By Alu-splice PCR we have trapped two exons and subsequently identified the full length cDNA of a human gene, Intersectin (ITSN), which maps to chromosome 21q22.1 between markers D21S320 and D21S325. The gene has the potential to code for at least two different protein isoforms by alternative splicing (ITSN-L and ITSN-S). Intersectin exists with a high degree of similarity in flies, frogs and mammals, suggesting a conserved role in higher eukaryotes. Analysis of the expression pattern of human and mouse Intersectin detected mRNAs in all adult and foetal tissues tested, with the longer isoform present in brain. In situ hybridisation studies in the developing mouse brain showed ITSN expression in both proliferating and differentiating neurons. The genomic structure of ITSN was determined using the chromosome 21 sequences deposited in the public databases. The protein contains several known motifs which implicate ITSN in clathrin mediated endocytosis and synaptic vesicle recycling. The expression pattern of Intersectin in mouse brain, its presumed function and its overexpression in brains from Down syndrome patients, suggest that Intersectin may contribute in a gene dosage-dependent manner to some of the abnormalities of Down syndrome.

21A variety of cell surface structures, including capsular polysaccharides (CPS), dictate 22interactions between bacteria and their environment including their viruses (bacteriophages). 23Members of the prominent human gut Bacteroidetes characteristically produce several phase-24 variable CPS, but their contributions to bacteriophage interactions are unknown. We used 25 engineered strains of the human symbiont Bacteroides thetaiotaomicron, which differ only in the 26 CPS they express, to isolate bacteriophages from two locations in the United States. Testing each 27 of 71 bacteriophages against a panel of strains that express wild-type phase-variable CPS, one of 28 eight different single CPS, or no CPS at all, revealed that each phage infects only a subset of 29 otherwise isogenic strains. Deletion of infection-permissive CPS from B. thetaiotaomicron was 30 sufficient to abolish infection for several individual bacteriophages, while infection of wild-type 31 B. thetaiotaomicron with either of two different bacteriophages rapidly selected for expression of 32 non-permissive CPS. Surprisingly, acapsular B. thetaiotaomicron also escapes complete killing 33 by these bacteriophages, but surviving bacteria exhibit increased expression of 8 distinct phase-34 variable lipoproteins. When constitutively expressed, one of these lipoproteins promotes 35 resistance to multiple bacteriophages. Finally, both wild-type and acapsular B. thetaiotaomicron 36 were able to separately co-exist with one bacteriophage for over two months in the mouse gut, 37suggesting that phase-variation promotes resistance but also generates sufficient numbers of 38 susceptible revertants to allow bacteriophage persistence. Our results reveal important roles for 39Bacteroides CPS and other cell surface structures that allow these bacteria to persist despite 40 bacteriophage predation and hold important implications for using bacteriophages therapeutically 41 to target gut symbionts. 42 43Bacteroides thetaiotaomicron and Bacteroides fragilis each encode 8 different CPS 14,15 and there 61 is broad genetic diversity of cps loci among different strains within these species (e.g., 47 62 different cps biosynthetic loci were identified in just 14 strains of B. thetaiotaomicron) 8 . In 63Bacteroides, CPS structures appear to surround the entire bacterial cell 16,17 and the cps 64 biosynthetic loci that encode these surface coatings are often under the control of phase variable 65 promoters 8,15,18 . In conjunction with other regulatory mechanisms, phase variable CPS 66 4 expression generates phenotypic heterogeneity within an otherwise isogenic population that may 67 facilitate survival in the face of diverse disturbances 8,15,19,20 . 68 Bacterial viruses or bacteriophages (herein, phages), like the bacteria on which they prey, 69 vary greatly across individual gut microbiomes and are even responsive to host dietary changes 70 and disease states [21][22][23][24][25] . Compared to gut bacteria, far less is understood about the phages of the 71 gut microbi...