Seasonal and vertical patterns of water availability and variability determine plant reproductive phenology.

BACKGROUND AND AIMS: Changing precipitation regimes can influence terrestrial plants and ecosystems. However, plant phenological responses to changing precipitation temporal patterns and the underlying mechanisms are largely unclear. This study was conducted to explore the effects of seasonal precipitation redistribution on plant reproductive phenology in a temperate steppe. METHODS: A field experiment with control (C), advanced (AP) and delayed (DP) growing-season precipitation peaks, and the combination of AP and DP (ADP) were employed. Seven dominant plant species were selected and divided into two functional groups (early- vs. middle-flowering species, shallow- vs. deep-rooted species) to monitor reproductive phenology including budding, flowering, and fruiting date, as well as reproductive duration for four growing seasons from 2015 to 2017, and 2022. KEY RESULTS: The AP, but not DP treatment advanced the phenological (i.e., budding, flowering, and fruiting) dates and lengthened the reproductive duration across the 4 growing seasons and 7 monitored species. In addition, the phenological responses showed divergent patterns among different plant functional groups, which could be attributed to shifts in soil moisture and its variability in different months and soil depths. Moreover, species with lengthened reproductive duration increased phenological overlap with other species, which could have a negative impact on their dominance under the AP treatment. CONCLUSIONS: Our findings reveal that changing precipitation seasonality could have considerable impacts on plant phenology by affecting soil water availability and variability. Incorporating these two factors simultaneously in the phenology models will help us understand the response of plant phenology under intensified changing precipitation scenarios. In addition, the observations of decreased dominance for the species with lengthened reproductive duration suggest that changing reproductive phenology can have a potential to affect community composition in grasslands under global change.

DR30318, a novel tri-specific T cell engager for Claudin 18.2 positive cancers immunotherapy.

BACKGROUND: Claudin 18.2 (CLDN18.2) is a highly anticipated target for solid tumor therapy, especially in advanced gastric carcinoma and pancreatic carcinoma. The T cell engager targeting CLDN18.2 represents a compelling strategy for enhancing anti-cancer efficacy. METHODS: Based on the in-house screened anti-CLDN18.2 VHH, we have developed a novel tri-specific T cell engager targeting CLDN18.2 for gastric and pancreatic cancer immunotherapy. This tri-specific antibody was designed with binding to CLDN18.2, human serum albumin (HSA) and CD3 on T cells. RESULTS: The DR30318 demonstrated binding affinity to CLDN18.2, HSA and CD3, and exhibited T cell-dependent cellular cytotoxicity (TDCC) activity in vitro. Pharmacokinetic analysis revealed a half-life of 22.2-28.6 h in rodents and 41.8 h in cynomolgus monkeys, respectively. The administration of DR30318 resulted in a slight increase in the levels of IL-6 and C-reactive protein (CRP) in cynomolgus monkeys. Furthermore, after incubation with human PBMCs and CLDN18.2 expressing cells, DR30318 induced TDCC activity and the production of interleukin-6 (IL-6) and interferon-gamma (IFN-γ). Notably, DR30318 demonstrated significant tumor suppression effects on gastric cancer xenograft models NUGC4/hCLDN18.2 and pancreatic cancer xenograft model BxPC3/hCLDN18.2 without affecting the body weight of mice.

Nitrogen addition does not alter symmetric responses of soil respiration to changing precipitation in a semi-arid grassland.

Concurrent changing precipitation regimes and atmospheric nitrogen (N) deposition can have profound influences on soil carbon (C) cycling. However, how N enrichment regulates the responses of soil C fluxes to increasing variability of precipitation remains elusive. As part of a field precipitation gradient experiment with nine levels of precipitation amounts (-60 %, -45 %, -30 %, -15 %, ambient precipitation, +15 %, +30 %, +45 %, and +60 %) and two levels of N addition (0 and 10 g N m-2 yr-1) in a semi-arid temperate steppe on the Mongolian Plateau, this work was conducted to investigate the responses of soil respiration to decreased and increased precipitation (DP and IP), N addition, and their possible interactions. Averaged over the three years from 2019 to 2021, DP suppressed soil respiration by 16.1 %, whereas IP stimulated it by 27.4 %. Nitrogen addition decreased soil respiration by 7.1 % primarily via reducing microbial biomass C. Soil respiration showed symmetric responses to DP and IP within all the four precipitation variabilities (i.e., 15 %, 30 %, 45 %, and 60 %) under ambient N. Nevertheless, N addition did not alter the symmetric responses of soil respiration to changing precipitation due to the comparable sensitivities of microbial biomass and root growth to DP and IP under the N addition treatment. These findings indicate that intensified precipitation variability does not change but N addition could alleviate soil C releases. The unchanged symmetric responses of soil respiration to precipitation variability under N addition imply that N deposition may not change the response pattern of soil C releases to predicted increases in precipitation variability in grasslands, facilitating the robust projections of ecosystem C cycling under future global change scenarios.

An innovative antibody fusion protein targeting PD-L1, VEGF and TGF-ß with enhanced antitumor efficacies.

Immunosuppressive pathways in the tumor microenvironment (TME) are inextricably linked to tumor progression. Mono-therapeutics of immune checkpoint inhibitors (ICIs, e.g. antibodies against programmed cell death protein-1/programmed cell death ligand-1, PD-1/PD-L1) is prone to immune escape while combination therapeutics tends to cause high toxicity and side effects. Therefore, using multi-functional molecules to target multiple pathways simultaneously is becoming a new strategy for cancer therapies. Here, we developed a trifunctional fusion protein, DR30206, composed of Bevacizumab (an antibody against VEGF), and a variable domain of heavy chain of heavy chain antibody (VHH) against PD-L1 and the extracellular domain (ECD) protein of TGF-ß receptor II (TGF-ß RII), which are fused to the N- and C-terminus of Bevacizumab, respectively. The original intention of DR30206 design was to enhance the immune responses pairs by targeting PD-L1 while inhibiting VEGF and TGF-ß in the TME. Our data demonstrated that DR30206 exhibits high antigen-binding affinities and efficient blocking capabilities, the principal drivers of efficacy in antibody therapy. Furthermore, the capability of eliciting antibody-dependent cellular cytotoxicity (ADCC) and mixed lymphocyte reaction (MLR) provides a greater possibility to enhance the immune response. Finally, in vivo experiments showed that the antitumor activity of DR30206 was superior to those of monoclonal antibody of PD-L1 or VEGF, PD-L1 and TGF-ß bispecific antibody or the combination inhibition of PD-L1 and VEGF. Our findings suggest there is a great potential for DR30206 to become a therapeutic for the treatment of multiple cancer types, especially lung cancer, colon adenocarcinoma and breast carcinoma.