Infection of erythrocytes with Plasmodium species induces clinical malaria. Parasite-specific CD4(+) T cells correlate with lower parasite burdens and severity of human malaria and are needed to ...control blood-stage infection in mice. However, the characteristics of CD4(+) T cells that determine protection or parasite persistence remain unknown. Here we show that infection of humans with Plasmodium falciparum resulted in higher expression of the inhibitory receptor PD-1 associated with T cell dysfunction. In vivo blockade of the PD-1 ligand PD-L1 and the inhibitory receptor LAG-3 restored CD4(+) T cell function, amplified the number of follicular helper T cells and germinal-center B cells and plasmablasts, enhanced protective antibodies and rapidly cleared blood-stage malaria in mice. Thus, chronic malaria drives specific T cell dysfunction, and proper function can be restored by inhibitory therapies to enhance parasite control.
Despite the fact that CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg cells) play a central role in maintaining self-tolerance and that IL-17-producing CD4(+) T cells (Th17 cells) are pathogenic in ...many autoimmune diseases, evidence to date has indicated that Th17 cells are resistant to suppression by human Foxp3(+) Treg cells. It was recently demonstrated that CD39, an ectonucleotidase which hydrolyzes ATP, is expressed on a subset of human natural Treg cells. We found that although both CD4(+)CD25(high)CD39(+) and CD4(+)CD25(high)CD39(-) T cells suppressed proliferation and IFN-gamma production by responder T cells, only the CD4(+)CD25(high)CD39(+), which were predominantly FoxP3(+), suppressed IL-17 production, whereas CD4(+)CD25(high)CD39(-) T cells produced IL-17. An examination of T cells from multiple sclerosis patients revealed a normal frequency of CD4(+)CD25(+)CD127(low)FoxP3(+), but interestingly a deficit in the relative frequency and the suppressive function of CD4(+)CD25(+)CD127(low)FoxP3(+)CD39(+) Treg cells. The mechanism of suppression by CD39(+) Treg cells appears to require cell contact and can be duplicated by adenosine, which is produced from ATP by the ectonucleotidases CD39 and CD73. Our findings suggest that CD4(+)CD25(+)Foxp3(+)CD39(+) Treg cells play an important role in constraining pathogenic Th17 cells and their reduction in multiple sclerosis patients might lead to an inability to control IL-17 mediated autoimmune inflammation.
Endosialin/TEM1 was originally discovered as a human embryonic fibroblast-specific antigen and was later found to be differentially expressed in tumor stroma and endothelium. Endosialin/TEM1 ...over-expression has been observed in many cancers of various tissue origin, including colon, breast, pancreatic, and lung. The knockout (KO) mouse model showed the absence of endosialin/TEM1 expression reduced growth, invasion, and metastasis of human tumor xenografts. In addition, lack of endosialin/TEM1 led to an increase in small immature blood vessels and decreased numbers of medium and large tumor vessels. This abnormal angiogenic response could be responsible for the reduced tumor growth and invasion observed in endosialin/TEM1 KO mice, suggesting a role for endosialin/TEM1 in controlling the interaction among tumor cells, endothelia, and stromal matrix. Here we report the identification of fibronectin (FN) and collagen types I and IV as specific ligands for endosialin/TEM1. More importantly, cells expressing endosialin/TEM1 exhibit enhanced adhesion to FN as well as enhanced migration through matrigel, although these properties could be blocked by a humanized antibody directed against human endosialin/TEM1. Our results pinpoint to a molecular mechanism by which expression of endosialin/TEM1 in the tumor stroma and endothelium may support tumor progression and invasion.
•Long-term rice straw removal reduced the total concentrations of Cd in soil.•Atmospheric deposition led to lower remediation efficiency of Cd by straw removal.•Long-term rice straw return obviously ...increased the bioavailability of Cd in soil.•Cd accumulation in late rice tissues was higher than early rice under straw return.
Several studies have demonstrated that reintroducing crop straw to fields may intensify cadmium (Cd) contamination in agricultural soils. However, the specific effects of long-term straw management practices on Cd concentration and its bioavailability in soil-rice ecosystems remain unclear. In this context, to explore the influence of straw return (SR) and straw removal (NSR) on Cd accumulation in both soil and rice within a double-cropping system, we conducted a four-year field study. Our research study unveiled that NSR consistently decreased soil Cd concentration and its bioavailability by approximately 16.93%–27.30% and 8.23%–21.05% respectively across both study sites. Conversely, SR resulted in a substantial increase in soil Cd bioavailability, ranging from 38.64%–53.95%. Notably, compared to NSR, SR significantly increased total soil Cd by 5.47%–36.58% and increased Cd content in brown rice by 8.00%–100.24%. Remarkably, after four consecutive years of NSR, brown rice Cd concentration at the Changfeng site compiled with national safety standards (GB 2762–2022). Additionally, returning early rice straw significantly raised soil Cd bioavailability for the subsequent crop, more so than late rice straw did for the early rice the following year. The findings suggest that traditional double-cropping cultivation with straw removal can effectively mitigate Cd contamination risks in crops and farmland in Hunan Province.
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Cadmium (Cd), a toxic non-essential metal, is easily accumulated in cacao tissues. This represents a risk for cacao exportation, and consequently it affects the economic well-being of the ...resource-poor-small-producers in Latin America. A greenhouse experiment was conducted with 53 wild and domesticated cacao genotypes to determine their response to Cd in terms of growth and Cd and essential nutrients accumulation. Cacao seedlings were grown for 6 months in an acidic soil with or without added Cd. The total concentration of macro (Ca, K, Mg, N and P) and micronutrients (B, Cu, Fe, Mn and Zn) as well as Cd were measured in shoots along with growth (biometric) parameters after harvest. The results revealed that even if there was a wide range of Cd concentrations among genotypes, there was a reduction in the concentration of essential nutrients in genotypes grown in Cd spiked soils, however these concentrations were not significantly different from the control. In the case of growth parameters, the effects of Cd were diverse across all genotypes some of them being more tolerant to Cd stress than others. Thus, different growth responses to Cd stress are related to a genotype effect. Based on their lower Cd concentration, a total of 11 cacao genotypes (AYP-22, PAS-105, UGU-126, ICT-1026, ICT-1087, ICT-1189, ICT-1292, PH-17, CCN-51, ICS-39 and TSH-565) are proposed here as low Cd-accumulating genotypes. Therefore, these genotypes are potentially useful as rootstock to reduce uptake and transport of Cd, especially in economically important cacao cultivars.
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•Research with the higher quantity of genotypes assessed for Cd uptake in cacao•53 genotypes assessed for Cd uptake in cacao from different origins•Growth parameters were related to genotype effect.•11 cacao genotypes proposed as low Cd accumulators
To explore the mechanism of how lead (Pb) and cadmium (Cd) stress affects photosynthesis of mulberry (Morus alba L.), we looked at the effects of different concentrations of Pb and Cd stress (at 100 ...and 200 μmol L−1), which are two heavy metal elements, on leaf chlorophyll (Chl), photosynthesis gas exchange, Chl fluorescence, and reactive oxygen species (ROS) metabolism in mulberry leaves. The results showed that higher concentrations of Pb and Cd reduced leaf Chl content, especially in Chl a where content was more sensitive than in Chl b. Under Pb and Cd stress, the photosynthetic carbon assimilation capacity of mulberry leaves was reduced, which was a consequence of combined limitations of stomatal and non-stomatal factors. The main non-stomatal factors were decreased photosystem II (PSII) and photosystem I (PSI) activity and carboxylation efficiency (CE). Damage to the donor side of the PSII reaction center was greater than the acceptor side. After being treated with 100 μmol L−1 of Pb and Cd, mulberry leaves continued to be able to dissipate excess excitation energy by starting non-photochemical quenching (NPQ), but when Pb and Cd concentrations were increased to 200 μmol L−1, the protection mechanism that depends on NPQ was impaired. Excessive excitation energy from chloroplasts promoted a great increase of ROS, such as superoxide anion (O2•-) and H2O2. Moreover, under high Pb and Cd stress, superoxide dismutase (SOD) and ascorbate peroxidase (APX) were also inhibited to some extent, and excessive ROS also resulted in a significantly higher degree of oxidative damage. Compared with Cd, the effect of Pb stress at the same concentration level displayed a significantly lower impact on Chl content, photosynthetic carbon assimilation, and stomatal conductance. Meanwhile, Pb stress mainly damaged activity of the oxygen-evolving complex (OEC) located on PSII donor side, but it reduced the electronic pressure on the PSII acceptor side and PSI. Furthermore, under Pb stress, the NPQ, SOD, and APX activity were all significantly higher than those under Cd stress. Thus under Pb stress, the degree of photoinhibition and oxidative damage of PSII and PSI in mulberry leaves were significantly lower than under Cd stress.
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•Photosynthetic functions and ROS metabolism in mulberry leaves were studied under Pb and Cd stress.•The photoinibition and oxidative damage in leaves under Cd stress were higher than Pb stress.•Pb and Cd stress caused chlorophyll (Chl) degradation in leaves, Chl a was more sensitive than Chl b.•Pb stress caused a higher degree of damage to the oxygen-evolving complex (OEC) in leaves than equivalent concentration of Cd stress.•Non-photochemical quenching (NPQ) plays a critical role in dissipating excess excitation energy under Pb and Cd stress.
The immunoproteasome plays a key role in generation of HLA peptides for T cell-mediated immunity. Integrative genomic and proteomic analysis of non-small cell lung carcinoma (NSCLC) cell lines ...revealed significantly reduced expression of immunoproteasome components and their regulators associated with epithelial to mesenchymal transition. Low expression of immunoproteasome subunits in early stage NSCLC patients was associated with recurrence and metastasis. Depleted repertoire of HLA class I-bound peptides in mesenchymal cells deficient in immunoproteasome components was restored with either IFNγ or 5-aza-2′-deoxycytidine (5-aza-dC) treatment. Our findings point to a mechanism of immune evasion of cells with a mesenchymal phenotype and suggest a strategy to overcome immune evasion through induction of the immunoproteasome to increase the cellular repertoire of HLA class I-bound peptides.
Cadmium (Cd) contamination has become an emergent environmental issue in agroecosystems worldwide. The impacts of Cd on microbial community and their ecological functional remain unrevealed. This ...study investigated the response of bacterial community and microbial ecological functions to Cd contamination in paddy soil of East China. Bacterial diversity and community structure significantly changed under Cd contamination. Proteobacteria and Acidobacteria were identified as biomarkers to indicate Cd contamination. The overall elemental cycling genes abundance was negatively correlated to soil Cd content. Acetyl-CoA synthesis, organic N mineralization, N fixation and nitrous reduction genes were especially sensitive to elevated Cd stress, resulting in loss of microbial derived soil C and N pool and increase in N2O emission potential. Bacteria interactions were sparser yet more competitive under Cd contamination. Cd resistant genera Massilia, Burkholderia, Streptomyces and Methylobacterium were essential to bacterial interactions via building connections with non-resistant species. Microbial Cd immobilization potential by urea hydrolysis was enhanced under Cd contamination, with Massilia being the keystone functional taxa involved in this process. Our study elucidated the ecological risks of altered microbial functions under Cd contamination in paddy soil, as well as the significance of Cd resistant bacteria to microbial community and ecological functionality.
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•Increased dominance of Proteobacteria and Acidobacteria indicates Cd contamination.•Cd decreases microbial derived C and N pool and increases N2O emission potential.•Cd resistant bacteria are essential for maintaining microbial interactions.•Genus Massilia is the keystone functional taxa with Cd immobilization potential.
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains one of the world's largest infectious disease problems. Despite decades of intensive study, the immune response to Mtb is ...incompletely characterised, reflecting the extremely complex interaction between pathogen and host. Pathways that may alter the balance between host protection and pathogenesis are therefore of great interest. One pathway shown to play a role in the pathogenesis of chronic infections, including TB, is the programmed death‐1 (PD‐1) pathway. We show here that the expression of the programmed death ligand 1 (PD‐L1), which interacts with PD‐1, is increased in whole blood from active TB patients compared with whole blood from healthy controls or Mtb‐exposed individuals, and that expression by neutrophils is largely responsible for this increase.
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