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The liver has recently been identified as a major organ for destruction of desialylated platelets. However, the underlying mechanism remains unclear. Kupffer cells, which are professional phagocytic cells in the liver, comprise the largest population of resident tissue macrophages in the body. Kupffer cells express a C-type lectin receptor, CLEC4F, that recognizes desialylated glycans with an unclear in vivo role in mediating platelet destruction. In this study, we generated a CLEC4F-deficient mouse model ( Clec4f −/− ) and found that CLEC4F was specifically expressed by Kupffer cells. Using the Clec4f −/− mice and a newly generated platelet-specific reporter mouse line, we revealed a critical role for CLEC4F on Kupffer cells in mediating destruction of desialylated platelets in the liver in vivo. Platelet clearance experiments and ultrastructural analysis revealed that desialylated platelets were phagocytized predominantly by Kupffer cells in a CLEC4F-dependent manner in mice. Collectively, these findings identify CLEC4F as a Kupffer cell receptor important for the destruction of desialylated platelets induced by bacteria-derived neuraminidases, which provide new insights into the pathogenesis of thrombocytopenia in disease conditions such as sepsis.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by defective intestinal barrier integrity toward the microbiota and epithelial damage. Double cortin-like kinase 1 (Dclk1), a marker of intestinal tuft cells, can regulate tissue regenerative responses, but its role in epithelial repair during bacterial-dependent chronic colitis is unclear. We addressed this question using our recently developed mouse model of spontaneous microbiota-dependent colitis induced by mucin-type O-glycan deficiency (DKO), which recapitulates most features of human UC. We generated DKO mice lacking intestinal epithelial Dclk1 (DKO;Dclk1ΔIEC) and analyzed colitis onset and severity using clinical and histologic indices, immune responses by qPCR and immunostaining, and epithelial responses using proliferation markers and organoid culture. We found 3–4-week-old DKO;Dclk1ΔIEC mice developed worsened spontaneous colitis characterized by reduced body weight, loose stool, severe colon thickening, epithelial lesions, and inflammatory cell infiltrates compared with DKO mice. The primary defect was an impaired epithelial proliferative response during inflammation. Dclk1 deficiency also reduced inflammation-induced proliferation and growth of colon organoids ex vivo. Mechanistically, Dclk1 expression was important for inflammation-induced Cox2 expression and prostaglandin E2 (PGE2) production in vivo, and PGE2 rescued proliferative defects in Dclk1-deficient colonic organoids. Although tuft cells were expanded in both DKO and DKO;Dclk1ΔIEC relative to WT mice, loss of Dclk1 was associated with reduced tuft cell activation (i.e., proliferation) during inflammation. Similar results were found in DKO vs. DKO;Dclk1ΔIEC mice at 3–6 months of age. Our results support that tuft cells, via Dclk1, are important responders to bacterial-induced colitis by enhancing epithelial repair responses, which in turn limits bacterial infiltration into the mucosa.

Most platelet membrane proteins are modified by mucin-type core 1-derived glycans (O-glycans). However, the biological importance of O-glycans in platelet clearance is unclear. Here, we generated mice with a hematopoietic cell-specific loss of O-glycans (HC C1galt1 −/−). These mice lack O-glycans on platelets and exhibit reduced peripheral platelet numbers. Platelets from HC C1galt1 −/− mice show reduced levels of α-2,3-linked sialic acids and increased accumulation in the liver relative to wild-type platelets. The preferential accumulation of HC C1galt1 −/− platelets in the liver was reduced in mice lacking the hepatic asialoglycoprotein receptor [Ashwell–Morell receptor (AMR)]. However, we found that Kupffer cells are the primary cells phagocytosing HC C1galt1 −/− platelets in the liver. Our results demonstrate that hepatic AMR promotes preferential adherence to and phagocytosis of desialylated and/or HC C1galt1 −/− platelets by the Kupffer cell through its C-type lectin receptor CLEC4F. These findings provide insights into an essential role for core 1 O-glycosylation of platelets in their clearance in the liver.

Lymph nodes expand after an inflammatory challenge to accommodate their increased cellularity. Turley and colleagues show that fibroblastic reticular cells regulate this expansion process through the interaction of podoplanin with its receptor CLEC-2 expressed on incoming dendritic cells. In lymph nodes, fibroblastic reticular cells (FRCs) form a collagen-based reticular network that supports migratory dendritic cells (DCs) and T cells and transports lymph. A hallmark of FRCs is their propensity to contract collagen, yet this function is poorly understood. Here we demonstrate that podoplanin (PDPN) regulates actomyosin contractility in FRCs. Under resting conditions, when FRCs are unlikely to encounter mature DCs expressing the PDPN receptor CLEC-2, PDPN endowed FRCs with contractile function and exerted tension within the reticulum. Upon inflammation, CLEC-2 on mature DCs potently attenuated PDPN-mediated contractility, which resulted in FRC relaxation and reduced tissue stiffness. Disrupting PDPN function altered the homeostasis and spacing of FRCs and T cells, which resulted in an expanded reticular network and enhanced immunity.

High-dimensional entanglement is significant for the fundamental studies of quantum physics and offers unique advantages in various quantum information processing tasks. Integrated quantum devices have recently emerged as a promising platform for creating, processing, and detecting complex high-dimensional entangled states. A crucial step toward practical quantum technologies is to verify that these devices work reliably with an optimal strategy. In this work, we experimentally implement an optimal quantum verification strategy on a three-dimensional maximally entangled state using local projective measurements on a silicon photonic chip. A 95% confidence is achieved from 1190 copies to verify the target quantum state. The obtained scaling of infidelity as a function of the number of copies is −0.5497 ± 0.0002, exceeding the standard quantum limit of −0.5 with 248 standard deviations. Our results indicate that quantum state verification could serve as an efficient tool for complex quantum measurement tasks.

Cosmc is a molecular chaperone thought to be required for expression of active T-synthase, the only enzyme that galactosylates the Tn antigen (GalNAcα1-Ser/Thr-R) to form core 1 Galβ1–3GalNAcα1-Ser/Thr (T antigen) during mucin type O-glycan biosynthesis. Here we show that ablation of the X-linked Cosmc gene in mice causes embryonic lethality and Tn antigen expression. Loss of Cosmc is associated with loss of T-synthase but not other enzymes required for glycoprotein biosynthesis, demonstrating that Cosmc is specific in vivo for the T-synthase. We generated genetically mosaic mice with a targeted Cosmc deletion and survivors exhibited abnormalities correlated with Tn antigen expression that are related to several human diseases.

Cigarette smoking raises the risk for cardiovascular disease, including the risk for abdominal aortic aneurysm. Shuangxi Wang et al . now show that nicotine itself is a causal factor in promoting abdominal aortic aneurysms in mice and delineate a pathogenic mechanism by which nicotine exposure leads to activation of the enzyme AMP-kinase in vascular smooth muscle cells and increased expression of the metallopeptidase MMP2. Smoking is the only modifiable risk factor that is associated with the development, expansion and rupture of abdominal aortic aneurysm (AAA). However, the causative link between cigarette smoke and AAA is unknown. Here we report a causative link between smoking and AAA in vivo . Acute infusion of angiotensin II (AngII) or nicotine, a major component of cigarette smoke, markedly increased the incidence of AAA in apolipoprotein E (apoE) knockout ( Apoe −/− ) mice and in mice deficient in both apoE and the AMP-activated kinase α1 subunit (AMPK-α1) ( Apoe −/− ; Prkaa1 −/− mice). In contrast, genetic deletion of AMPK-α2 ( Apoe −/− ; Prkaa2 −/− mice) ablated nicotine- or AngII-triggered AAA in vivo . Mechanistically, we found that both nicotine and AngII activated AMPK-α2 in cultured vascular smooth muscle cells (VSMCs), resulting in the phosphorylation of activator protein 2α (AP-2α) and consequent matrix metallopeptidase 2 (MMP2) gene expression. We conclude that smoking (through nicotine) instigates AAA through AMPK-α2–mediated AP-2α–dependent MMP2 expression in VSMCs.

Chronic kidney disease (CKD) is associated with cognitive impairment in older adults. Mitochondrial dysfunction (MD) is a key contributor to aging-related diseases, yet its potential role in mediating the relationship between renal function and cognitive function (CF) remains unclear. Therefore, we aimed to examine this association in older adults and to evaluate the mediating effect of MD. Our study analyzed data from the 2011-2014 National Health and Nutrition Examination Survey, including participants aged ≥60. CF was assessed using the Animal Fluency Test (AFT), the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word Learning Test, and the Digit Symbol Substitution Test (DSST). Multivariate linear regression models were used to explore the relationships between renal function and CF, CKD, and methylmalonic acid (MMA) levels, and CF. Mediation analysis was conducted to assess the role of MD, as reflected by serum MMA levels, in the link between renal function and cognitive impairment. A total of 2,437 participants aged ≥60 were included. Regression analysis showed a significant positive association between renal function and CF (β = 0.018, 95%CI: 0.013-0.024,  < 0.001). After adjusting for potential confounders, MMA levels mediated 13.33% of the relationship between renal function and CF. The indirect effect of renal function on CF MMA was significant (β = 0.000949, 95%CI: 0.000419-0.002463,  = 0.002), as was the direct effect (β = 0.006165, 95%CI: 0.000271-0.010456,  = 0.034). This study identifies a potential link between CKD and CF in older US adults. MD, assessed by serum MMA levels, may partially mediate this relationship, with MMA potentially serving as a biomarker for cognitive impairment.

Quantum devices for generating entangled states have been extensively studied and widely used. As so, it becomes necessary to verify that these devices truly work reliably and efficiently as they are specified. Here we experimentally realize the recently proposed two-qubit entangled state verification strategies using both local measurements (nonadaptive) and active feed-forward operations (adaptive) with a photonic platform. About 3283/536 number of copies (N) are required to achieve a 99% confidence to verify the target quantum state for nonadaptive/adaptive strategies. These optimal strategies provide the Heisenberg scaling of the infidelity ϵ as a function of N (ϵ~Nr) with the parameter r = −1, exceeding the standard quantum limit with r = −0.5. We experimentally obtain the scaling parameters of r = −0.88 ± 0.03 and −0.78 ± 0.07 for nonadaptive and adaptive strategies, respectively. Our experimental work could serve as a standardized procedure for the verification of quantum states.

Lymphangiogenesis plays a pivotal role in diverse pathological conditions. Here, we demonstrate that a carbohydrate-binding protein, galectin-8, promotes pathological lymphangiogenesis. Galectin-8 is markedly upregulated in inflamed human and mouse corneas, and galectin-8 inhibitors reduce inflammatory lymphangiogenesis. In the mouse model of corneal allogeneic transplantation, galectin-8-induced lymphangiogenesis is associated with an increased rate of corneal graft rejection. Further, in the murine model of herpes simplex virus keratitis, corneal pathology and lymphangiogenesis are ameliorated in Lgals8 −/− mice. Mechanistically, VEGF-C-induced lymphangiogenesis is significantly reduced in the Lgals8 −/− and Pdpn −/− mice; likewise, galectin-8-induced lymphangiogenesis is reduced in Pdpn −/− mice. Interestingly, knockdown of VEGFR-3 does not affect galectin-8-mediated lymphatic endothelial cell (LEC) sprouting. Instead, inhibiting integrins α1β1 and α5β1 curtails both galectin-8- and VEGF-C-mediated LEC sprouting. Together, this study uncovers a unique molecular mechanism of lymphangiogenesis in which galectin-8-dependent crosstalk among VEGF-C, podoplanin and integrin pathways plays a key role. Pathological lymphangiogenesis is associated with various eye diseases. Here the authors show that a carbohydrate-binding protein, galectin-8, promotes pathological lymphangiogenesis in the eye by regulating the crosstalk among VEGF-C, podoplanin and integrin pathways, and thus may represent a useful therapeutic target.