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Keywords: Life Sciences
(Complete Item Description)
- Abstract: Background
MUC2 mucin produced by intestinal goblet cells is the major component of the intestinal mucus barrier. The inflammatory bowel disease ulcerative colitis is characterized by depleted goblet cells and a reduced mucus layer, but the aetiology remains obscure. In this study we used random mutagenesis to produce two murine models of inflammatory bowel disease, characterized the basis and nature of the inflammation in these mice, and compared the pathology with human ulcerative colitis.
Methods and Findings
By murine N-ethyl-N-nitrosourea mutagenesis we identified two distinct noncomplementing missense mutations in Muc2 causing an ulcerative colitis-like phenotype. 100% of mice of both strains developed mild spontaneous distal intestinal inflammation by 6 wk (histological colitis scores versus wild-type mice, p , 0.01) and chronic diarrhea Monitoring over 300 mice of each strain demonstrated that 25% and 40% of each strain, respectively, developed severe clinical signs of colitis by age 1 y. Mutant mice showed aberrant Muc2 biosynthesis, less stored mucin in goblet cells, a diminished mucus barrier, and increased susceptibility to colitis induced by a luminal toxin. Enhanced local production of IL-1b, TNF-a, and IFN-c was seen in the distal colon, and intestinal permeability increased 2-fold. The number of leukocytes within mesenteric lymph nodes increased 5-fold and leukocytes cultured in vitro produced more Th1 and Th2 cytokines (IFN-c, TNF-a, and IL-13). This pathology was accompanied by accumulation of the Muc2 precursor and ultrastructural and biochemical evidence of endoplasmic reticulum (ER) stress in goblet cells, activation of the unfolded protein response, and altered intestinal expression of genes involved in ER stress, inflammation, apoptosis, and wound repair. Expression of mutated Muc2 oligomerisation domains in vitro demonstrated that aberrant Muc2 oligomerisation underlies the ER stress. In human ulcerative colitis we demonstrate similar accumulation of nonglycosylated MUC2 precursor in goblet cells together with ultrastructural and biochemical evidence of ER stress even in noninflamed intestinal tissue. Although our study demonstrates that mucin misfolding and ER stress initiate colitis in mice, it does not ascertain the genetic or environmental drivers of ER stress in human colitis.
Conclusions
Characterization of the mouse models we created and comparison with human disease suggest that ER stress-related mucin depletion could be a fundamental component of the pathogenesis of human colitis and that clinical studies combining genetics, ER stress-related pathology and relevant environmental epidemiology are warranted.
- Subject:
Science and Technology
- Grade Level:
Post-secondary
- Collection:
SciVee
(Complete Item Description)
- Abstract: Projects to facilitate collaboration between biologists and computer scientists. Lecture from the Women in Bioinformatics series. Fran Lewitter, Ph.D. Director of the Bioinformatics and Research Computing Department, Whitehead Institute, MIT
- Subject:
Science and Technology
- Grade Level:
Post-secondary
- Collection:
SciVee
(Complete Item Description)
- Abstract: Plants and animals that live in water create some amount of acid in the water. The carbon dioxide that plants and animals release into the water makes the water acidic and unsafe for living organisms. This is why the water of captive aquatic animals and plants must be changed often.
(Complete Item Description)
- Abstract: The information presented in each ActionBioscience.org article has been correlated to the U.S. National Science Education Standards (NSES). Articles may be listed below in more than one category of the standards and educators may determine other curricular applications for the articles.
- Subject:
Science and Technology
- Grade Level:
Primary, Secondary
- Collection:
Action Bioscience
(Complete Item Description)
- Abstract: CD8+ cytotoxic T-lymphocytes (CTLs) perform a critical role in the immune control of viral infections, including those caused by human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV). As a result, genetic variation at CTL epitopes is strongly influenced by host-specific selection for either escape from the immune response, or reversion due to the replicative costs of escape mutations in the absence of CTL recognition. Under strong CTL-mediated selection, codon positions within epitopes may immediately “toggle” in response to each host, such that genetic variation in the circulating virus population is shaped by rapid adaptation to immune variation in the host population. However, this hypothesis neglects the substantial genetic variation that accumulates in virus populations within hosts. Here, we evaluate this quantity for a large number of HIV-1– (n ≥ 3,000) and HCV-infected patients (n ≥ 2,600) by screening bulk RT-PCR sequences for sequencing “mixtures” (i.e., ambiguous nucleotides), which act as site-specific markers of genetic variation within each host. We find that nonsynonymous mixtures are abundant and significantly associated with codon positions under host-specific CTL selection, which should deplete within-host variation by driving the fixation of the favored variant. Using a simple model, we demonstrate that this apparently contradictory outcome can be explained by the transmission of unfavorable variants to new hosts before they are removed by selection, which occurs more frequently when selection and transmission occur on similar time scales. Consequently, the circulating virus population is shaped by the transmission rate and the disparity in selection intensities for escape or reversion as much as it is shaped by the immune diversity of the host population, with potentially serious implications for vaccine design.
- Subject:
Science and Technology
- Grade Level:
Post-secondary
- Collection:
SciVee
(Complete Item Description)
- Abstract: Students explore the meaning of physical and behavioral adaptation, consider how migration fits in, and identify adaptations that help the Journey North species they track survive.
- Subject:
Science and Technology
- Grade Level:
Primary
- Collection:
Journey North
(Complete Item Description)
- Abstract: The adult zebra fish is the final stage in the zebra fish life cycle. At this point, the adult can lay eggs and a male zebra fish will fertilize them.
(Complete Item Description)
- Abstract: Algae are a collection of a millions of photosynthetic protists. These algae are red because of a special pigment. They cement themselves onto rocks in moist areas.
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- Abstract: This red algal cell (Chlamydomonas nivalis) gives mountain snow packs a red tint. It uses the pollutants in snow as food. It cannot be seen without a microscope.
(Complete Item Description)
- Abstract: Amphibians are vertebrates. Amphibians lay eggs to reproduce and undergo metamorphosis to go from offspring to adult. They are cold-blooded, meaning they rely on their surrounding environment and the sun to stay warm.
(Complete Item Description)
- Abstract: Objects appear to be certain colors because of reflection and absorbance. Light is made up of different wavelengths that our eyes detect and convert into colors. The apple looks green because it reflects the wavelengths that correspond to the color we see as green. The apple absorbs all other wavelengths of light.
(Complete Item Description)
- Abstract: Anemones are carnivores and use their tentacles to move food into their mouths. Their tentacles contain stinging cells to kill prey. Sea anemones attach to rocks in lower and middle intertidal zones and are vulnerable to drying out.
(Complete Item Description)
- Abstract: Animals such as some geckos, lizards, and salamanders can shed their tails to escape a predatory attack. This process is called autotomy. The missing tail eventually grows back.
(Complete Item Description)
- Abstract: Zebras generally stay in herds together. Zebras standing together may tend to look like one very large animal to predators. Also, predatory attacks send the zebras running in every direction. The stripes could confuse the attacker as to which animal it is chasing after, leaving it without any food in the end.
(Complete Item Description)
- Abstract: Items in nature, such as twigs and leaves, can show bite and chew marks where animals have been eating off of plants. Animals make trails by traveling over the same area several times to get to a destination.
(Complete Item Description)
- Abstract: Oysters are important to the environment because they help filter out some of the toxins and trash in water. When something irritates the oyster's insides, it secretes a substance to coat the irritant. A pearl is then formed. Humans wear pearls as jewelry.
(Complete Item Description)
- Abstract: Sheep can be sheared of their woolly coat. Humans use this coat, known as wool, to make warm clothing for the winter months.
(Complete Item Description)
- Abstract: Fish are vertebrates, meaning they have a skeletal system to support their bodies. All fish live underwater. Fish have gills to help them breathe underwater and fins to help them swim. Most fish are cold-blooded, meaning their body temperature is regulated by the surrounding water temperature.
(Complete Item Description)
- Abstract: One reason why leeches are considered to be annelids is because they have segmented bodies. Leeches suck blood from animals to get food. They release an anesthetic into the animal they are feeding on so that the animal doesn't realize they are feeding on them.
(Complete Item Description)
- Abstract: This turtle has a back full of green, mossy algae. When the turtle is stationary in the water, it can camouflage itself to look like a moss-covered rock.
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