Effects of complex pollution by microplastics and heavy metals on soil physicochemical properties and microbial communities under alternate wetting and drying conditions.

Microplastics (MPs) broadly coexist with heavy metals (HMs) in soil, Cd and Cu are the main types of soil HMs contamination, in addition to polystyrene (PS), which is also widely present in the environment and prone to aging. However, differences in the effects of MPs and HMs on soil properties and microbial characteristics under alternating wetting and drying (AWD) remain unclear. Thus, this study investigated the effects of four conventional (0.2% (w/w)) and aged MPs in indoor incubation experiments on soil properties under desiccation (Dry) and AWD. We found that with the influence of the "enzyme lock" theory, the coexistence of MPs and HMs under Dry had a more pronounced effect on soil physicochemical properties, whereas the effects on soil enzyme activity under AWD were more significant. In addition, MPs decreased the available Cu by 4.27% and, conversely, increased the available Cd by 8.55%. Under Dry, MPs affected microbial function mainly through physicochemical properties, with a contribution of approximately 72.4%, whereas under AWD enzyme activity and HMs were significantly greater, with increases of 28.2% and 7.9%, respectively. These results indicate that the effects of MPs on environmental variation and microbial profiles under AWD conditions differed significantly from those under Dry.

Cadonilimab, a tetravalent PD-1/CTLA-4 bispecific antibody with trans-binding and enhanced target binding avidity.

Clinical studies have shown that combination therapy of antibodies targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) significantly improves clinical benefit over PD-1 antibody alone. However, broad application of this combination has been limited by toxicities. Cadonilimab (AK104) is a symmetric tetravalent bispecific antibody with a crystallizable fragment (Fc)-null design. In addition to demonstrating biological activity similar to that of the combination of CTLA-4 and PD-1 antibodies, cadonilimab possess higher binding avidity in a high-density PD-1 and CTLA-4 setting than in a low-density PD-1 setting, while a mono-specific anti-PD-1 antibody does not demonstrate this differential activity. With no binding to Fc receptors, cadonilimab shows minimal antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and interleukin-6 (IL-6)/IL-8 release. These features all likely contribute to significantly lower toxicities of cadonilimab observed in the clinic. Higher binding avidity of cadonilimab in a tumor-like setting and Fc-null design may lead to better drug retention in tumors and contribute to better safety while achieving anti-tumor efficacy.

Ligufalimab, a novel anti-CD47 antibody with no hemagglutination demonstrates both monotherapy and combo antitumor activity.

BACKGROUND: CD47 is a widely expressed transmembrane glycoprotein that delivers an antiphagocytic signal on macrophages through its interaction with SIRPα. CD47 is highly expressed in cancer cells and its overexpression is correlated with poor prognosis. CD47 blocking antibodies are actively being developed worldwide for cancer therapy, and the most challenging concern is associated with hematotoxicity. Ligufalimab (AK117) is a novel humanized IgG4 anti-CD47 antibody without hemagglutination effect. Blockade of CD47-SIRPα pathway by AK117 leads to a promising therapeutic strategy for cancer treatment with unique safety features. METHODS: AK117 was discovered through a screening hierarchy excluding hemagglutination. AK117 was characterized by detecting CD47-SIRPα blocking potential. Its effect on human red blood cells was examined and the mechanism of its binding with erythrocytes was studied. The abilities of AK117 and its combination with various opsonizing antibodies to promote macrophage-dependent phagocytosis of multiple human tumor cells were determined using fluorescence microscopy and flow cytometry. In vivo, the antitumor efficacy of AK117 monotherapy and combination with AK112 (an anti-PD-1/VEGF-A bispecific antibody) was assessed in a variety of xenograft models. Toxicologic studies were evaluated in non-human primates. RESULTS: AK117 bound to CD47 with high affinity and blocked the CD47-SIRPα interaction. AK117 did not induce hemagglutination and showed significantly lower degree of erythrophagocytosis compared with Hu5F9-G4, and this mechanism of hemagglutination resistance might be related to the binding conformation. AK117 enhanced macrophage-mediated phagocytosis in both hematologic cancer and solid tumor cell lines as a single agent or in combination with cetuximab and rituximab in vitro, respectively. The antitumor effects of AK117 as a single agent or in combination with AK112 were also encouraging in various xenograft models. In non-human primates, AK117 showed less hematotoxicity compared with Hu5F9-G4. CONCLUSIONS: AK117 eliminated hemagglutination and also enabled to maintain full effectiveness of CD47 blockade on tumor cells, which resulted in excellent antitumor efficacy and favorable safety profile of AK117. A series of clinical trials of AK117 as a therapeutic agent in combination with various agents such as AK112 are in progress for the treatment of multiple hematologic malignancies and solid tumors.

Tetracycline adsorption trajectories on aged polystyrene in a simulated aquatic environment: A mechanistic investigation.

Microplastics (MPs) have attracted widespread attention as an organic class of pollutants as well as pollutant carriers in recipient aquatic ecosystems. In this study, tetracycline (TC) adsorption by polystyrene (PS), with multiple aging-based temporal changes in the adsorption mechanism, was observed. The results revealed that the pseudo-second-order model accurately predicted the TC adsorption kinetics for different types of PS. In addition, the isothermal adsorption processes fit the Freundlich model; however, their interactions were drastically weakened at lower temperatures or increasing salinities. Corresponding to the electrostatic interactions, adsorption TC was largely pH-dependent, with the maximum adsorbed TC content on the PS surface at a pH of 5 in an aqueous environment. More importantly, mechanistic studies have revealed that, compared to virgin PS, TC complexes with aged PS are principally controlled by hydrogen bonding and ionic interactions, followed by π-π, polar-polar, and van der Waals interactions. These findings will aid in understanding the insights of TC and aged PS interactions and the underlying interactive molecular forces, which will be advantageous for comprehending the real case scenario of inter-pollutant interactions and related environmental pollution.

Penpulimab, an Fc-Engineered IgG1 Anti-PD-1 Antibody, With Improved Efficacy and Low Incidence of Immune-Related Adverse Events.

Background: IgG4 anbibodies are deficient in stability and may contribute to tumor-associated escape from immune surveillance. We developed an IgG1 backbone anti-programmed cell death protein-1 (PD-1) antibody, penpulimab, which is designed to remove crystallizable fragment (Fc) gamma receptor (FcγR) binding that mediates antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and proinflammatory cytokine release. Methods: Aggregation of different anti-PD-1 antibodies was tested by size exclusion chromatography, and melting temperature midpoint (Tm) and aggregation temperature onset (Tagg) were also determined. The affinity constants of penpulimab for PD-1 and human FcγRs were measured by surface plasmon resonance and biolayer interferometry. ADCC and ADCP were determined in cellular assays and antibody-dependent cytokine release (ADCR) from human macrophages was detected by ELISA. Binding kinetics of penpulimab to human PD-1 was determined by Biacore, and epitope/paratope mapping of PD-1/penpulimab was investigated using x-ray crystallography. Additionally, patients from six ongoing trials were included for analysis of immune-related adverse events (irAEs). Results: Penpulimab demonstrated better stability and a lower level of host-cell protein residue compared with IgG4 backbone anti-PD-1 antibodies. As expected, penpulimab exhibited no apparent binding to FcγRIa, FcγRIIa_H131, FcγRIIIa_V158 and FcγRIIIa_F158, elicited no apparent ADCC and ADCP activities, and induced no remarkable IL-6 and IL-8 release by activated macrophages in vitro. Penpulimab was shown in the co-crystal study to bind to human PD-1 N-glycosylation site at N58 and had a slower off-rate from PD-1 versus nivolumab or pembrolizumab. Four hundred sixty-five patients were analyzed for irAEs. Fifteen (3.2%) patients had grade 3 or above irAEs. No death from irAEs was reported. Conclusions: IgG1 backbone anti-PD1 antibody penpulimab has a good stability and reduced host cell protein residue, as well as potent binding to the antigen. Fc engineering has eliminated Fc-mediated effector functions of penpulimab including ADCC, ADCP and reduced ADCR, which may contribute to its more favorable safety profile. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: AK105-101: NCT03352531, AK105-201: NCT03722147, AK105-301: NCT03866980, AK105-202:NCT03866967, AK105-203: NCT04172571, AK105-204: NCT04172506.

Dynamics of sediment phosphorus affected by mobile aeration: Pilot-scale simulation study in a hypereutrophic pond.

Controlling the release of phosphorus (P) in sediments is important to prevent eutrophication and harmful algal blooms in water bodies. Here we explored the effect of mobile aerators on the control of P release from sediments in a eutrophic pond. The dissolved oxygen in the water body recovered significantly after six months of aeration, becoming 4.2-5.8 times higher than in the control. The pH and Eh values at the sediment-water interface considerably increased, while the concentration of soluble reactive phosphorus (SRP) in pore water significantly decreased, resulting in the alteration of SRP fluxes from 1.69 mg/m2 d to -53.49 mg/m2 d. Moreover, the inert P in sediments increased by 5.2% of the total P at the end of the study compared with the initial state, and the calcium-bound phosphorus (HCl-P) increased by 96.6%. However, although aeration reduced the concentration of SRP in the water column, the total P concentration was 2.45 times higher than that of the control, and the content of redox-sensitive P (BD-P) in the sediment also increased by 200%. Overall, although mobile aeration can maintain the microenvironment of the sediment interface and increase the inert P content in the sediment to reduce the P flux, it cannot reduce the risk of release of mobile P.

[Effect of activation of cellular immunity on p58+ cells expressing killer-cell-inhibitory receptor cells].

UNLABELLED: The purpose of this study was to evaluate the effects of cellular immunity activation on P58(+) cells expressing killer cell inhibitory receptor (KIR) and their regulatory function on cellular immunity, and provid theoretical data for preventing graft-vers-host disease (GVHD) in stem cell transplantation therapy. The mononuclear cells from human peripheral blood were incubated with IL-2, Con A and Lipostin (LP) for 72 hours. The KIR expressing cells, P58.1(+) and P58.2(+) cells, were analyzed by flow cytometry. The results showed that the percentages of CD3(+), CD4(+), CD8(+), CD16(+)CD56(+), P58.1(+) and P58.2(+) cells were greatly increased after treated with IL-2, Con A and LP, separately or in combination, and the percentages of above cells in combined treatment groups were higher than those of single stimulated groups, especially the percentage of cells in the IL-2 + LP group was significantly higher than those in IL-2 and LP singly treated groups. IN CONCLUSION: IL-2, Con A and LP possess the ability to induce the expression of KIR and stimulate proliferation of P58.1(+) and P58.2(+) cells while to activate the celluar immunity response, the expression of P58 gene may be regulated by the activation of cellular immunity.