Inhibitory CD33-related Siglec receptors regulate immune cell activation upon engaging ubiquitous sialic acids (Sias) on host cell surface glycans. Through molecular mimicry, Sia-expressing pathogen ...group B
Streptococcus
binds inhibitory human Siglec-9 (hSiglec-9) to blunt neutrophil activation and promote bacterial survival. We unexpectedly discovered that hSiglec-9 also specifically binds high molecular weight hyaluronan (HMW-HA), another ubiquitous host glycan, through a region of its terminal Ig-like V-set domain distinct from the Sia-binding site. HMW-HA recognition by hSiglec-9 limited neutrophil extracellular trap (NET) formation, oxidative burst, and apoptosis, defining HMW-HA as a regulator of neutrophil activation. However, the pathogen group A
Streptococcus
(GAS) expresses a HMW-HA capsule that engages hSiglec-9, blocking NET formation and oxidative burst, thereby promoting bacterial survival. Thus, a single inhibitory lectin receptor detects two distinct glycan “self-associated molecular patterns” to maintain neutrophil homeostasis, and two leading human bacterial pathogens have independently evolved molecular mimicry to exploit this immunoregulatory mechanism.
Key message
HMW-HA is the first example of a non-sialic acid containing glycan to be recognized by CD33-related Siglecs.
HMW-HA engagement of hSiglec-9 attenuates neutrophil activation.
Group A
Streptococcus
exploits hSiglec-9 recognition via its polysaccharide HMW-HA capsule to subvert neutrophil killing.
Cadmium (Cd) pollution poses a risk to human health for its accumulation in soil and crops, but this can be alleviated by calcium (Ca) addition. However, its mechanism remains unclear yet. In this ...study, Arabidopsis thaliana was used to explore the alleviating effects of Ca on Cd toxicity and its specific function during uptake, upward-translocation, and distribution of Cd. Supplementing plants with 5mM CaCl2 alleviated the intoxication symptoms caused by 50μM CdCl2, such as smaller leaves, early bolting and root browning. Ca addition decreased uptake of Cd, possibly by reducing the physical adsorption of Cd since the root cell membrane was well maintained and lignin deposition was decreased as well, and by decreasing symplastic Cd transport. Expression of the genes involved (AtZIP2 and AtZIP4) was also decreased. In addition, Ca accumulated in the plant shoot to help facilitating the upward-translocation of Cd, with evidence of higher translocation factor and expression of genes that were involved in Ca transport (AtPCR1) and Cd xylem loading (AtHMA2 and AtHMA4). Dithizone-staining of Cd in leaves showed that in Cd+Ca-treated plants, Ca addition initially protected the leaf stomata by preventing Cd from entering guard cells, but with prolonged Cd treatment facilitated the Cd accumulation around trichomes and maybe its excretion. We conclude that Ca promotes the upward-translocation of Cd and changes its distribution in leaves. The results may have relevance for bioremediation.
•Ca addition decreased the uptake of Cd possibly by reducing the physical adsorption of Cd.•Ca addition facilitated the upward-translocation of Cd.•Ca addition protected the leaf stomata by preventing Cd from entering guard cells.
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant inheritable vascular dysplasia caused by mutations in genes encoding either endoglin or activin receptor-like kinase-1 (ALK1). ...Functional significance of endoglin missense mutations remains largely unknown leading to a difficult discrimination between polymorphisms and pathogenic mutations. In order to study the functional significance of endoglin mutations and to help HHT1 diagnosis, we developed a cellular assay based on the ability of endoglin to enhance ALK1 response to bone morphogenetic protein 9 (BMP9). We generated and characterized 31 distinct ENG mutants reproducing human HHT1 missense mutations identified in patients of the Molecular Genetics Department in Lyon. We found that 16 mutants behaved like wild-type (WT) endoglin, and thus corresponded to benign rare variants. The 15 other variants showed defects in BMP9 response and were identified as pathogenic mutations. Interestingly, two mutants (S278P and F282V) had lost their ability to bind BMP9, identifying two crucial amino acids for BMP9 binding to endoglin. For all the others, the functional defect was correlated with a defective trafficking to the cell surface associated with retention in the endoplasmic reticulum. Further, we demonstrated that some intracellular mutants dimerized with WT endoglin and impaired its cell-surface expression thus acting as dominant-negatives. Taken together, we show that endoglin loss-of-function can result from different mechanisms in HHT1 patients. We also provide a diagnostic tool helping geneticists in screening for novel or conflicting ENG mutations.
CD38 is a multifunctional enzyme implicated in chemotaxis of myeloid cells and lymphocyte activation, but also expressed by resident cells such as endothelial and smooth muscle cells. CD38 is ...important for host defense against microbes. However, CD38's role in the pathogenesis of atherosclerosis is controversial with seemingly conflicting results reported so far. To clarify the discrepancy of current literature on the effect of CD38 ablation on atherosclerosis development, we implanted a shear stress modifier around the right carotid artery in CD38−/− and WT mice. Hypercholesterolemia was induced by human gain-of-function PCSK9 (D374Y), introduced using AAV vector (serotype 9), combined with an atherogenic diet for a total of 9 weeks. Atherosclerosis was assessed at the aortic root, aortic arch and the right carotid artery. The findings can be summarized as follows: i) CD38−/− and WT mice had a similar atherosclerotic burden in all three locations, ii) No significant differences in monocyte infiltration or macrophage content could be seen in the plaques, and iii) The amount of collagen deposition in the plaques were also similar between CD38−/− and WT mice. In conclusion, our data suggest that CD38−/− mice are neither protected against nor prone to atherosclerosis compared to WT mice.
•CD38 ablation has no effect on atherosclerosis at three distinct locations in mice.•Monocyte infiltration into atherosclerotic plaques does not depend on CD38.•The collagen content in atherosclerosis is similar in CD38−/− and WT mice.•CD38 ablation does not affect body weight, adiposity or liver weight.
Tumor infiltration by different T lymphocyte subsets is known to be associated with favorable prognosis in colorectal cancer. Still debated is the role of innate immune system. We investigated ...clinical relevance, phenotypes, and functional features of colorectal cancer-infiltrating CD66b
neutrophils and their crosstalk with CD8
T cells.
CD66b
and CD8
cell infiltration was analyzed by IHC on a tissue microarray including >650 evaluable colorectal cancer samples. Phenotypic profiles of tissue-infiltrating and peripheral blood CD66b
cells were evaluated by flow cytometry. CD66b
/CD8
cells crosstalk was investigated by
experiments.
CD66b
cell infiltration in colorectal cancer is significantly associated with increased survival. Interestingly, neutrophils frequently colocalize with CD8
T cells in colorectal cancer. Functional studies indicate that although neutrophils are devoid of direct antitumor potential, coculture with peripheral blood or tumor-associated neutrophils (TAN) enhances CD8
T-cell activation, proliferation, and cytokine release induced by suboptimal concentrations of anti-CD3 mAb. Moreover, under optimal activation conditions, CD8
cell stimulation in the presence of CD66b
cells results in increasing numbers of cells expressing CD45RO/CD62L "central memory" phenotype. Importantly, combined tumor infiltration by CD66b
and CD8
T lymphocytes is associated with significantly better prognosis, as compared with CD8
T-cell infiltration alone.
Neutrophils enhance the responsiveness of CD8
T cells to T-cell receptor triggering. Accordingly, infiltration by neutrophils enhances the prognostic significance of colorectal cancer infiltration by CD8
T cells, suggesting that they might effectively promote antitumor immunity.
.
Cadmium (Cd) speciation ratio in arable land determines the Cd exposure risk and Cd uptake in crops. However, the driving mechanisms of Cd speciation change on the vertical scale of paddy fields ...remain poorly understood. In this study, the effects of plow layer and plow pan on Cd speciation distribution were investigated in a long-term Cd-contaminated rice ecosystem. The Cd accumulative effect within rice grain was enhanced with high levels of activated Cd speciation ratios in soils. Activated Cd speciation ratios were higher in plow layer soils, while stabilized Cd speciation ratios were elevated in plow pan soils. Soil physicochemical properties and soil microbes synergistically affected the Cd speciation changes in different ways between the two soil layers. Soil pH and organic elements in plow layer environment directly hindered the transformation of stabilized Cd speciation, while in plow pan environment, soil pH and organic elements indirectly decreased activated Cd speciation ratios and resulted in the accumulation of stabilized Cd speciation
regulating the predominant bacterial taxa. This study will improve our understanding of how soil environments regulate Cd speciation distributions in rice ecosystems and help to seek effective remediation methods of Cd-contaminated paddy fields to reduce the Cd accumulation in rice.
Small-sized fluorescent carbon dots (CDs) are gaining increasing attention in the field of biomedical applications. The environmental and biological compatibility of positively charged CDs has been ...extensively investigated; however, the potential cytotoxicity caused by negatively and particularly neutrally charged small CDs has been significantly overlooked. In this study, we conducted a comprehensive investigation into the cellular membrane disruption effect of weakly negatively charged 3-nm CDs using a combination of various biophysical techniques. Our findings demonstrate that even at a low concentration of 0.5 μg mL−1, these CDs induce significant perturbations on the cellular membrane, resulting in increased membrane permeability due to asymmetric disruption of the bilayer structure. Furthermore, CDs exhibit distinct mechanisms at different concentrations, including prompt insertion into the bilayer at low concentrations (<20 μg mL−1) and a synergistic effect after a threshold time at high concentrations (e.g., 25–200 μg mL−1). Moreover, these CDs possess specific antibacterial properties against Acinetobacter baumannii (with a minimum inhibitory concentration of 50 μg mL−1) while showing minimal hemolytic or cytotoxic effects on mammalian cells. This study provides comprehensive insights into the biophysical aspects of cellular membrane toxicity caused by small weakly negatively charged CDs and contributes to assessing their potential biomedical applications.
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•3-nm CDs at 0.5 μg mL−1 can induce cell membrane permeabilization.•Low- and high-concentration CDs induce distinct membrane permeabilization processes.•The CDs asymmetrically disturb lipid packing in both leaflets of the membrane.•The incorporation of CDs into a membrane disrupts its electrical properties.•The CDs exhibit antibacterial ability with minimal hemolytic or cytotoxic effects.
Background Allergic contact dermatitis (ACD) is the most common occupational disease. Although murine contact hypersensitivity provides a framework for understanding ACD, it carries important ...differences from its human counterpart. Unlike the contact hypersensitivity model, which is induced by potent sensitizers (ie, dinitrofluorobenzene), human ACD is induced by weak-to-moderate sensitizers (ie, nickel), which cannot induce reactions in mice. Distinct hapten-specific immune-polarizing responses to potent inducers were suggested in mice, with unclear relevance to human ACD. Objective We explored the possibility of distinct T-cell polarization responses in skin to common clinically relevant ACD allergens. Methods Gene-expression and cellular studies were performed on common allergens (ie, nickel, fragrance, and rubber) compared with petrolatum-occluded skin, using RT-PCR, gene arrays, and immunohistochemistry. Results Despite similar clinical reactions in all allergen groups, distinct immune polarizations characterized different allergens. Although the common ACD transcriptome consisted of 149 differentially expressed genes across all allergens versus petrolatum, a much larger gene set was uniquely altered by individual allergens. Nickel demonstrated the highest immune activation, with potent inductions of innate immunity, TH 1/TH 17 and a TH 22 component. Fragrance, and to a lesser extent rubber, demonstrated a strong TH 2 bias, some TH 22 polarization, and smaller TH 1/TH 17 contributions. Conclusions Our study offers new insights into the pathogenesis of ACD, expanding the understanding of T-cell activation and associated cytokines in allergen-reactive tissues. It is the first study that defines the common transcriptome of clinically relevant sensitizers in human skin and identifies unique pathways preferentially activated by different allergens, suggesting that ACD cannot be considered a single entity.
Lack of insight into mechanisms governing breast cancer metastasis has precluded the development of curative therapies. Metastasis-initiating cancer cells (MICs) are uniquely equipped to establish ...metastases, causing recurrence and therapeutic resistance. Using various metastasis models, we discovered that certain primary tumours elicit a systemic inflammatory response involving interleukin-1β (IL-1β)-expressing innate immune cells that infiltrate distant MIC microenvironments. At the metastatic site, IL-1β maintains MICs in a ZEB1-positive differentiation state, preventing MICs from generating highly proliferative E-cadherin-positive progeny. Thus, when the inherent plasticity of MICs is impeded, overt metastases cannot be established. Ablation of the pro-inflammatory response or inhibition of the IL-1 receptor relieves the differentiation block and results in metastatic colonization. Among patients with lymph node-positive breast cancer, high primary tumour IL-1β expression is associated with better overall survival and distant metastasis-free survival. Our data reveal complex interactions that occur between primary tumours and disseminated MICs that could be exploited to improve patient survival.
Context. Strong lenses are extremely useful probes of the distribution of matter on galaxy and cluster scales at cosmological distances, however, they are rare and difficult to find. The number of ...currently known lenses is on the order of 1000. Aims. The aim of this study is to use crowdsourcing to carry out a lens search targeting massive galaxies selected from over 442 square degrees of photometric data from the Hyper Suprime-Cam (HSC) survey. Methods. Based on the S16A internal data release of the HSC survey, we chose a sample of ∼300 000 galaxies with photometric redshifts in the range of 0.2 < z phot < 1.2 and photometrically inferred stellar masses of log M * > 11.2. We crowdsourced lens finding on this sample of galaxies on the Zooniverse platform as part of the Space Warps project. The sample was complemented by a large set of simulated lenses and visually selected non-lenses for training purposes. Nearly 6000 citizen volunteers participated in the experiment. In parallel, we used Y ATTA L ENS , an automated lens-finding algorithm, to look for lenses in the same sample of galaxies. Results. Based on a statistical analysis of classification data from the volunteers, we selected a sample of the most promising ∼1500 candidates, which we then visually inspected: half of them turned out to be possible (grade C) lenses or better. By including lenses found by Y ATTA L ENS or serendipitously noticed in the discussion section of the Space Warps website, we were able to find 14 definite lenses (grade A), 129 probable lenses (grade B), and 581 possible lenses. Y ATTA L ENS found half the number of lenses that were discovered via crowdsourcing. Conclusions. Crowdsourcing is able to produce samples of lens candidates with high completeness, when multiple images are clearly detected, and with higher purity compared to the currently available automated algorithms. A hybrid approach, in which the visual inspection of samples of lens candidates pre-selected by discovery algorithms or coupled to machine learning is crowdsourced, will be a viable option for lens finding in the 2020s, with forthcoming wide-area surveys such as LSST, Euclid , and WFIRST.
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