cinobufacin can inhibit the proliferation of SW1900 cells by blocking the TGFß/Smads pathway of pancreatic stellate cells. These results provide a clinical basis for the treatment of pancreatic cancer.

The Reduction in the Deformation of HDPE Composites Using Self-Lubricating Fillers in an Aqueous Environment.

Reducing the deformation of polymer matrix materials can decrease the fluctuation of coefficient of friction (COF), and friction-induced vibration and its amplitudes. HDPE composites with T-ZnOw as a fixed strengthening filler were modified with the addition of Si3N4 particles at different concentrations. The COFs, wear rates, micro-morphologies, and friction-induced vibrations were obtained by conducting sliding tests against carbon steel balls in an aqueous environment at a low velocity and high load. The mechanism of the reduction in frictional fluctuation due to the addition of Si3N4 particles was revealed through the frictional responses. The results demonstrated that 4 wt% addition of Si3N4 in HDPE can enhance the strain-stress property and improve the lubrication by forming a lubricating film. Therefore, the surface deformation and the fluctuations of COFs and its vibrations were reduced. The aggregation phenomenon and reduced strain-stress response at a high concentration of Si3N4 disrupted the positive fluctuating reduction, and resulted in a rough surface with severe tearing and cracking deformations. Additionally, it led to fluctuating wear behaviors with high COF and vibrations. The results obtained in this study can elucidate the effects of adding Si3N4 particles to enhance lubrication in polymer composites. Additionally, the results provide a new research method for designing and manufacturing polymer-based composites with low friction-induced fluctuations.

Nonsurgical molding of congenital auricular deformities and analysis of the correction outcomes: A single-center, retrospective study in east China.

Objective: Our research was carried out to provide a clinical reference for the application of nonsurgical therapy in newborns with congenital auricular deformities in east China. Methods: A retrospective study of consecutive newborns using noninvasive ear molding was conducted in Hangzhou in east China's Zhejiang Province. The demographic and clinical information and photographs of the ear before and after treatment were taken. The diagnosis of each auricular deformity was identified, and the treatment outcome was evaluated. Results: A total of 224 patients including 356 congenital ear anomalies received noninvasive ear molding. The median age of infants to initiate treatment was 39.5 days. The median treatment duration was 42.5 days. The median follow-up time was 137.0 days. The overall treatment effective rate of all infants with nonoperative ear molding was 92.1%, and mild skin irritation and ulceration occurred in 34 ear deformities (9.6%). It confirmed that the treatment efficiency was satisfactory and the complication rate was still acceptable despite the late initiation treatment of neonates in east China. Further analysis of treatment outcomes among three subgroups of infants (the ages to initiate the ear molding were respectively less than or equal to 28, 29-56, and more than 57 days) revealed that initiation treatment was significantly related to the treatment results and the earlier the initiation treatment, the higher the effective rate and the lower the complication incidence. Conclusion: Our study hints that newborns in east China may have a longer period for correction. What is more, although our study affirmed a longer period for noninvasive molding, early diagnosis and treatment are still recommended to improve therapy efficiency and reduce treatment duration and complications.

Rare case of granular cell tumor of perianal region: a case report and literature review.

Granular cell tumors (GCTs) are rare submucosal neoplasms, with tumors in the oral mucosa accounting for about a third of all cases. In contrast, GCT is a rare anal neoplasm, with fewer than 30 cases of perianal GCT reported in the literature. We report the case of a 36-year-old woman with a perianal lump with no obvious local lesion as the main clinical complaint. The tumor was completely resected and histologically confirmed as a GCT. The patient remained under continuous follow-up. GCT is difficult for surgeons and pathologists to diagnose, and biopsy and immunohistochemical analysis are prerequisites for an accurate diagnosis. An integrated understanding of GCT in terms of its differential diagnosis will contribute to better identification and more appropriate treatment of this disease.

Co-ablation versus cryoablation for the treatment of stage III-IV non-small cell lung cancer: A prospective, noninferiority, randomized, controlled trial (RCT).

BACKGROUND: This study compared a co-ablation (CA) system, which is a novel ablation device, with an argon-helium cryoablation (AHC) system. We aimed to compare the efficacy and safety of CA and AHC for the treatment of stage III-IV non-small cell lung cancer (NSCLC). METHODS: We conducted a multicenter randomized controlled trial (RCT) to determine whether CA was noninferior to AHC. The primary efficacy endpoints were the iceball coverage rate (ICR) and the disease control rate (DCR) one month after treatment. Noninferiority was declared if the lower limit of two-sided 95% confidence interval (CI) was less than 10%. The ICR and DCR were identified by logistic regression. Treatment safety was assessed. RESULTS: A total of 81 patients underwent randomization (41 assigned to the CA and 40 assigned to the AHC groups)and transthoracic ablation. The ICRs in the CA and AHC groups were 99.24% ± 2.18% and 98.66% ± 3.79%, respectively. Central lesions were associated with an increased risk of an incomplete ICR. The DCRs in the CA and AHC groups were 97.6% and 95%, respectively. A smaller lesion area in the CA group was significantly correlated with a better DCR. The rate of complications was 29.26% in the CA group and 30% in the AHC group. (P = 0.943). There was less probe usage per patient in the CA group. CONCLUSIONS: We determined that CA is noninferior to AHC in terms of efficacy and safety for the treatment of stage III-IV NSCLC. A smaller lesion area in the CA group was significantly correlated with a better DCR. KEY POINTS: CA was noninferior to AHC for stage III-IV NSCLC.

Discovery of Small Molecule NSC290956 as a Therapeutic Agent for KRas Mutant Non-Small-Cell Lung Cancer.

HRas-GTP has a transient intermediate state with a "non-signaling open conformation" in GTP hydrolysis and nucleotide exchange. Due to the same hydrolysis process and the structural homology, it can be speculated that the active KRas adopts the same characteristics with the "open conformation." This implies that agents locking this "open conformation" may theoretically block KRas-dependent signaling. Applying our specificity-affinity drug screening approach, NSC290956 was chosen by high affinity and specificity interaction with the "open conformation" structure HRasG60A-GppNp. In mutant KRas-driven non-small-cell lung cancer (NSCLC) model system, NSC290956 effectively suppresses the KRas-GTP state and gives pharmacological KRas inhibition with concomitant blockages of both the MAPK-ERK and AKT-mTOR pathways. The dual inhibitory effects lead to the metabolic phenotype switching from glycolysis to mitochondrial metabolism, which promotes the cancer cell death. In the xenograft model, NSC290956 significantly reduces H358 tumor growth in nude mice by mechanisms similar to those observed in the cells. Our work indicates that NSC290956 can be a promising agent for the mutant KRas-driven NSCLC therapy.

Head-To-Head Comparison of Treatment Failure and Costs among COPD Patients Who Used Noninvasive Ventilation in the Ward versus in the ICU: A Propensity-Matched Cohort Study.

Background: Head-to-head comparison of treatment failure and costs among chronic obstruct pulmonary disease (COPD) patients who used noninvasive ventilation (NIV) in the ward versus in the ICU is lacking. Methods: This retrospective study was performed in a department of respiratory and critical care medicine in a teaching hospital. COPD patients who used NIV in the respiratory ward or respiratory ICU were screened. We enrolled patients with PaCO2 more than 45 mmHg and pH less than 7.35 before the use of NIV. Results: We enrolled 83 patients who initiated NIV in the ward and 319 patients in the ICU. Only 5 (6%) patients in the ward were required to transfer to ICU for intensive care. The vital signs were worse but improved faster within 24 h of NIV among patients in the ICU than those in the ward. The NIV failure, hospital mortality, and the length of stay in hospital did not differ between the two groups. However, the duration of NIV was shorter (median 4.0 vs. 6.1 days, p < 0.01) and hospital costs were higher (median 4638 vs. 3093 $USD, p < 0.01) among patients in the ICU than those in the ward. After propensity matching, 42 patients were left in each group, and the baseline data were comparable between the two groups. The findings in the overall cohort were confirmed again in the propensity-matched cohort. Conclusions: Among COPD patients, the use of NIV in the ward leads to longer duration of NIV, but lower hospital costs, and similar NIV failure and mortality compared with those in the ICU.

Subinhibitory concentrations of Honokiol reduce α-Hemolysin (Hla) secretion by Staphylococcus aureus and the Hla-induced inflammatory response by inactivating the NLRP3 inflammasome.

Staphylococcus aureus (S. aureus) is one of the most serious human pathogens. α-Hemolysin (Hla) secreted by S. aureus is a key toxin for various infections. We herein report that Honokiol, a natural plant polyphenol, inhibits the secretion and hemolytic activity of staphylococcal Hla with concomitant growth inhibition of S. aureus and protection of S. aureus-mediated cell injury within subinhibitory concentrations. In parallel, Honokiol attenuates the staphylococcal Hla-induced inflammatory response by inhibiting NLRP3 inflammasome activation in vitro and in vivo. Consequently, the biologically active forms of the inflammatory cytokines IL-1ß and IL-18 are reduced significantly in response to Honokiol in mice infected with S. aureus. Experimentally, we confirm that Honokiol binds to monomeric Hla with a modest affinity without impairing its oligomerization. Based on molecular docking analyses in silico, we make a theoretical discovery that Honokiol is located outside of the triangular region of monomeric Hla. The binding model restricts the function of the residues related to membrane channel formation, which leads to the functional disruption of the assembled membrane channel. This research creates a new paradigm for developing therapeutic agents against staphylococcal Hla-mediated infections.

Lighting Up the Thioflavin T by Parallel-Stranded TG(GA) n DNA Homoduplexes.

Thioflavin T (ThT) was once regarded to be a specific fluorescent probe for the human telomeric G-quadruplex, but more other kinds of DNA were found that can also bind to ThT in recent years. Herein, we focus on G-rich parallel-stranded DNA and utilize fluorescence, absorbance, circular dichroism, and surface plasmon resonance spectroscopy to investigate its interaction with ThT. Pyrene label and molecular modeling are applied to unveil the binding mechanism. We find a new class of non-G-quadruplex G-rich parallel-stranded ( ps) DNA with the sequence of TG(GA) n can bind to ThT and increase the fluorescence with an enhancement ability superior to G-quadruplex. The optimal binding specificity for ThT is conferred by two parts. The first part is composed of two bases TG at the 5' end, which is a critical domain and plays an important role in the formation of the binding site for ThT. The second part is the rest alternative d(GA) bases, which forms the ps homoduplex and cooperates with the TG bases at the 5' end to bind the ThT.

Solvent effect on FRET spectroscopic ruler.

A discrepancy has emerged in recent years between single-molecule Förster resonance energy transfer (smFRET) measurements and small angle X-ray scattering (SAXS) or small angle neutron scattering experiments in the study of unfolded or intrinsically disordered proteins in denaturing solutions. Despite significant advances that have been made in identifying various factors which may have contributed to the manifestation of the so-called smFRET-SAXS discrepancy, no consensus has been reached so far on its original source or eventual resolution. In this study, we investigate this problem from the perspective of the solvent effect on FRET spectroscopic ruler (SEFSR), a generic term we use to describe various solvent-dependent factors affecting the accuracy of the FRET experimental method that is known as a "spectroscopic ruler." Some factors belonging to SEFSR, such as direct dye-solvent interaction and labeling configuration, seem to have not received due attention regarding their significance in contributing to the discrepancy. We identify SEFSR by measuring a rigid segment of a double-stranded DNA in various solutions using the smFRET method and evaluate its relative importance in smFRET experiments by measuring segments of a single-stranded DNA and polyethylene glycol (PEG) in solutions. We find that SEFSR can produce non-negligible FRET-inferred interdye distance changes in various solutions, with an intensity following the Hofmeister series in ionic solutions and dependent on labeling configurations. SEFSR is found to be significant in GuHCl and urea solutions, which can fully cover the apparent expansion signal of dye-labeled PEG. Our findings suggest that SEFSR may have played an important role in contributing to the smFRET-SAXS discrepancy.

Effects of flexibility and electrostatic interactions on the coupled binding-folding mechanisms of Chz.core and H2A.z-H2B.

The intrinsically disordered protein (IDP) Chz.core, which is the interaction core of Chz1, shows binding preference to histone variant H2A.z. Although there are several studies on the binding process of Chz.core, the detailed coupled binding-folding processes are still elusive. In this study, we explored the coupled binding-folding mechanism and the effect of flexibility by continuously monitoring the flexibility degree of Chz.core. We applied an all-atom structure-based model (SBM), which takes advantage of providing both backbone and sidechain information about the conformational changes of Chz.core during binding. We presented a somewhat different "fly-casting" picture that the long IDP can undergo a tertiary stretching and bending with larger capture radii than ordered proteins. Our results suggest that the higher flexibility of Chz.core contributes to the shorter times for capturing events, leading to higher recognition efficiencies. In addition, compared to the ordered proteins, the high flexibility of the intrinsically disordered protein enables Chz.core to have a lower binding barrier and a faster association rate, which are favorable for the binding process to its partner H2A.z-H2B.

Electrostatic forces govern the binding mechanism of intrinsically disordered histone chaperones.

A unified picture to understand the protein recognition and function must include the native binding complex structure ensembles and the underlying binding mechanisms involved in specific biological processes. However, quantifications of both binding complex structures and dynamical mechanisms are still challenging for IDP. In this study, we have investigated the underlying molecular mechanism of the chaperone Chz1 and histone H2A.Z-H2B association by equilibrium and kinetic stopped-flow fluorescence spectroscopy. The dependence of free energy and kinetic rate constant on electrolyte mean activity coefficient and urea concentration are uncovered. Our results indicate a previous unseen binding kinetic intermediate. An initial conformation selection step of Chz1 is also revealed before the formation of this intermediate state. Based on these observations, a mixed mechanism of three steps including both conformation selection and induced fit is proposed. By combination of the ion- and denaturant-induced experiments, we demonstrate that electrostatic forces play a dominant role in the recognition of bipolar charged intrinsically disordered protein Chz1 to its preferred partner H2A.Z-H2B. Both the intra-chain and inter-chain electrostatic interactions have direct impacts on the native collapsed structure and binding mechanism.