SUMMARYThe gut barrier, composed of a single layer of intestinal epithelial cells (IECs) held together by tight junctions, prevents the entrance of harmful microorganisms, antigens and toxins from the gut lumen into the blood. Small intestinal homeostasis is normally maintained by the rate of shedding of senescent enterocytes from the villus tip exactly matching the rate of generation of new cells in the crypt. However, in various localized and systemic inflammatory conditions, intestinal homeostasis can be disturbed as a result of increased IEC shedding. Such pathological IEC shedding can cause transient gaps to develop in the epithelial barrier and result in increased intestinal permeability. Although pathological IEC shedding has been implicated in the pathogenesis of conditions such as inflammatory bowel disease, our understanding of the underlying mechanisms remains limited. We have therefore developed a murine model to study this phenomenon, because IEC shedding in this species is morphologically analogous to humans. IEC shedding was induced by systemic lipopolysaccharide (LPS) administration in wild-type C57BL/6 mice, and in mice deficient in TNF-receptor 1 (Tnfr1−/−), Tnfr2 (Tnfr2−/−), nuclear factor kappa B1 (Nfκb1−/−) or Nfĸb2 (Nfĸb2−/−). Apoptosis and cell shedding was quantified using immunohistochemistry for active caspase-3, and gut-to-circulation permeability was assessed by measuring plasma fluorescence following fluorescein-isothiocyanate–dextran gavage. LPS, at doses ≥0.125 mg/kg body weight, induced rapid villus IEC apoptosis, with peak cell shedding occurring at 1.5 hours after treatment. This coincided with significant villus shortening, fluid exudation into the gut lumen and diarrhea. A significant increase in gut-to-circulation permeability was observed at 5 hours. TNFR1 was essential for LPS-induced IEC apoptosis and shedding, and the fate of the IECs was also dependent on NFκB, with signaling via NFκB1 favoring cell survival and via NFκB2 favoring apoptosis. This model will enable investigation of the importance and regulation of pathological IEC apoptosis and cell shedding in various diseases.
Although by age forty, individuals with Down syndrome (DS) develop amyloid-β (Aβ) plaques and tau-containing neurofibrillary tangles (NFTs) linked to cognitive impairment in Alzheimer's disease (AD), not all people with DS develop dementia. Whether Aβ plaques and NFTs are associated with individuals with DS with (DSD+) and without dementia (DSD−) is under investigated. Here, we applied quantitative immunocytochemistry and fluorescent procedures to characterize NFT pathology using antibodies specific for tau phosphorylation (pS422, AT8), truncation (TauC3, MN423), and conformational (Alz50, MC1) epitopes, as well as Aβ and its precursor protein (APP) in frontal cortex (FC) and striatal tissue from DSD+ and DSD− cases. Expression profiling of single pS422 labeled FC layer V and VI neurons was also determined using laser capture microdissection and custom-designed microarray analysis. Analysis revealed
The objective of this experiment was to compare the effects of dietary mannan oligosaccharide (MOS) and a feed-grade antimicrobial (AM) on growth performance of nursery pigs reared on three different farms (A and B were large-scale commercial farms, and C was located at Michigan State University). On all farms, production was continuous flow by building, but all-in/all-out by room. Within each nursery facility, all pigs on the experiment were in one room. Pigs (Farm A, n = 771, weaning age = 18.4 d; Farm B, n = 576, weaning age = 19.0 d; Farm C, n = 96, weaning age = 20.6 d) were blocked (within farm) by BW and sex and allotted randomly to dietary treatments arranged in a 2 x 2 factorial. The two factors were 1) with and without MOS (0.3% in Phase I, 0.2% in Phases II, III, and IV; as-fed basis) and 2) with and without AM (110 mg of tylosin and 110 mg of sulfamethazine/kg of diet in all phases; as-fed basis). The four nursery phases were 4, 7, 14, and 17 d, respectively. With 35, 20, and 4 pigs per pen on Farms A, B, and C, respectively, space allowances per pig were 0.29, 0.26, and 0.56 m2. Across all farms, the addition of AM and MOS plus AM increased (P < 0.05) ADG (368, 406, and 410 g/d for control, AM, and MOS plus AM, respectively and increased ADFI (661, 703, and 710 g/d for control, AM, and MOS plus AM, respectively) for the entire 42-d experiment. The addition of MOS also increased ADG (P < 0.05) from d 0 to 42 of the experiment (394 g/d). Performance differed depending on farm (P < 0.01). Antimicrobial did not affect growth performance on Farm B, but it increased (P < 0.05) ADG on Farms A and C, ADFI on Farm A, and G:F on Farm C. Growth improvements with MOS on Farms A and B were not significant; however, pigs on Farm C fed MOS had greater (P < 0.05) ADG, ADFI, and G:F than controls. The results of this study suggest that MOS may be an alternative to tylosin and sulfa-methazine as a growth promotant in nursery diets.
Heterozygous triggering receptor expressed on myeloid cells (TREM2) mutations are an Alzheimer's disease (AD) risk factor. Nonmutated TREM2 dysregulation occurs in AD brain. Whether TREM2 is altered in prodromal AD remains unknown. Western blotting was used to determine levels of TREM2 (∼25 kDa) and Iba1 in the frontal cortex and TREM2 in the hippocampus from people who died with an ante-mortem clinical diagnosis of non- and mild-cognitive impairment, mild/moderate AD, and severe AD (sAD). Immunohistochemistry defined the relationship between amyloid and Iba1 profiles. Polymerase chain reaction analysis revealed that all subjects did not carry the most common R47H TREM2 variant. TREM2 was significantly upregulated in sAD frontal cortex but stable in hippocampus. Frontal TREM2 mRNA and protein level patterns were similar but not significantly different. Iba1 immunopositive microglia counts increased significantly in frontal cortex containing plaques in sAD. TREM2 and Iba1 levels were not associated with plaques, tangles, neuropathological criteria, or cognitive performance. Frontal cortex TREM2 upregulation is a late event and may not play a major role early in the pathogenesis of the disease.
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