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;Dclk1
) 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;Dclk1
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;Dclk1
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;Dclk1
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.
The relationship between brain volume and intelligence has been a topic of a scientific debate since at least the 1830s. To address the debate, a meta-analysis of the relationship between in vivo ...brain volume and intelligence was conducted. Based on 37 samples across 1530 people, the population correlation was estimated at 0.33. The correlation is higher for females than males. It is also higher for adults than children. For all age and sex groups, it is clear that brain volume is positively correlated with intelligence.
The trustworthiness of research findings has been questioned in many domains of science. This article calls for a review of the trustworthiness of the scientific literature in ...industrial–organizational (I–O) psychology and a reconsideration of common practices that may harm the credibility of our literature. We note that most hypotheses in I–O psychology journals are confirmed. Thus, we are either approaching omniscience or our journals are publishing an unrepresentative sample of completed research. We view the latter explanation as more likely. We review structural problems in the publication process and in the conduct of research that is likely to promote a distortion of scientific knowledge. We then offer recommendations to make the I–O literature more accurate and trustworthy.
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.
Lymphomas originate in and spread primarily along the lymphatic system. However, whether lymphatic vessels contribute to the growth and spreading of lymphomas is largely unclear. Mantle cell lymphoma ...(MCL) represents an aggressive non-Hodgkin's lymphoma. We found that MCL exhibited abundant intratumor lymphatic vessels. Our results demonstrated that the immunomodulatory drug lenalidomide potently inhibited the growth and dissemination of MCL in a xenograft MCL mouse model, at least in part, by inhibiting functional tumor lymphangiogenesis. Significant numbers of tumor-associated macrophages expressing vascular endothelial growth factor-C were found in both human MCL and mouse MCL xenograft samples. Lenalidomide treatment resulted in a significant reduction in the number of MCL-associated macrophages. In addition, in vivo depletion of monocytes/macrophages impaired functional tumor lymphangiogenesis and inhibited MCL growth and dissemination. Taken together, our results indicate that tumor lymphangiogenesis contributes to the progression of MCL and that lenalidomide is effective in decreasing MCL growth and metastasis most likely by inhibiting recruitment of MCL-associated macrophages.
Background Multiple scoring systems have been devised to quantify angiographic coronary artery disease (CAD) burden, but it is unclear how these scores relate to each other and which scores are most ...accurate. The aim of this study was to compare coronary angiographic scoring systems (1) with each other and (2) with intravascular ultrasound (IVUS)–derived plaque burden in a population undergoing angiographic evaluation for CAD. Methods Coronary angiographic data from 3600 patients were scored using 10 commonly used angiographic scoring systems and interscore correlations were calculated. In a subset of 50 patients, plaque burden and plaque area in the left anterior descending coronary artery were quantified using IVUS and correlated with angiographic scores. Results All angiographic scores correlated with each other (range for Spearman coefficient ρ 0.79-0.98, P < .0001); the 2 most widely used scores, Gensini and CASS-70, had a ρ = 0.90 ( P < .0001). All scores correlated significantly with average plaque burden and plaque area by IVUS (range ρ 0.56-0.78, P < .0001 and 0.43-0.62, P < .01, respectively). The CASS-50 score had the strongest correlation ( ρ 0.78 and 0.62, P < .0001) and the Duke Jeopardy score the weakest correlation ( ρ 0.56 and 0.43, P < .01) with plaque burden and area, respectively. Conclusions Angiographic scoring systems are strongly correlated with each other and with atherosclerotic plaque burden. Scoring systems therefore appear to be a valid estimate of CAD plaque burden.
Background & Aims Core 1– and core 3–derived mucin-type O-linked oligosaccharides (O-glycans) are major components of the colonic mucus layer. Defective forms of colonic O-glycans, such as Tn ...antigen, frequently are observed in patients with ulcerative colitis and colorectal cancer, but it is not clear if they contribute to pathogenesis. We investigated whether and how impaired O-glycosylation contributes to the development of colitis-associated colorectal cancer using mice lacking intestinal core 1– and core 3–derived O -glycans. Methods We generated mice that lack the core 1– and core 3–derived intestinal O-glycans (DKO mice) and analyzed them, along with mice that lack the intestinal epithelial core 1 O-glycans (IEC C1galt1 - /- mice) or mice that lack core 3 O-glycans (C3 Gnt-/- mice). Intestinal tissues were collected at different time points and analyzed for levels of mucin and Tn antigen, development of colitis, and tumor formation using imaging, quantitative polymerase chain reaction, immunoblot, and enzyme-linked immunosorbent assay techniques. We also used cellular and genetic approaches, as well as intestinal microbiota depletion, to identify inflammatory mediators and pathways that contribute to disease in DKO and wild-type littermates (controls). Results Intestinal tissues from DKO mice contained higher levels of Tn antigen and had more severe spontaneous chronic colitis than tissues from intestinal epithelial cell (IEC) C1galt1 - /- mice, whereas spontaneous colitis was absent in C3GnT - /- and control mice. IEC C1galt1 - /- mice and DKO mice developed spontaneous colorectal tumors, although the onset of tumors in the DKO mice occurred earlier (age, 8–9 mo) than that in IEC C1galt1 -/- mice (approximately age 12 months). Antibiotic depletion of the microbiota did not cause loss of Tn antigen but did reduce the development of colitis and cancer formation in DKO mice. Colon tissues from DKO mice, but not control mice, contained active forms of caspase 1 and increased caspase 11, which were reduced after antibiotic administration. Supernatants from colon tissues of DKO mice contained increased levels of interleukin-1β and interleukin-18, compared with those from control mice. Disruption of the caspase 1 and caspase 11 genes in DKO mice (DKO/ Casp 1/11 - /- mice) decreased the development of colitis, characterized by reduced colonic thickening, hyperplasia, and inflammatory infiltrate, compared with DKO mice. Conclusions Impaired expression of O-glycans causes colonic mucus barrier breach and subsequent microbiota-mediated activation of caspase 1–dependent inflammasomes in colonic epithelial cells of mice. These processes could contribute to colitis-associated colon cancer in human beings.
Obesity-induced diabetes is characterized by hyperglycemia, insulin resistance, and progressive beta cell failure. In islets of mice with obesity-induced diabetes, we observe increased beta cell ...death and impaired autophagic flux. We hypothesized that intermittent fasting, a clinically sustainable therapeutic strategy, stimulates autophagic flux to ameliorate obesity-induced diabetes. Our data show that despite continued high-fat intake, intermittent fasting restores autophagic flux in islets and improves glucose tolerance by enhancing glucose-stimulated insulin secretion, beta cell survival, and nuclear expression of NEUROG3, a marker of pancreatic regeneration. In contrast, intermittent fasting does not rescue beta-cell death or induce NEUROG3 expression in obese mice with lysosomal dysfunction secondary to deficiency of the lysosomal membrane protein, LAMP2 or haplo-insufficiency of BECN1/Beclin 1, a protein critical for autophagosome formation. Moreover, intermittent fasting is sufficient to provoke beta cell death in nonobese lamp2 null mice, attesting to a critical role for lysosome function in beta cell homeostasis under fasting conditions. Beta cells in intermittently-fasted LAMP2- or BECN1-deficient mice exhibit markers of autophagic failure with accumulation of damaged mitochondria and upregulation of oxidative stress. Thus, intermittent fasting preserves organelle quality via the autophagy-lysosome pathway to enhance beta cell survival and stimulates markers of regeneration in obesity-induced diabetes.
During early embryonic development in mammals, including humans and mice, megakaryocytes (Mks) first originate from primitive hematopoiesis in the yolk sac. These embryonic Mks (eMks) circulate in ...the vasculature with unclear function. Herein, we report that podoplanin (PDPN), the ligand of C-type lectin-like receptor (CLEC-2) on Mks/platelets, is temporarily expressed in neural tissue during midgestation in mice. Loss of PDPN or CLEC-2 resulted in aneurysms and spontaneous hemorrhage, specifically in the lower diencephalon during midgestation. Surprisingly, more eMks/platelets had enhanced granule release and localized to the lower diencephalon in mutant mouse embryos than in wild-type littermates before hemorrhage. We found that PDPN counteracted the collagen-1–induced secretion of angiopoietin-1 from fetal Mks, which coincided with enhanced TIE-2 activation in aneurysm-like sprouts of PDPN-deficient embryos. Blocking platelet activation prevented the PDPN-deficient embryo from developing vascular defects. Our data reveal a new role for PDPN in regulating eMk function during midgestation.
•Heightened activation of eMks/platelets cause formation of aneurysms in developing brains of mice lacking PDPN.•PDPN lessens collagen-1–induced secretion of angiopoietin-1 from eMks, preventing detrimental TIE-2 activation in sprouting endothelium.
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Mucin-type O-linked oligosaccharides (O-glycans) are primary components of the intestinal mucins that form the mucus gel layer overlying the gut epithelium. Impaired expression of intestinal ...O-glycans has been observed in patients with ulcerative colitis (UC), but its role in the etiology of this disease is unknown. Here, we report that mice with intestinal epithelial cell-specific deficiency of core 1-derived O-glycans, the predominant form of O-glycans, developed spontaneous colitis that resembled human UC, including massive myeloid infiltrates and crypt abscesses. The colitis manifested in these mice was also characterized by TNF-producing myeloid infiltrates in colon mucosa in the absence of lymphocytes, supporting an essential role for myeloid cells in colitis initiation. Furthermore, induced deletion of intestinal core 1-derived O-glycans caused spontaneous colitis in adult mice. These data indicate a causal role for the loss of core 1-derived O-glycans in colitis. Finally, we detected a biosynthetic intermediate typically exposed in the absence of core 1 O-glycan, Tn antigen, in the colon epithelium of a subset of UC patients. Somatic mutations in the X-linked gene that encodes core 1 β1,3-galactosyltransferase-specific chaperone 1 (C1GALT1C1, also known as Cosmc), which is essential for core 1 O-glycosylation, were found in Tn-positive epithelia. These data suggest what we believe to be a new molecular mechanism for the pathogenesis of UC.
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