Intranasal PAMAM-G3 scavenges cell-free DNA attenuating the allergic airway inflammation.

Allergic airway inflammation (AAI), including allergic rhinitis (AR) and allergic asthma, is driven by epithelial barrier dysfunction and type 2 inflammation. However, the underlying mechanism remains uncertain and available treatments are constrained. Consequently, we aim to explore the role of cell-free DNA (cfDNA) in AAI and assess the potential alleviating effects of cationic polymers (CPs) through cfDNA elimination. Levels of cfDNA were evaluated in AR patients, allergen-stimulated human bronchial epithelium (BEAS-2B cells) and primary human nasal epithelium from both AR and healthy control (HC), and AAI murine model. Polyamidoamine dendrimers-generation 3 (PAMAM-G3), a classic type of cationic polymers, were applied to investigate whether the clearance of cfDNA could ameliorate airway epithelial dysfunction and inhibit AAI. The levels of cfDNA in the plasma and nasal secretion from AR were higher than those from HC (P < 0.05). Additionally, cfDNA levels in the exhaled breath condensate (EBC) were positively correlated with Interleukin (IL)-5 levels in EBC (R = 0.4191, P = 0.0001). Plasma cfDNA levels negatively correlated with the duration of allergen immunotherapy treatment (R = -0.4297, P = 0.006). Allergen stimulated cfDNA secretion in vitro (P < 0.001) and in vivo (P < 0.0001), which could be effectively scavenged with PAMAM-G3. The application of PAMAM-G3 inhibited epithelial barrier dysfunction in vitro and attenuated the development of AAI in vivo. This study elucidates that cfDNA, a promising biomarker for monitoring disease severity, aggravates AAI and the application of intranasal PAMAM-G3 could potentially be a novel therapeutic intervention for AAI. Allergen stimulates the secretion of cell-free DNA (cfDNA) in both human and mouse airway. Intranasal polyamidoamine dendrimers-generation 3 (PAMAM-G3) scavenges cfDNA and alleviates allergic airway inflammation.

Comparing Protein and Gene Expression Signature between Nasal Polyps and Nasal Fluids in Chronic Rhinosinusitis.

INTRODUCTION: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a serious inflammatory condition. Nasal fluids (NFs) present a noninvasive alternative to nasal biopsy for studying CRSwNP pathogenesis. We aimed to compare the protein and mRNA inflammation signature between nasal polyps (NPs) and NFs. METHOD: The performance of polyvinyl alcohol (PVA) sponges and NFs absorbable device (NFAD) for collecting NFs from 20 patients with CRSwNP was compared using the Luminex assay. The other group consisted of four healthy controls and an additional 21 CRSwNP patients (including eosinophilic CRSwNP [ECRSwNP] and non-eosinophilic CRSwNP [NECRSwNP]) for protein quantification by Olink platform and gene expression evaluation by RNA-sequencing. Spearman's analysis was performed to detect correlations between protein expression levels in NFs and clinical assessment variables. RESULTS: NFAD-collected NFs contained at least a 2-fold higher concentration of cytokines than that obtained using PVA sponge, and these cytokines levels are significantly associated with NPs (ρ > 0.45, p < 0.05). Differentially expressed proteins between NFs and NPs were significantly correlated in the ECRSwNP subgroup compared with controls (ρ = 0.41, p < 0.01). Levels of Th2/IL-13, MCP4, and CCL4, characteristic of eosinophilic infiltration, were increased in ECRSwNP patients. A significant correlation between gene and protein expression was observed (ρ = 0.34, p < 0.01). PDL2 levels in NFs were positively correlated with ECRSwNP postoperative recurrence, the nasal VAS, and SNOT-22 scores (ρ > 0.68, p < 0.05 for all). CONCLUSION: Our study revealed similarities and discrepancies in inflammatory signatures between NPs and NFs in the same CRSwNP patient.

The SMYD3-dependent H3K4me3 status of IGF2 intensifies local Th2 differentiation in CRSwNP via positive feedback.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous and common upper airway disease divided into various inflammatory endotypes. Recent epidemiological findings showed a T helper 2 (Th2)-skewed dominance in CRSwNP patients. Histone modification alterations can regulate transcriptional and translational expression, resulting in abnormal pathogenic changes and the occurrence of diseases. Trimethylation of histone H3 lysine 4 (H3K4me3) is considered an activator of gene expression through modulation of accessibility for transcription, which is closely related to CRSwNP. H3K4me3 levels in the human nasal epithelium may change under Th2-biased inflammatory conditions, resulting in exaggerated local nasal Th2 responses via the regulation of naïve CD4+ T-cell differentiation. Here, we revealed that the level of SET and MYND domain-containing protein 3 (SMYD3)-mediated H3K4me3 was increased in NPs from Th2 CRSwNP patients compared with those from healthy controls. We demonstrated that SMYD3-mediated H3K4me3 is increased in human nasal epithelial cells under Th2-biased inflammatory conditions via S-adenosyl-L-methionine (SAM) production and further found that the H3K4me3high status of insulin-like growth factor 2 (IGF2) produced in primary human nasal epithelial cells could promote naïve CD4+ T-cell differentiation into Th2 cells. Moreover, we found that SAM production was dependent on the c-Myc/methionine adenosyltransferase 2A (MAT2A) axis in the nasal epithelium. Understanding histone modifications in the nasal epithelium has immense potential utility in the development of novel classes of therapeutics targeting Th2 polarization in Th2 CRSwNP. Video Abstract.

Possible rodent equivalent of the posterior cingulate cortex (area 23) interconnects with multimodal cortical and subcortical regions.

Posterior cingulate cortex (area 23, A23) in human and monkeys is a critical component of the default mode network and is involved in many diseases such as Alzheimer's disease, autism, depression, attention deficit hyperactivity disorder and schizophrenia. However, A23 has not yet identified in rodents, and this makes modeling related circuits and diseases in rodents very difficult. Using a comparative approach, molecular markers and unique connectional patterns this study has uncovered the location and extent of possible rodent equivalent (A23~) of the primate A23. A23 ~ but not adjoining areas in the rodents displays strong reciprocal connections with anteromedial thalamic nucleus. Rodent A23 ~ reciprocally connects with the medial pulvinar and claustrum as well as with anterior cingulate, granular retrosplenial, medial orbitofrontal, postrhinal, and visual and auditory association cortices. Rodent A23 ~ projects to dorsal striatum, ventral lateral geniculate nucleus, zona incerta, pretectal nucleus, superior colliculus, periaqueductal gray, and brainstem. All these findings support the versatility of A23 in the integration and modulation of multimodal sensory information underlying spatial processing, episodic memory, self-reflection, attention, value assessment and many adaptive behaviors. Additionally, this study also suggests that the rodents could be used to model monkey and human A23 in future structural, functional, pathological, and neuromodulation studies.

Impact of obstructive sleep apnea on cancer risk: a systematic review and meta-analysis.

PURPOSE: We aimed to study the effect of obstructive sleep apnea (OSA) on cancer risk. METHODS: We searched PubMed, Embase, and Cochrane databases for relevant studies. The qualities of included studies were assessed using Newcastle-Ottawa Scale (NOS). Unadjusted and adjusted analyses were performed. We also conducted subgroup analyses stratified by gender, severity of OSA, study design, and cancer type. RESULTS: After literatures search, 18 studies were included in the present study. In the unadjusted analysis, we discovered an increased cancer risk in patients with OSA with a pooled relative risk (RR) in the OSA group of 1.49 (95% confidence interval (CI): 1.32-1.69, I2 = 32%, P = 0.15). In adjusted analysis, OSA correlated with cancer risk (RR: 1.36, 95% CI: 1.18-1.56, I2 = 54%, P < 0.01). In subgroup stratified by gender and OSA severity, OSA statistically with cancer risk in females (RR: 1.27, 95% CI: 1.06-1.51) and moderate to severe OSA groups (RR: 2.62, 95% CI: 1.64; 4.19). In subgroup stratified by study design, a trend toward statistically significant differences was observed in prospective studies (RR: 1.21, 95% CI: 0.99-1.48) and cross-sectional studies (RR: 1.81, 95% CI: 0.96-3.41). Patients with OSA in the retrospective study group had a statistically higher chance of developing cancer (RR: 1.41, 95% CI: 1.11-1.79). When stratified by cancer group, statistically significant differences was observed in many types of cancer (breast cancer: RR: 1.32, 95% CI: 1.03-1.70; central nervous system cancer: RR: 1.71, 95% CI: 1.06-2.75; kidney cancer: RR: 1.81, 95% CI: 1.20-2.74; liver cancer: RR: 1.19, 95% CI: 1.10-1.29; and pancreatic cancer: RR: 1.23, 95% CI: 1.14-1.33). CONCLUSIONS: This systematic review and meta-analysis suggests that obstructive sleep apnea may increase risk of cancer.

The effects of bilateral prostriata lesions on spatial learning and memory in the rat.

Area prostriata is the primary limbic structure for rapid response to the visual stimuli in the far peripheral visual field. Recent studies have revealed that the prostriata receives inputs not only from the visual and auditory cortices but also from many structures critical for spatial processing and navigation. To gain insight into the functions of the prostriata in spatial learning and memory the present study examines the effects of bilateral lesions of the prostriata on motor ability, exploratory interest and spatial learning and memory using the open field, elevated plus-maze and Morris water maze tests. Our results show that the spatial learning and memory abilities of the rats with bilateral prostriata lesions are significantly reduced compared to the control and sham groups. In addition, the lesion rats are found to be less interested in space exploration and more anxious while the exercise capacity of the rats is not affected based on the first two behavioral tests. These findings suggest that the prostriata plays important roles in spatial learning and memory and may be involved in anxiety as well.

Mimicking the Oxygen-Evolving Center in Photosynthesis.

The oxygen-evolving center (OEC) in photosystem II (PSII) of oxygenic photosynthetic organisms is a unique heterometallic-oxide Mn4CaO5-cluster that catalyzes water splitting into electrons, protons, and molecular oxygen through a five-state cycle (Sn, n = 0 ~ 4). It serves as the blueprint for the developing of the man-made water-splitting catalysts to generate solar fuel in artificial photosynthesis. Understanding the structure-function relationship of this natural catalyst is a great challenge and a long-standing issue, which is severely restricted by the lack of a precise chemical model for this heterometallic-oxide cluster. However, it is a great challenge for chemists to precisely mimic the OEC in a laboratory. Recently, significant advances have been achieved and a series of artificial Mn4XO4-clusters (X = Ca/Y/Gd) have been reported, which closely mimic both the geometric structure and the electronic structure, as well as the redox property of the OEC. These new advances provide a structurally well-defined molecular platform to study the structure-function relationship of the OEC and shed new light on the design of efficient catalysts for the water-splitting reaction in artificial photosynthesis.

Redox-Induced Structural Change in Artificial Heterometallic-Oxide Cluster Mimicking the Photosynthetic Oxygen-Evolving Center.

The oxygen-evolving center (OEC) in photosynthesis is a unique Mn4 CaO5 -cluster that catalyzes the water-splitting reaction in nature. Understanding its catalytic mechanism for the O=O bond formation is of great challenge and long-standing issue, which is severely restricted by the lack of precise structure and mechanism mimics of this heterometallic-oxide cluster. Herein, we report two synthetic (Mn3 XO4 )2 O-clusters (X=Sr2+ , La3+ ) that closely mimic the heterometallic-oxide Mn3 XO4 cubane and three different types of µ-oxide bridges (µ2 -O2- , µ3 -O2- , and µ4 -O2- ) simultaneously as seen in the OEC. By resolving the crystal structures of both oxidized and reduced forms of the cluster, we have identified significant redox-induced structural changes that take place on the µ2 -oxide bridge, rather than the µ4 -oxide or µ3 -oxide bridges. Our results provide chemical insights into understanding the reactivity of three different types of oxide bridges in the biological Mn4 CaO5 -cluster in PSII.

Chemoarchitecture of area prostriata in adult and developing mice: Comparison with presubiculum and parasubiculum.

Retrosplenial area 29e, which was a cortical region described mostly in earlier rodent literature, is often included in the dorsal presubiculum (PrSd) or postsubiculum (PoS) in modern literature and commonly used brain atlases. Recent anatomical and molecular studies have revealed that retrosplenial area 29e belongs to the superficial layers of area prostriata, which in primates is found to be important in fast analysis of quickly moving objects in far peripheral visual field. As in primates, the prostriata in rodents adjoins area 29 (granular retrosplenial area), area 30 (agranular retrosplenial area), medial visual cortex, PrSd/PoS, parasubiculum (PaS), and postrhinal cortex (PoR). The present study aims to reveal the chemoarchitecture of the prostriata versus PrSd/PoS or PaS by means of a systematic survey of gene expression patterns in adult and developing mouse brains. First, we find many genes that display differential expression across the prostriata, PrSd/PoS, and PaS and that show obvious laminar expression patterns. Second, we reveal subsets of genes that selectively express in the dorsal or ventral parts of the prostriata, suggesting the existence of at least two subdivisions. Third, we detect some genes that shows differential expression in the prostriata of postnatal mouse brains from adjoining regions, thus enabling identification of the developing area prostriata. Fourth, gene expression difference of the prostriata from the medial primary visual cortex and PoR is also observed. Finally, molecular and connectional features of the prostriata in rodents and nonhuman primates are discussed and compared.

Identification and molecular epidemiology of routinely determined Streptococcus pneumoniae with negative Quellung reaction results.

BACKGROUND: Some streptococci strains identified as Streptococcus pneumoniae (S. pneumoniae) by routine clinical methods exhibiting negative Quellung reaction results may belong to other species of viridans group streptococci or non-typeable S. pneumoniae. The purpose of this study was to investigate the identification and molecular characteristics of S. pneumoniae with negative Quellung reaction results. METHODS: One hundred and five isolates identified as S. pneumoniae using routine microbiological methods with negative Quellung reaction results were included. Multilocus sequence analysis (MLSA) was used as a gold standard in species identification, and the capacity of matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) in identification was evaluated. Capsular genes and sequence types of S. pneumoniae isolates were determined by sequential multiplex PCR and multilocus sequence typing. Antimicrobial susceptibility patterns were determined via broth microdilution with a commercialized 96-well plate. RESULTS: Among the isolates, 81 were identified as S. pneumoniae and 24 were S. pseudopneumoniae by MLSA. MALDI-TOF MS misidentified six S. pneumoniae isolates as S. pseudopneumoniae and nine S. pseudopneumoniae isolates as S. pneumoniae or S. mitis/S. oralis. Thirty-one sequence types (STs) were detected for these 81 S. pneumoniae isolates, and the dominant ST was ST-bj12 (16, 19.8%). The non-susceptibility rates of S. pseudopneumoniae were comparable to those of NESp strains. CONCLUSIONS: Some S. pneumoniae isolates identified by routine methods were S. pseudopneumoniae. Most NESp strains have a different genetic background compared with capsulated S. pneumoniae strains. The resistance patterns of S. pseudopneumoniae against common antibiotics were comparable to those of NESp.

Synthesizing Mechanism of the Mn4 Ca Cluster Mimicking the Oxygen-Evolving Center in Photosynthesis.

The photosynthetic oxygen-evolving center (OEC) is a unique Mn4 CaO5 cluster that serves as a blueprint to develop superior water-splitting catalysts for the generation of solar fuels in artificial photosynthesis. It is a great challenge and long-standing issue to reveal the synthesizing mechanism of this Mn4 CaO5 cluster in both natural and artificial photosynthesis. Herein, efforts were made to reveal the synthesizing mechanism of an artificial Mn4 CaO4 cluster, a close mimic of the OEC. Four key intermediates were successfully isolated and structurally characterized for the first time. It was demonstrated that the Mn4 CaO4 cluster could be formed through a reaction between a thermodynamically stable Mn3 CaO4 cluster and an unusual four-coordinated MnIII ion, followed by stabilization process through binding an organic base (e.g., pyridine) on the "dangling" Mn ion. These findings shed new light on the synthesizing mechanism of the OEC and rational design of new artificial water-splitting catalysts.

Adiabatic versus non-adiabatic electron transfer at 2D electrode materials.

2D electrode materials are often deployed on conductive supports for electrochemistry and there is a great need to understand fundamental electrochemical processes in this electrode configuration. Here, an integrated experimental-theoretical approach is used to resolve the key electronic interactions in outer-sphere electron transfer (OS-ET), a cornerstone elementary electrochemical reaction, at graphene as-grown on a copper electrode. Using scanning electrochemical cell microscopy, and co-located structural microscopy, the classical hexaamineruthenium (III/II) couple shows the ET kinetics trend: monolayer > bilayer > multilayer graphene. This trend is rationalized quantitatively through the development of rate theory, using the Schmickler-Newns-Anderson model Hamiltonian for ET, with the explicit incorporation of electrostatic interactions in the double layer, and parameterized using constant potential density functional theory calculations. The ET mechanism is predominantly adiabatic; the addition of subsequent graphene layers increases the contact potential, producing an increase in the effective barrier to ET at the electrode/electrolyte interface.

Rodent Area Prostriata Converges Multimodal Hierarchical Inputs and Projects to the Structures Important for Visuomotor Behaviors.

Area prostriata is a limbic structure critical to fast processing of moving stimuli in far peripheral visual field. Neural substrates underlying this function remain to be discovered. Using both retrograde and anterograde tracing methods, the present study reveals that the prostriata in rat and mouse receives inputs from multimodal hierarchical cortical areas such as primary, secondary, and association visual and auditory cortices and subcortical regions such as the anterior and midline thalamic nuclei and claustrum. Surprisingly, the prostriata also receives strong afferents directly from the rostral part of the dorsal lateral geniculate nucleus. This shortcut pathway probably serves as one of the shortest circuits for fast processing of the peripheral vision and unconscious blindsight since it bypasses the primary visual cortex. The outputs of the prostriata mainly target the presubiculum (including postsubiculum), pulvinar, ventral lateral geniculate nucleus, lateral dorsal thalamic nucleus, and zona incerta as well as the pontine and pretectal nuclei, most of which are heavily involved in subcortical visuomotor functions. Taken together, these results suggest that the prostriata is poised to quickly receive and analyze peripheral visual and other related information and timely initiates and modulates adaptive visuomotor behaviors, particularly in response to unexpected quickly looming threats.

Structural Reorganization of a Synthetic Mimic of the Oxygen-Evolving Center in Multiple Redox Transitions Revealed by Electrochemical FTIR Spectra.

In photosynthesis, the protein-bound natural oxygen-evolving center (OEC) undergoes multiple oxidation-state transitions in the light-driven water splitting reactions with a stepwise change in the oxidation potential. Because the protein is vulnerable to electrochemical oxidation, the multiple oxidation/reduction-state transitions can hardly be achieved by electrochemical oxidation with a continuous change in the oxidation potential. An OEC mimic that can undergo four redox transitions has been synthesized (Zhang, C., Science, 2015, 348, 690-693). Here we report an electrochemical FTIR spectroscopic study of this synthetic complex at its multiple oxidation states in the low-frequency region for Mn-O bonds. Compared with those of the native OEC induced by pulsed laser flashes, our results also show the existence of two structural isomers in the S2 state, with the closed cubane conformer being more stable than the open cubane conformer, in contrast to that of the native OEC in which the open form is more stable.

Rare-Earth Elements Can Structurally and Energetically Replace the Calcium in a Synthetic Mn4CaO4-Cluster Mimicking the Oxygen-Evolving Center in Photosynthesis.

The oxygen-evolving center (OEC) in photosynthesis is a unique biological Mn4CaO5 cluster catalyzing the water-splitting reaction. A great current challenge is to achieve a robust and precise mimic of the OEC in the laboratory. Herein, we report synthetic Mn4XO4 clusters (X = calcium, yttrium, gadolinium) that closely resemble the OEC with regard to the main metal-oxide core and peripheral ligands, as well as the oxidation states of the four Mn ions and the redox potential of the cluster. We demonstrate that rare-earth elements can structurally replace the calcium in neutral Mn4XO4 clusters. All three Mn4XO4 clusters with different redox-inactive metal ions display essentially the same redox properties, challenging the conventional view that the Lewis acidity of the redox-inactive metal ions could modulate the redox potential of the heteronuclear-oxide clusters. The new synthetic rare-earth element-containing Mn4XO4 clusters reported here provide robust and structurally well-defined chemical models and shed new light on the design of new water-splitting catalysts in artificial photosynthesis.

One single-center serological survey on measles, rubella and mumps antibody levels of people in Youyang, China.

Although measles, rubella and mumps elimination had achieved great progress in recent years, outbreaks were still reported worldwide. Serological surveillance on the remaining susceptibility in the population is essential to evaluate the preventive policy, estimate the current risk of infection, and predict evolutions in the future. In this study, we aimed to investigate the prevalence of seropositivity of antibodies against measles, rubella and mumps in a population of all ages in Youyang, southwest China. A cross-sectional hospital-based study was conducted among 657 cases who attended to Youyang Hospital from Sep 2018 to Aug 2019. Sero IgG antibodies were measured by ELISA. No difference in the seropositivity of antibodies against measles, rubella and mumps was found between neither urban vs. rural, nor male vs. female. The overall seropositivity of anti-measles, rubella, mumps IgG antibodies was 81.1% (95% CI: 78.0-83.9), 65.9% (95% CI: 62.2-69.4) and 63.2% (95% CI: 59.4-66.8), respectively. The IgG seropositivity varied with age significantly. In this study, the seropositivity of antibodies against measles, rubella and mumps among the participants was insufficient in the population, especially among infants, teenagers and productive women, who were suggested to booster the immunity. To better control and eliminate measles, mumps and rubella-related diseases, nation-wide active laboratory-supported surveillance, outbreak investigation and revaccination for vulnerable population are needed.

[RCT of Reduction in Catheter-Related Complications by Using Intracavitary Electrocardiogram-Assisted Guidance in Neonatal PICC Placement].

OBJECTIVE: To investigate the effect of intracavitary electrocardiogram (IC-ECG) guidance on peripherally inserted central catheter (PICC) related complications in neonatal patients. METHODS: A total of 210 neonatal patients were included in the study. They were admitted to the Neonatal Intensive Care Unit, Sichuan Provincial People's Hosptial between January, 2017 and December, 2019 and had PICC lines were placed in their upper limbs. The patients were randomly assigned to the observation group, which had PICC placement through conventional anatomical landmark guidance combined with IC-ECG guidance ( n=105) or to the control group, which had PICC placement through only conventional anatomical landmark guidance ( n=105) for PICC catheter tip positioning. Patient baseline data and data on subsequent catheter-related complications of the two groups were collected and compared. RESULTS: There were no significant difference between the two groups in sex composition, gestational age, postnatal days on the day of PICC placement, duration of PICC placement, disease profile, and the site of puncture ( P>0.05). The observation group showed a significantly lower overall incidence of catheter-related complications (3.8%), compared to that of the control group (21.9%) ( P<0.05). The observation group showed significantly lower incidence of phlebitis and arrhthmia compared to that of the control group ( P<0.05). CONCLUSION: A combination of anatomical landmark guidance and IC-ECG guidance to assist the placement of PICC decreases catheter-related complications.

Decline of serologic immunity to diphtheria, tetanus and pertussis with age suggested a full life vaccination in mainland China.

Background: Diphtheria-tetanus-pertussis (DTP) vaccine has already been involved in national vaccination program for several decades in China. The immunity against these diseases in the people of all ages is not well investigated.Materials and methods: Serum samples were tested for IgG antibodies to diphtheria toxoid (DT), tetanus toxoid (TT) and pertussis toxin (PT) by using commercial ELISA kits.Results: A total of 666 sera of patients from 1 day to 89 years of age was collected from 2018 to 2019. The protective rates of diphtheria, tetanus and pertussis were 45.5%, 54.4% and 4.7%, respectively. Only 4.7% of the study population had seropositivity against three of the diseases. Young infant (<3 m) and adult (>18y) were generally lack of protective antibody against diphtheria (81.7% and 58.3%) and tetanus (91.5% and 86.2%). An obvious increase in immunity level of diphtheria and tetanus was observed at 3 m-3y, but there was no significant increase of immunity to pertussis at any age group. All age groups showed low immunity to pertussis.Conclusions: The present results revealed the susceptibility to diphtheria and tetanus in young infants and adults, and the susceptibility to pertussis over the ages, which highlight the need to improve the current vaccination program.

Multicharge ß-cyclodextrin supramolecular assembly for ATP capture and drug release.

A hyaluronidase-responsive polysaccharide supramolecular assembly was constructed from an amphiphilic ß-cyclodextrin bearing seven hexylimidazolium units (AMCD), adamantyl-grafted hyaluronic acid, and chlorambucil, which showed specific cancer cell targeting and controlled drug release abilities. Interestingly, ternary supramolecular assembly can disassemble in the presence of hyaluronidase, and the released AMCD can assemble with ATP to form a stable 1 : 1 complex, which enhanced the efficacy of chlorambucil on cancer chemotherapy by inhibiting ATP hydrolysis.