Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Patientenorientierte Versorgung chronisch Kranker

Schaeffer D, Müller-Mundt G. Patientenorientierte Versorgung chronisch Kranker. In: Pfaff H, Schrappe M, Lauterbach KW, Engelmann U, Halber M, eds. Gesundheitsversorgung und Disease-Management. Grundlagen und Anwendungen der Versorgungsforschung. Bern, Göttingen, Toronto, Seattle: Huber; 2003: 143-148

CYBB/NOX2 in conventional DCs controls T cell encephalitogenicity during neuroinflammation

Whereas central nervous system (CNS) homeostasis is highly dependent on tissue surveillance by immune cells, dysregulated entry of leukocytes during autoimmune neuroinflammation causes severe immunopathology and neurological deficits. To invade the CNS parenchyma, encephalitogenic T helper (TH) cells must encounter their cognate antigen(s) presented by local major histocompatibility complex (MHC) class II-expressing antigen-presenting cells (APCs). The precise mechanisms by which CNS-associated APCs facilitate autoimmune T cell reactivation remain largely unknown. We previously showed that mice with conditional deletion of the gene encoding the essential autophagy protein ATG5 in dendritic cells (DCs) are resistant to EAE development. Here, we report that the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2, also known as CYBB/NOX2, in conventional DCs (cDCs) regulates endocytosed MOG (myelin oligodendrocyte protein) antigen processing and supports MOG-antigen presentation to CD4+ T cells through LC3-associated phagocytosis (LAP). Genetic ablation of Cybb in cDCs is sufficient to restrain encephalitogenic TH cell recruitment into the CNS and to ameliorate clinical disease development upon the adoptive transfer of MOG-specific CD4+ T cells. These data indicate that CYBB-regulated MOG-antigen processing and LAP in cDCs licenses encephalitogenic TH cells to initiate and sustain autoimmune neuroinflammation. Abbreviations: Ag: antigen; APC: antigen-presenting cell; AT: adoptive transfer; ATG/Atg: autophagy-related; BAMs: border-associated macrophages; BMDC: bone marrow-derived DC; CD: cluster of differentiation; CNS: central nervous system; CSF2/GM-CSF: colony stimulating factor 2 (granulocyte-macrophage); CYBB/NOX2/gp91phox: cytochrome b-245, beta polypeptide; DC: dendritic cell; EAE: experimental autoimmune encephalomyelitis; fl: floxed; FOXP3: forkhead box P3; GFP: green fluorescent protein; H2-Ab: histocompatibility 2, class II antigen A, beta 1; IFN: interferon; IL: interleukin; ITGAX/CD11c: integrin subunit alpha X; LAP: LC3-associated phagocytosis; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MFI: median fluorescence intensity; MG: microglia; MHCII: major histocompatibility complex class II; MOG: myelin oligodendrocyte glycoprotein; MS: multiple sclerosis; NADPH: nicotinamide adenine dinucleotide phosphate; ODC: oligodendroglial cell; OVA: ovalbumin; pDC: plasmacytoid DC; Ptd-L-Ser: phosphatidylserine; PTPRC: protein tyrosine phosphatase, receptor type, C; ROS: reactive oxygen species; SLE: systemic lupus erythematosus; TH cells: T helper cells; TLR: toll-like receptor; ZBTB46: zinc finger and BTB domain containing 46. Keywords: Antigen presentation; CYBB/NOX2; LC3-associated phagocytosis; autophagy; dendritic cells; experimental autoimmune encephalomyelitis; multiple sclerosis

Fecal immunochemical testing results and characteristics of colonic lesions

Fecal immunochemical tests (FIT) are used to detect blood in feces, which might indicate the presence of colorectal neoplasia. The aim of this study was to investigate whether FIT results vary depending on the characteristics of colonic lesions. This was a retrospective analysis of lesions detected in a cohort of asymptomatic individuals (aged 50 - 75 years) who were invited to participate in a FIT-based screening pilot in The Netherlands. The mean FIT result was compared across subgroups of individuals defined by histopathology of the most advanced lesion detected. In addition, the results were compared with data from a primary colonoscopy screening trial, in which participants also completed a FIT. In three rounds of FIT-based screening, a total of 877 FIT-positive individuals underwent colonoscopy. Higher mean FIT results (hemoglobin [Hb]/g feces) were observed in individuals with carcinomas (199 μg Hb/g) and advanced adenomas (87 μg Hb/g) compared with participants with nonadvanced adenomas (50 μg Hb/g) or those with serrated lesions (46 μg Hb/g) (P  < 0.001). In the primary colonoscopy trial, 1256 participants completed a FIT test and underwent colonoscopy. The number of participants with nonadvanced adenomas as the most advanced lesion was comparable between this group and the FIT-based screening group (20 % vs. 22 %). In FIT-based screening, the mean FIT results varied depending on the characteristics of the most advanced colonic lesion. The proportion of participants with a nonadvanced adenoma as the most advanced lesion was similar in the FIT-based screening group and in the primary colonoscopy screening group, suggesting that these lesions are coincidental findings rather than FIT-detected findings. www.trialregister.nl number NTR275