Synthesis and utilization of polyol-modified high specific surface area Ca(OH)2: an investigation.

Calcium hydroxide (Ca(OH)2) finds widespread use in the petrochemical industry, particularly in flue gas desulfurization applications. However, its conventional usage is limited by its inherently low specific surface area, hampering its efficiency. To address this limitation, this study aims to develop a simple and industrially scalable preparation process for Ca(OH)2 with a high specific surface area, thereby enhancing its effectiveness in various applications. This study aimed to develop a preparation process for making Ca(OH)2 with a high specific surface area, suitable for industry and easy to make. Ca(OH)2 with a specific surface area of 41.555 m2/g was successfully synthesized by incorporating polyols during lime digestion. The prepared high specific surface area Ca(OH)2 is more than five times the specific surface area of ordinary Ca(OH)2. Incorporation of polyols within the lime digestion process induces a reduction in both Ca(OH)2 grain size and particle dimensions, concurrently amplifying the specific surface area and optimizing mass transfer efficiency. Specifically, the desulfurization breakthrough time for Ca(OH)2 subject to a 15% triethanolamine modification was notably extended to 879 s, surpassing the desulfurization breakthrough time of unaltered Ca(OH)2 by more than tenfold. Moreover, the modified Ca(OH)2 exhibited remarkable efficacy in neutralizing acidic wastewater. A new approach for the preparation of high-performance Ca(OH)2 is proposed in this study, which could facilitate the industrial production of Ca(OH)2 with high specific surface area.

Advances in local drug delivery technologies for improved rheumatoid arthritis therapy.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by an inflammatory microenvironment and cartilage erosion within the joint cavity. Currently, antirheumatic agents yield significant outcomes in RA treatment. However, their systemic administration is limited by inadequate drug retention in lesion areas and non-specific tissue distribution, reducing efficacy and increasing risks such as infection due to systemic immunosuppression. Development in local drug delivery technologies, such as nanostructure-based and scaffold-assisted delivery platforms, facilitate enhanced drug accumulation at the target site, controlled drug release, extended duration of the drug action, reduced both dosage and administration frequency, and ultimately improve therapeutic outcomes with minimized damage to healthy tissues. In this review, we introduced pathogenesis and clinically used therapeutic agents for RA, comprehensively summarized locally administered nanostructure-based and scaffold-assisted drug delivery systems, aiming at improving the therapeutic efficiency of RA by alleviating the inflammatory response, preventing bone erosion and promoting cartilage regeneration. In addition, the challenges and future prospects of local delivery for clinical translation in RA are discussed.

Exploring functional dysconnectivity in schizophrenia: alterations in eigenvector centrality mapping and insights into related genes from transcriptional profiles.

Schizophrenia is a mental health disorder characterized by functional dysconnectivity. Eigenvector centrality mapping (ECM) has been employed to investigate alterations in functional connectivity in schizophrenia, yet the results lack consistency, and the genetic mechanisms underlying these changes remain unclear. In this study, whole-brain voxel-wise ECM analyses were conducted on resting-state functional magnetic resonance imaging data. A cohort of 91 patients with schizophrenia and 91 matched healthy controls were included during the discovery stage. Additionally, in the replication stage, 153 individuals with schizophrenia and 182 healthy individuals participated. Subsequently, a comprehensive analysis was performed using an independent transcriptional database derived from six postmortem healthy adult brains to explore potential genetic factors influencing the observed functional dysconnectivity, and to investigate the roles of identified genes in neural processes and pathways. The results revealed significant and reliable alterations in the ECM across multiple brain regions in schizophrenia. Specifically, there was a significant decrease in ECM in the bilateral superior and middle temporal gyrus, and an increase in the bilateral thalamus in both the discovery and replication stages. Furthermore, transcriptional analysis revealed 420 genes whose expression patterns were related to changes in ECM, and these genes were enriched mainly in biological processes associated with synaptic signaling and transmission. Together, this study enhances our knowledge of the neural processes and pathways involved in schizophrenia, shedding light on the genetic factors that may be linked to functional dysconnectivity in this disorder.

Engineering unactivated platelets for targeted drug delivery.

As a vital component of blood, platelets play crucial roles in hemostasis and maintaining vascular integrity, and actively participate in inflammation and immune regulation. The unique biological properties of natural platelets have enabled their utilization as drug delivery vehicles. The advancement and integration of various techniques, including biological, chemical, and physicochemical methods, have enabled the preparation of engineered platelets. Platelets can serve as drug delivery platforms combined with immunotherapy and chemokine therapy to enhance their therapeutic impact. This review focuses on the recent advancements in the application of unactivated platelets for drug delivery. The construction strategies of engineered platelets are comprehensively summarized, encompassing internal loading, surface modification, and genetic engineering techniques. Engineered platelets hold vast potential for treating cardiovascular diseases, cancers, and infectious diseases. Furthermore, the challenges and potential considerations in creating engineered platelets with natural activity are discussed.

Heuristic strategy of intuitive statistical inferences in 7- to 10-year-old children.

Intuitive statistical inferences refer to making inferences about uncertain events based on limited probabilistic information, which is crucial for both human and non-human species' survival and reproduction. Previous research found that 7- and 8-year-old children failed in intuitive statistical inference tasks after heuristic strategies had been controlled. However, few studies systematically explored children's heuristic strategies of intuitive statistical inferences and their potential numerical underpinnings. In the current research, Experiment 1 (N = 81) examined 7- to 10-year-olds' use of different types of heuristic strategies; results revealed that children relied more on focusing on the absolute number strategy. Experiment 2 (N = 99) and Experiment 3 (N = 94) added continuous-format stimuli to examine whether 7- and 8-year-olds could make genuine intuitive statistical inferences instead of heuristics. Results revealed that both 7- and 8-year-olds and 9- and 10-year-olds performed better in intuitive statistical inference tasks with continuous-format stimuli, even after focusing on the absolute number strategy had been controlled. The results across the three experiments preliminarily hinted that the ratio processing system might rely on the approximate number system. Future research could clarify what specific numerical processing mechanism may be used and how it might support children's statistical intuitions.

TP53R175H mutation promotes breast cancer cell proliferation through CORO1A-P38 MAPK pathway regulation.

Breast cancer is the most commonly diagnosed cancer in women. Among all types, triple-negative breast cancer is particularly challenging to cure because of its high recurrence rates and invasive and metastatic capacity. Although numerous studies have explored the role of TP53 mutations in cancer, there is a dearth of research regarding the correlation between TP53 mutations and breast cancer cell proliferation. In this study, our aim was to examine the impact of TP53 mutations on the prognosis of patients with breast cancer bioinformatics techniques. To detect cell proliferation, a CCK8 assay was performed, and western blotting was used to identify the expression of p53, p38, and p-p38 proteins. Cellular mRNA sequencing was used to screen target genes of TP53 mutations, and molecular docking was performed to identify the drugs that could hinder the proliferation of breast cancer cells.The results showed that the TP53 mutation rate is higher in patients with triple-negative breast cancer than non-triple-negative breast cancer, and those with TP53 mutations tended to have a poorer prognosis than those without. Patients with R175H site mutations also had shorter survival times than those without. Cytological experiments revealed that the TP53R175H mutation increases the rate of breast cancer cell proliferation. In conjunction with this, CORO1A was found to be a downstream target of TP53 mutations, and it was determined to promote breast cancer cell proliferation. Moreover, CORO1A overexpression resulted in the downregulation of p-p38 levels. Molecular docking studies further revealed that tea polyphenols can inhibit breast cancer proliferation by binding to p53.

Transdermally delivered tolerogenic nanoparticles induced effective immune tolerance for asthma treatment.

Induction of antigen-specific immune tolerance for the treatment of allergic or autoimmune diseases is an attractive strategy. Herein, we investigated the protective effect of a transdermal microneedle patch against allergic asthma by stimulating allergen-specific immune tolerance. We fabricated biodegradable tolerogenic nanoparticles (tNPs) that are loaded with a model allergen ovalbumin (OVA) and an immunomodulator rapamycin, and filled the tNPs into microneedle tips by centrifugation to form sustained-release microneedles. After intradermal immunization, the microneedles successfully delivered the cargos into the skin and sustainedly released them for over 96 h. Importantly, the microneedles induced allergen-specific regulatory T cells (Treg), decreased the levels of pro-inflammatory cytokines and antibodies while increased anti-inflammation cytokines, finally leading to restored immune homeostasis. The lung tissue analysis illustrated that the sustained-release microneedles significantly reduced the infiltration of eosinophils, decreased the accumulation of mucus and collagen, and significantly relived asthma symptoms. Our results suggested that the sustained-release microneedle-based transdermal delivery system can induce antigen-specific immune tolerance with improved compliance and efficacy, providing a new therapeutic strategy for the treatment of allergic and autoimmune diseases.

Piezoelectric Polymer Solid Electrolyte Integrating Electromechanical Coupling and Ferroelectric Polarization Effects.

The unsatisfactory lithium-ion conductivity (σ) and limited mechanical strength of polymer solid electrolytes hinder their wide applications in solid-state lithium metal batteries (SSLMBs). Here, a thin piezoelectric polymer solid electrolyte integrating electromechanical coupling and ferroelectric polarization effects has been designed and prepared to achieve long-term stable cycling of SSLMBs. The ferroelectric Bi4 Ti3 O12 nanoparticle (BIT NPs) loaded poly(vinylidene fluoride-trifluoroethylene) (P(VDF-TrFE)) piezoelectric nanofibers (B-P NFs) membranes are introduced into the poly(ethylene oxide) (PEO) matrix, endowing the composite electrolyte with unique polarization and piezoelectric effects. The piezoelectric nanofiber membrane with a 3D network structure not only promotes the dissociation of lithium (Li) salts through the polarization effect but also cleverly utilizes the coupling effect of a mechanical stress-local electric field to achieve dynamic regulation of the Li electroplating process. Through the corresponding experimental tests and density functional theory calculations, the intrinsic mechanism of piezoelectric electrolytes improving σ and suppressing Li dendrites is fully revealed. The obtained piezoelectric electrolyte has achieved stable cycling of LiFePO4 batteries over 2000 cycles and has also shown good practical application potential in flexible pouch batteries.

Novel antiviral discoveries for Japanese encephalitis virus infections through reporter virus-based high-throughput screening.

Japanese encephalitis (JE) caused by JE virus (JEV), remains a global public health concern. Currently, there is no specific antiviral drug approved for the treatment of JE. While vaccines are available for prevention, they may not cover all at-risk populations. This underscores the urgent need for prophylaxis and potent anti-JEV drugs. In this context, a high-content JEV reporter system expressing Nanoluciferase (Nluc) was developed and utilized for a high-throughput screening (HTS) of a commercial antiviral library to identify potential JEV drug candidates. Remarkably, this screening process led to the discovery of five drugs with outstanding antiviral activity. Further mechanism of action analysis revealed that cepharanthine, an old clinically approved drug, directly inhibited virus replication by blocking GTP binding to the JEV RNA-dependent RNA polymerase. Additionally, treatment with cepharanthine in mice models alleviated JEV infection. These findings warrant further investigation into the potential anti-JEV activity of cepharanthine as a new therapeutic approach for the treatment of JEV infection. The HTS method employed here proves to be an accurate and convenient approach that facilitates the rapid development of antiviral drugs.

Efficient Flexible Fabric-Based Top-Emitting Polymer Light-Emitting Devices for Wearable Electronics.

Low-cost fabric-based top-emitting polymer light-emitting devices (Fa-TPLEDs) have aroused increasing attention due to their remarkable potential applications in wearable displays. However, it is still challenging to realize efficient all-solution-processed devices from bottom electrodes to top electrodes with large-scale fabrication. Here, a smooth reflective Ag cathode integrated on fabric by one-step silver mirror reaction and a composite transparent anode of polydimethylsiloxane/silver nanowires/poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) via a water-assisted peeling method are presented, both of which possess excellent optoelectrical properties and robust mechanical flexibility. The Fa-TPLEDs are constructed by spin-coating functional layers on the bottom reflective cathodes and laminating the top transparent anodes. The Fa-TPLEDs show a current efficiency of 16.3 cd A-1 , an external quantum efficiency of 4.9% and angle-independent electroluminescence spectra. In addition, the Fa-TPLEDs possess excellent mechanical stability, maintaining a current efficiency of 14.3 cd A-1 after 200 bending cycles at a radius of 4 mm. The results demonstrate that the integration of solution-processed reflective cathodes and transparent anodes sheds light on a new avenue to construct low-cost and efficient fabric-based devices, showing great potential applications in emerging smart flexible/wearable electronics.

Both chimpanzee adenovirus-vectored and DNA vaccines induced long-term immunity against Nipah virus infection.

Nipah virus (NiV) is a highly lethal zoonotic paramyxovirus that poses a severe threat to humans due to its high morbidity and the lack of viable countermeasures. Vaccines are the most crucial defense against NiV infections. Here, a recombinant chimpanzee adenovirus-based vaccine (AdC68-G) and a DNA vaccine (DNA-G) were developed by expressing the codon-optimized full-length glycoprotein (G) of NiV. Strong and sustained neutralizing antibody production, accompanied by an effective T-cell response, was induced in BALB/c mice by intranasal or intramuscular administration of one or two doses of AdC68-G, as well as by priming with DNA-G and boosting with intramuscularly administered AdC68-G. Importantly, the neutralizing antibody titers were maintained for up to 68 weeks in the mice that received intramuscularly administered AdC68-G and the prime DNA-G/boost AdC68-G regimen, without a significant decline. Additionally, Syrian golden hamsters immunized with AdC68-G and DNA-G via homologous or heterologous prime/boost immunization were completely protected against a lethal NiV virus challenge, without any apparent weight loss, clinical signs, or pathological tissue damage. There was a significant reduction in but not a complete absence of the viral load and number of infectious particles in the lungs and spleen tissue following NiV challenge. These findings suggest that the AdC68-G and DNA-G vaccines against NiV infection are promising candidates for further development.

JUN mediates glucocorticoid resistance by stabilizing HIF1a in T cell acute lymphoblastic leukemia.

Dexamethasone (Dex) plays a critical role in T-ALL treatment, but the mechanisms of Dex resistance are poorly understood. Here, we demonstrated that the expression of JUN was regulated in Dex-resistant T-ALL cell lines and patient samples. JUN knockdown increased the sensitivity to Dex. Moreover, the survival data showed that high expression of JUN related to poor prognosis of T-ALL patients. Then, we generated dexamethasone-resistant clones and conducted RNA-seq and ATAC-seq. We demonstrated that the upregulation of JUN was most significant and regulated by JNK pathway in Dex-resistant cells. High-throughput screening showed that HIF1α inhibitors synergized with Dex could enhance Dex resistance cells death in vitro and in vivo. Additionally, JUN combined and stabilized HIF1α in Dex resistance cells. These results reveal a new mechanism of Dex resistance in T-ALL and provide experimental evidence for the potential therapeutic benefit of targeting the JNK-JUN-HIF1α axis for T-ALL treatment.

Vaccines based on the fusion protein consensus sequence protect Syrian hamsters from Nipah virus infection.

Nipah virus (NiV), a bat-borne paramyxovirus, results in neurological and respiratory diseases with high mortality in humans and animals. Developing vaccines is crucial for fighting these diseases. Previously, only a few studies focused on the fusion (F) protein alone as the immunogen. Numerous NiV strains have been identified, including 2 representative strains from Malaysia (NiV-M) and Bangladesh (NiV-B), which differ significantly from each other. In this study, an F protein sequence with the potential to prevent different NiV strain infections was designed by bioinformatics analysis after an in-depth study of NiV sequences in GenBank. Then, a chimpanzee adenoviral vector vaccine and a DNA vaccine were developed. High levels of immune responses were detected after AdC68-F, pVAX1-F, and a prime-boost strategy (pVAX1-F/AdC68-F) in mice. After high titers of humoral responses were induced, the hamsters were challenged by the lethal NiV-M and NiV-B strains separately. The vaccinated hamsters did not show any clinical signs and survived 21 days after infection with either strain of NiV, and no virus was detected in different tissues. These results indicate that the vaccines provided complete protection against representative strains of NiV infection and have the potential to be developed as a broad-spectrum vaccine for human use.

ATF4 renders human T-cell acute lymphoblastic leukemia cell resistance to FGFR1 inhibitors through amino acid metabolic reprogramming.

Abnormalities of FGFR1 have been reported in multiple malignancies, suggesting FGFR1 as a potential target for precision treatment, but drug resistance remains a formidable obstacle. In this study, we explored whether FGFR1 acted a therapeutic target in human T-cell acute lymphoblastic leukemia (T-ALL) and the molecular mechanisms underlying T-ALL cell resistance to FGFR1 inhibitors. We showed that FGFR1 was significantly upregulated in human T-ALL and inversely correlated with the prognosis of patients. Knockdown of FGFR1 suppressed T-ALL growth and progression both in vitro and in vivo. However, the T-ALL cells were resistant to FGFR1 inhibitors AZD4547 and PD-166866 even though FGFR1 signaling was specifically inhibited in the early stage. Mechanistically, we found that FGFR1 inhibitors markedly increased the expression of ATF4, which was a major initiator for T-ALL resistance to FGFR1 inhibitors. We further revealed that FGFR1 inhibitors induced expression of ATF4 through enhancing chromatin accessibility combined with translational activation via the GCN2-eIF2α pathway. Subsequently, ATF4 remodeled the amino acid metabolism by stimulating the expression of multiple metabolic genes ASNS, ASS1, PHGDH and SLC1A5, maintaining the activation of mTORC1, which contributed to the drug resistance in T-ALL cells. Targeting FGFR1 and mTOR exhibited synergistically anti-leukemic efficacy. These results reveal that FGFR1 is a potential therapeutic target in human T-ALL, and ATF4-mediated amino acid metabolic reprogramming contributes to the FGFR1 inhibitor resistance. Synergistically inhibiting FGFR1 and mTOR can overcome this obstacle in T-ALL therapy.

Glucose-decorated engineering platelets for active and precise tumor-targeted drug delivery.

Precise targeted delivery of therapeutic agents is crucial for tumor therapy. As an emerging fashion, cell-based delivery provides better biocompatibility and lower immunogenicity and enables a more precise accumulation of drugs in tumor cells. In this study, a novel engineering platelet was constructed through cell membrane fusion with a synthesized glycolipid molecule, DSPE-PEG-Glucose (DPG). The obtained glucose-decorated platelets (DPG-PLs) maintained their resting state with structural and functional integrities, while they would be activated and triggered to release their payloads once they arrive at the tumor microenvironment. Glucose decoration was verified to impart the DPG-PLs with stronger binding effects toward tumor cells that overexpress GLUT1 on their surfaces. Together with the natural homing property toward tumor sites and bleeding injury, doxorubicin (DOX)-loaded platelets (DPG-PL@DOX) exhibited the strongest antitumor effects on a mouse melanoma model, and the antitumor effect was significantly enhanced in the tumor bleeding model. DPG-PL@DOX provides an active and precise solution for tumor-targeted drug delivery, especially for postoperative treatments.

Cord Blood Plasma Metabolome-wide Associations With Height From Birth to Adolescence.

Although the maternal intrauterine metabolic environment has been recognized to have a profound impact on fetal growth and development with lifelong health implications, to our knowledge, there have been few large-scale birth cohort studies linking the cord metabolome (reflecting both the maternal and fetal metabolic state) with postnatal height measurements across the pediatric age range. Using data from the Boston Birth Cohort, an ongoing prospective birth cohort, this study investigated the association of cord plasma metabolites with children's height from birth to adolescence. Height was analyzed as attained height and longitudinal trajectories. Distinctive cord metabolite types were associated with attained height at different developmental windows: triacylglycerols [TAGs], diacylglycerols [DAGs], cholesterol ester [CEs], phospholipids, amino acids [AAs], acylcarnitines [ACs], and nucleotides in early (age 0-4 years) and middle (age 6-12 years) childhood; various metabolite types other than TAGs in later childhood (after age 14 years). Functional principal component analysis on children's repeated height measurements summarized two typical height trajectory components: loadings on first eigenfunction [FPC1] representing overall height by age, and loadings on second eigenfunction [FPC2] representing speed of pubertal height growth. Although only one cord metabolite was correlated with FPC1 after accounting for multiple testing, the study found 27 metabolites with significant overall effect on FPC2 among females and 18 among males. These metabolites were mostly phospholipids (including phosphatidylethanolamines [PEs], phosphatidylethanolamine plasmalogens [PE_Ps], phosphatidylcholines [PCs], lysophosphatidylethanolamines [LPEs], and lysophosphatidylcholines [LPCs]), AAs, and nucleotides. Their associations with height differed between overweight/obesity (OWO) and non-OWO children, especially among females. In this prospective study of US understudied urban, low-income, racially diverse children, we demonstrated that cord plasma metabolites were significantly associated with postnatal attained height at different age windows as well as height trajectories from birth to adolescence. We also revealed how these associations differed by children's sex and OWO status. Our findings help elucidate metabolic pathways underlying fetal origins of height growth across developmental stages. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

A Drug-Free, Hair Follicle Cycling Regulatable, Separable, Antibacterial Microneedle Patch for Hair Regeneration Therapy.

The development of painless hair loss therapy without side-effect is challenging. The dermal papilla is the signal center of hair follicles and plays a key role in the regulation of their cycling. Activation of dermal papilla cells (DPCs) would promote hair regeneration. In this study, a separable microneedle patch comprised of chitosan lactate (CL) and exosomes (EXO) from adipose-derived stem cells is fabricated. After insertion of the microneedle into the skin, the hyaluronic acid substrate dissolves fast and the swellable polyvinyl alcohol needles are retained. The EXO sustainedly released from needles can be endocytosed by DPCs and promote cell proliferation via the activation of the Wnt signaling pathway, while the L-lactate released by CL can promote cell growth by activating lactate dehydrogenase. CL and EXO synergetically facilitate hair regeneration through regulating hair follicle cycling. In animal tests, compared with topical administration of minoxidil, the drug-free microneedle patches can more significantly promote hair regeneration within 7 days with lower dosing frequency. Furthermore, the inherent antibacterial properties of CL make it possible to avoid potential infection. Such transdermally administrated drug-free microneedle patches provide a simple, safe, and efficient strategy for hair loss treatment and exhibit great potential in clinical application.

Recombinant chimpanzee adenovirus vector vaccine expressing the spike protein provides effective and lasting protection against SARS-CoV-2 infection in mice.

SARS-CoV-2 infection is a global public health threat. Vaccines are considered amongst the most important tools to control the SARS-CoV-2 pandemic. As expected, deaths from SARS-CoV-2 infection have dropped dramatically with widespread vaccination. However, there are concerns over the duration of vaccine-induced protection, as well as their effectiveness against emerging variants of concern. Here, we constructed a recombinant chimpanzee adenovirus vectored vaccine expressing the full-length spike of SARS-CoV-2 (AdC68-S). Rapid and high levels of humoral and cellular immune responses were observed after immunization of C57BL/6J mice with one or two doses of AdC68-S. Notably, neutralizing antibodies were observed up to at least six months after vaccination, without substantial decline. Single or double doses AdC68-S immunization resulted in lower viral loads in lungs of mice against SARS-CoV-2 challenge both in the short term (21 days) and long-term (6 months). Histopathological examination of AdC68-S immunized mice lungs showed mild histological abnormalities after SARS-CoV-2 infection. Taken together, this study demonstrates the efficacy and durability of the AdC68-S vaccine and constitutes a promising candidate for clinical evaluation.

In situ injectable nano-complexed hydrogel based on chitosan/dextran for combining tumor therapy via hypoxia alleviation and TAMs polarity regulation.

The tumor microenvironment (TME) is characterized by low pH, hypoxia, and infiltrated tumor-associated macrophages (TAMs). Therefore, regulation of TAMs polarization into anti-tumor M1 phenotype and meanwhile alleviation of the hypoxia in TME are expected to improve anti-tumor therapeutic efficacy. To this end, a novel in situ injectable nano-complexed hydrogel was developed in this study for combining tumor therapy. Thereunto, hyaluronic acid modified transfersomes loaded with chlorogenic acid functioned to reverse M2 type into M1 type via CD44 mediated internalization, the nanomedicine was entrapped in Schiff-based crosslinked injectable hydrogel (fabricated with carboxymethyl chitosan and oxidized dextran) whose linkage was labile to the acidic TME for controlled drug release. Moreover, catalase was integrated in the hydrogel enabling to convert hydrogen peroxide in TME into dissolved oxygen and alleviate tumor hypoxia. The multifunctional nano-complexed injectable hydrogel was verified to efficiently inhibit tumor growth through synergetic effects of hypoxia alleviation and TAMs polarity regulation.