Linkage disequilibrium between the four most common cystic fibrosis mutations and microsatellite haplotypes in the Celtic population of Brittany

Microsatellite haplotypes were determined for 117 chromosomes carrying the four most frequent mutations in the cystic fibrosis (CF) gene identified in the Breton population of Celtic origin, as well as for 83 normal chromosomes (noncarriers of a CF mutation). Each of the three non-Delta F508 mutations was associated with a single haplotype: 1078delT with 16-31-13, G551D with 16-7-17, and W846X with 16-32-13. Although these results suggest identity-by-descent for each mutation, recurrent mutations, although unlikely, could not be completely ruled out. The four most frequent haplotypes on normal chromosomes and the three most frequent haplotypes on Delta F508 chromosomes are the same as those found in Ireland, Spain, and Italy. This suggests that some haplotypes, associated or not with the Delta F508 mutation, were present in an ancestral population from which all four populations descended

Genealogy and Regional Distribution of Lipoprotein Lipase Deficiency in French-Canadians of Quebec

Lipoprotein lipase (LPL) deficiency, an autosomal recessive disorder causing chylomicronemia, has a high prevalence in the French-Canadian population of Quebec. The molecular basis of LPL deficiency has been defined, and two major mutations have been shown to have an uneven geographic distribution. Two mutations, one at residue 188 (M-188) and the other at residue 207 (M-207), are described here; they account for 95% of the mutant alleles. The carrier rate of M-188 was highest in western Quebec (1/326) but that of M-207 was much higher in the eastern part of the province (1/85). Genealogical reconstruction has revealed that both mutations were introduced to the French-Canadian population by migrants from France in the seventeenth century. M-188 is likely to have a Scottish ancestor, whereas M-207 appears to be of French origin

Sodium/glucose cotransporter-1, sweet receptor, and disaccharidase expression in the intestine of the domestic dog and cat: two species of different dietary habit

The domestic cat (Felis catus), a carnivore, naturally eats a very low carbohydrate diet. In contrast, the dog (Canis familiaris), a carno-omnivore, has a varied diet. This study was performed to determine the expression of the intestinal brush border membrane sodium/glucose cotransporter, SGLT1, sweet receptor, T1R2/T1R3, and disaccharidases in these species adapted to contrasting diets. The expression (this includes function) of SGLT1, sucrase, maltase and lactase were determined using purified brush border membrane vesicles and by quantitative immunohistochemistry of fixed tissues. The pattern of expression of subunits of the sweet receptor T1R2 and T1R3 was assessed using fluorescent immunohistochemistry. In proximal, middle, and distal small intestine, SGLT1 function in dogs was 1.9- to 2.3-fold higher than in cats (P = 0.037, P = 0.0011, P = 0.027, respectively), and SGLT1 protein abundance followed an identical pattern. Both cats and dogs express T1R3 in a subset of intestinal epithelial cells, and dogs, but not cats, express T1R2. In proximal and middle regions, there were 3.1- and 1.6-fold higher lactase (P = 0.006 and P = 0.019), 4.4- and 2.9-fold higher sucrase (both P < 0.0001), and 4.6- and 3.1-fold higher maltase activity (P = 0.0026 and P = 0.0005), respectively, in the intestine of dogs compared with cats. Dogs have a potential higher capacity to digest and absorb carbohydrates than cats. Cats may suffer from carbohydrate malabsorption following ingestion of high-carbohydrate meals. However, dogs have a digestive ability to cope with diets containing significant levels of carbohydrate

Efficacy of CD40 agonists is mediated by distinct cDC subsets and subverted by suppressive macrophages

Agonistic aCD40 therapy has been shown to inhibit cancer progression in only a fraction of patients. Understanding the cancer cell-intrinsic and microenvironmental determinants of aCD40 therapy response is therefore crucial to identify responsive patient populations and to design efficient combinatorial treatments. Here, we show that the therapeutic efficacy of aCD40 in subcutaneous melanoma relies on preexisting, type 1 classical dendritic cell (cDC1)-primed CD8 thorn T cells. However, after administration of aCD40, cDC1s were dispensable for antitumor efficacy. Instead, the abundance of activated cDCs, potentially derived from cDC2 cells, increased and further activated antitumor CD8 thorn T cells. Hence, distinct cDC subsets contributed to the induction of aCD40 responses. In contrast, lung carcinomas, characterized by a high abundance of macrophages, were resistant to aCD40 therapy. Combining aCD40 therapy with macrophage depletion led to tumor growth inhibition only in the presence of strong neoantigens. Accordingly, treatment with immunogenic cell death-inducing chemotherapy sensitized lung tumors to aCD40 therapy in sub-cutaneous and orthotopic settings. These insights into the micro -environmental regulators of response to aCD40 suggest that dif-ferent tumor types would benefit from different combinations of therapies to optimize the clinical application of CD40 agonists.Significance: This work highlights the temporal roles of different dendritic cell subsets in promoting CD8 thorn T-cell-driven responses to CD40 agonist therapy in cancer