Instability in the composition of gut bacterial communities (dysbiosis) has been linked to common human intestinal disorders, such as Crohn's disease and colorectal cancer. Here, we show that dysbiosis caused by Nod2 deficiency gives rise to a reversible, communicable risk of colitis and colitis-associated carcinogenesis in mice. Loss of either Nod2 or RIP2 resulted in a proinflammatory microenvironment that enhanced epithelial dysplasia following chemically induced injury. The condition could be improved by treatment with antibiotics or an anti-interleukin-6 receptor-neutralizing antibody. Genotype-dependent disease risk was communicable via maternally transmitted microbiota in both Nod2-deficient and WT hosts. Furthermore, reciprocal microbiota transplantation reduced disease risk in Nod2-deficient mice and led to long-term changes in intestinal microbial communities. Conversely, disease risk was enhanced in WT hosts that were recolonized with dysbiotic fecal microbiota from Nod2-deficient mice. Thus, we demonstrated that licensing of dysbiotic microbiota is a critical component of disease risk. Our results demonstrate that NOD2 has an unexpected role in shaping a protective assembly of gut bacterial communities and suggest that manipulation of dysbiosis is a potential therapeutic approach in the treatment of human intestinal disorders.

The colonic epithelium self-renews every 3 to 5 d, but our understanding of the underlying processes preserving wound healing from carcinogenesis remains incomplete. Here, we demonstrate that Nod-like receptor pyrin domain-containing protein 6 (NLRP6) suppresses inflammation and carcinogenesis by regulating tissue repair. NLRP6 was primarily produced by myofibroblasts within the stem-cell niche in the colon. Although NLRP6 expression was lowered in diseased colon, NLRP6-deficient mice were highly susceptible to experimental colitis. Upon injury, NLRP6 deficiency deregulated regeneration of the colonic mucosa and processes of epithelial proliferation and migration. Consistently, absence of NLRP6 accelerated colitis-associated tumor growth in mice. A gene-ontology analysis on a whole-genome expression profiling revealed a link between NLRP6 and self-renewal of the epithelium. Collectively, the integrity of the epithelial barrier is preserved by NLRP6 that may be manipulated to develop drugs capable of preventing adenoma formation in inflammatory bowel diseases.colonic myofibroblasts | colorectal cancer

Under stressful environments, many green algae such as Haematococcus pluvialis accumulate secondary ketocarotenoids such as canthaxanthin and astaxanthin. The carotenogenesis, responsible for natural phenomena such as red snows, generally accompanies larger metabolic changes as well as morphological modifications, i.e., the conversion of the green flagellated macrozoids into large red cysts. Astaxanthin accumulation constitutes a convenient way to store energy and carbon, which will be used for further synthesis under less stressful conditions. Besides this, the presence of high amount of astaxanthin enhances the cell resistance to oxidative stress generated by unfavorable environmental conditions including excess light, UV-B irradiation, and nutrition stress and, therefore, confers a higher survival capacity to the cells. This better resistance results from the quenching of oxygen atoms for the synthesis itself as well as from the antioxidant properties of the astaxanthin molecules. Therefore, astaxanthin synthesis corresponds to a multifunctional response to stress. In this contribution, the various biochemical, genetic, and molecular data related to the biosynthesis of ketocarotenoids by Haematococcus pluvialis and other taxa are reviewed and compared. A tentative regulatory model of the biochemical network driving astaxanthin production is proposed.

The only recognized genetic determinant of the common forms of Alzheimer's disease (AD) is the e4 allele of the apolipoprotein E gene (APOE). To identify new candidate genes, we recently performed transcriptomic analysis of 2741 genes in chromosomal regions of interest using brain tissue of AD cases and controls. From 82 differentially expressed genes, 1156 polymorphisms were genotyped in two independent discovery subsamples (n = 945). Seventeen genes exhibited at least one polymorphism associated with AD risk, and following correction for multiple testing, we retained the interleukin (IL)-33 gene. We first confirmed that the IL-33 expression was decreased in the brain of AD cases compared with that of controls. Further genetic analysis led us to select three polymorphisms within this gene, which we analyzed in three independent case-control studies. These polymorphisms and a resulting protective haplotype were systematically associated with AD risk in non-APOE e4 carriers. Using a large prospective study, these associations were also detected when analyzing the prevalent and incident AD cases together or the incident AD cases alone. These polymorphisms were also associated with less cerebral amyloid angiopathy (CAA) in the brain of non-APOE e4 AD cases. Immunohistochemistry experiments finally indicated that the IL-33 expression was consistently restricted to vascular capillaries in the brain. Moreover, IL-33 overexpression in cellular models led to a specific decrease in secretion of the Ab 40 peptides, the main CAA component. In conclusion, our data suggest that genetic variants in IL-33 gene may be associated with a decrease in AD risk potentially in modulating CAA formation.

Highly purified preparations of cytochrome b 6 f complex from the unicellar freshwater alga Chlamydomonas reinhardtii contain about 1 molecule of chlorophyll a/ cytochrome f. Several lines of evidence indicate that the chlorophyll is an authentic component of the complex rather than a contaminant. In particular, (i) the stoichiometry is constant; (ii) the chlorophyll is associated with the complex at a specific binding site, as evidenced by resonance Raman spectroscopy; (iii) it does not originate from free chlorophyll released from thylakoid membranes upon solubilization; and (iv) its rate of exchange with free, radioactive chlorophyll a is extremely slow (weeks

Multiple or pleiotropic drug resistance in the yeastIn this study, we demonstrate that relief of estradiol toxicity in yeast cells expressing VEO requires functional PDR5 and SNQ2 genes, since a ⌬pdr5 ⌬snq2 double deletion leads to an increased estradiol toxicity. Furthermore, using URA3 as an estradiol-inducible reporter gene, we show that Pdr5 and Snq2, when overexpressed from high-copy plasmids, can reduce the intracellular concentration of estradiol. In contrast, a ⌬pdr5 ⌬snq2 double deletion mutant accumulates almost 30-fold more intracellular estradiol than the isogenic wild type. Indirect immunofluorescence showed that a pdr1-3 mutant massively overexpresses Pdr5 at the plasma membrane, suggesting that estradiol efflux from the cells occurs across the plasma membrane. Our data demonstrate that Pdr5 and Snq2 can transport steroid substrates in vivo and suggest that steroids and/or related membrane lipids could represent physiological substrates for certain yeast ABC transporters, which are otherwise involved in the development of pleiotropic drug resistance. Pleiotropic drug resistance (PDR)1 in yeast is a well documented phenomenon that appears quite similar to P-glycoprotein (Pgp or Mdr1) and MRP-mediated multidrug resistance in mammalian cells (1, 2). For example, two homologous yeast ABC transporter genes, PDR5 (3, 4) and SNQ2 (5), were recently shown to represent functional and structural homologues of mammalian Mdr1 and MRP (6), since their overexpression in yeast is associated with PDR development. Elevated levels of Pdr5 and Snq2 lead to resistance against a variety of structurally unrelated cytotoxic compounds including mycotoxins (3), cycloheximide (7), 4-nitroquinoline N-oxide and sulfomethuron methyl (5). However, each transporter mediates resistance to only a distinct subset of drugs, and there is very little overlap in the substrate specificity of Pdr5 and Snq2 (3,8).Transcription of both PDR5 and SNQ2 is controlled by the transcription regulatory proteins Pdr1 and Pdr3 (4, 9, 10). Loss-of-function mutations such as ⌬pdr1 and ⌬pdr3 deletions result in a dramatic decrease of Pdr5 and Snq2 expression (11) and cause a marked drug hypersensitivity. In turn, several gain-of-function alleles of pdr1 and pdr3 have been isolated by their ability to confer a pleiotropic drug resistance phenotype (12, 13). In such drug-resistant pdr mutants, expression of the drug efflux pumps Pdr5 and Snq2 is dramatically increased (11), and it has been shown that pdr1-mediated cycloheximide resistance requires the presence of functional PDR5 (14).Notably, another pdr1 mutant allele was previously cloned as a suppressor of the estradiol-induced squelching phenomenon caused by a VP16-estrogen receptor fusion protein (VEO) expressed in yeast (15). Induction by estradiol of such a chimeric protein, which has the hormone-binding and the DNAbinding domain of the human estrogen receptor fused to the acidic activation domain of the viral protein VP16, leads to a toxic transcriptional transactivation known as transcriptional...

Synechococcus spp. constitute a major and ubiquitous component of marine ecosystems. The genome of one strain of this genus, WH8102, has recently been completely sequenced. Since it can also be genetically manipulated, this clone has the potential to become a new model organism; however, to date, it remains poorly characterised in terms of pigment composition, optical properties and photophysiology. It has a very high phycourobilin to phycoerythrobilin (PUB:PEB) ratio (ca. 1.95 at low light), and is therefore representative of Synechococcus populations found in oligotrophic areas of the ocean. We show here that this strain has a very wide growth irradiance range from <15 to > 650 µmol photons m -2 s -1 continuous white light, with a maximum growth rate (µ max = 1.13 ± 0.02 d -1 ) at 207 µmol quanta m -2 s -1 (I max ). As cells acclimated to high light, drastic variations in the chlorophyll a (chl a), β-carotene and phycoerythrin (PE) contents were observed, reaching a quasi steady state around I max . In contrast, the zeaxanthin content remained approximately constant whatever the light level. Similarly, the carbon and nitrogen contents did not significantly vary with irradiance. Red and orange fluorescences, as measured by flow cytometry, were found to correlate well with chl a and PE contents, respectively. Spectrometric analyses of phycobilisome (PBS)-containing fractions from cells grown under different photon fluxes suggest a specific reduction of the PEII content relative to other phycobiliproteins (PBPs) during acclimation of the PBSs to high light.

No abstract