A Lactobacillus rhamnosus GG-derived Soluble Protein,p40, Stimulates Ligand Release from Intestinal Epithelial Cells to Transactivate Epidermal Growth Factor Receptor

p40, a Lactobacillus rhamnosus GG (LGG)-derived soluble protein, ameliorates intestinal injury and colitis, reduces apoptosis, and preserves barrier function by transactivation of the EGF receptor (EGFR) in intestinal epithelial cells. The aim of this study is to determine the mechanisms by which p40 transactivates the EGFR in intestinal epithelial cells. Here we show that p40-conditioned medium activates EGFR in young adult mouse colon epithelial cells and human colonic epithelial cell line, T84 cells. p40 up-regulates a disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) catalytic activity, and broad spectrum metalloproteinase inhibitors block EGFR transactivation by p40 in these two cell lines. In ADAM17-deficient mouse colonic epithelial (ADAM17^−/− MCE) cells, p40 transactivation of EGFR is blocked, but can be rescued by re-expression with WT ADAM17. Furthermore, p40 stimulates release of heparin binding (HB)-EGF, but not transforming growth factor (TGF)α or amphiregulin, in young adult mouse colon cells and ADAM17^−/− MCE cells overexpressing WT ADAM17. Knockdown of HB-EGF expression by siRNA suppresses p40 effects on transactivating EGFR and Akt, preventing apoptosis, and preserving tight junction function. The effects of p40 on HB-EGF release and ADAM17 activation in vivo are examined after administration of p40-containing pectin/zein hydrogel beads to mice. p40 stimulates ADAM17 activity and EGFR activation in colonic epithelial cells and increases HB-EGF levels in blood from WT mice, but not from mice with intestinal epithelial cell-specific ADAM17 deletion. Thus, these data define a mechanism of a probiotic-derived soluble protein in modulating intestinal epithelial cell homeostasis through ADAM17-mediated HB-EGF release, leading to transactivation of EGFR.     

Linking brains and brawn: exercise and the evolution of human neurobiology

The hunting and gathering lifestyle adopted by human ancestors around 2 Ma required a large increase in aerobic activity. High levels of physical activity altered the shape of the human body, enabling access to new food resources (e.g. animal protein) in a changing environment. Recent experimental work provides strong evidence that both acute bouts of exercise and long-term exercise training increase the size of brain components and improve cognitive performance in humans and other taxa. However, to date, researchers have not explored the possibility that the increases in aerobic capacity and physical activity that occurred during human evolution directly influenced the human brain. Here, we hypothesize that proximate mechanisms linking physical activity and neurobiology in living species may help to explain changes in brain size and cognitive function during human evolution. We review evidence that selection acting on endurance increased baseline neurotrophin and growth factor signalling (compounds responsible for both brain growth and for metabolic regulation during exercise) in some mammals, which in turn led to increased overall brain growth and development. This hypothesis suggests that a significant portion of human neurobiology evolved due to selection acting on features unrelated to cognitive performance.     

Methods to temporally align gait cycle data

The need for the temporal alignment of gait cycle data is well known; however, there is little consensus concerning which alignment method to use. In this paper, we discuss the pros and cons of some methods commonly applied to temporally align gait cycle data (normalization to percent gait cycle, dynamic time warping, derivative dynamic time warping, and piecewise alignment methods). In addition, we empirically evaluate these different methods' abilities to produce successful temporal alignment when mapping a test gait cycle trajectory to a target trajectory. We demonstrate that piecewise temporal alignment techniques outperform other commonly used alignment methods (normalization to percent gait cycle, dynamic time warping, and derivative dynamic time warping) in typical biomechanical and clinical alignment tasks. Lastly, we present an example of how these piecewise alignment techniques make it possible to separately examine intensity and temporal differences between gait cycle data throughout the entire gait cycle, which can provide greater insight into the complexities of movement patterns.     

TNF transactivation of EGFR stimulates cytoprotective COX-2 expression in gastrointestinal epithelial cells

TNF and epidermal growth factor (EGF) are well-known stimuli of cyclooxygenase (COX)-2 expression, and TNF stimulates transactivation of EGF receptor (EGFR) signaling to promote survival in colon epithelial cells. We hypothesized that COX-2 induction and cell survival signaling downstream of TNF are mediated by EGFR transactivation. TNF treatment was more cytotoxic to COX-2(-/-) mouse colon epithelial (MCE) cells than wild-type (WT) young adult mouse colon (YAMC) epithelial cells or COX-1(-/-) cells. TNF also induced COX-2 protein and mRNA expression in YAMC cells, but blockade of EGFR kinase activity or expression inhibited COX-2 upregulation. TNF-induced COX-2 expression was reduced and absent in EGFR(-/-) and TNF receptor-1 (TNFR1) knockout MCE cells, respectively, but was restored upon expression of the WT receptors. Inhibition of mediators of EGFR transactivation, Src family kinases and p38 MAPK, blocked TNF-induced COX-2 protein and mRNA expression. Finally, TNF injection increased COX-2 expression in colon epithelium of WT, but not kinase-defective EGFR(wa2) and EGFR(wa5), mice. These data indicate that TNFR1-dependent transactivation of EGFR through a p38- and/or an Src-dependent mechanism stimulates COX-2 expression to promote cell survival. This highlights an EGFR-dependent cell signaling pathway and response that may be significant in colitis-associated carcinoma.     

Conversion of TNFα from Antiproliferative to Proliferative Ligand in Mouse Intestinal Epithelial Cells by Regulating Mitogen-Activated Protein Kinase

The mechanisms regulating the balance between intestinal epithelial cell proliferation and differentiation are essential to maintaining an intact mucosal barrier. Mitogen-activated protein (MAP) kinases appear to be key transducers of extracellular signals in these pathways. The goal of this study was to investigate the regulation of MAP kinase by tumor necrosis factor α (TNFα) and epidermal growth factor (EGF) in intestinal epithelial cells. The young adult mouse colon cell line was studied for TNFα and/or EGF regulation of MAP kinase in the presence or absence of the MAP kinase kinase (MEK1) inhibitor PD 98059. Proliferation was determined by hemocytometry, and activated MAP kinase was identified by Western blot analysis, in vitro kinase assay, and confocal laser immunofluorescent microscopy. TNFα stimulated sustained nuclear MAP kinase activity, while EGF stimulated transient cytoplasmic MAP kinase activity. Changing TNFα's sustained MAP kinase activation to transient converted TNFα from an anti-proliferative to a proliferative ligand. These findings demonstrate that both TNFα and EGF activate MAP kinase in intestinal epithelial cells. The kinetics and subcellular distribution of this enzyme activity may be pivotal in the transduction of divergent cellular responses in the intestinal epithelium with implications for altered proliferative signals in inflammatory bowel disease.     

Investigating unique environmental contributions to the neural representation of written words: a monozygotic twin study

The visual word form area (VWFA) is a region of left inferior occipitotemporal cortex that is critically involved in visual word recognition. Previous studies have investigated whether and how experience shapes the functional characteristics of VWFA by comparing neural response magnitude in response to words and nonwords. Conflicting results have been obtained, however, perhaps because response magnitude can be influenced by other factors such as attention. In this study, we measured neural activity in monozygotic twins, using functional magnetic resonance imaging. This allowed us to quantify differences in unique environmental contributions to neural activation evoked by words, pseudowords, consonant strings, and false fonts in the VWFA and striate cortex. The results demonstrate significantly greater effects of unique environment in the word and pseudoword conditions compared to the consonant string and false font conditions both in VWFA and in left striate cortex. These findings provide direct evidence for environmental contributions to the neural architecture for reading, and suggest that learning phonology and/or orthographic patterns plays the biggest role in shaping that architecture.     

Cows, ground surface potentials and earth resistivity

The "stray voltage" problem on dairy farms is discussed briefly. By reference to published literature it is shown that a "step voltage" (SV), i.e., a potential difference between front and hind hooves of a dairy cow, much less than the often quoted threshold value of 0.5 V, when applied for long periods of time, could possibly affect cow health and milk production. Values as low as approximately 10 mV could conceivably be significant. A measurement program carried out on 19 representative Minnesota dairy farms during the summer of 1997 is described. Nine farms had above average (HP) and 10 below average (LP) milk production. Results show that SV was 4.2 times higher on the LP than HP. However, only three farms had SV greater than 9 mV, and low milk production on these farms could possibly be due to absence of recommended vaccinations rather than high SV. Soil resistivity rho measured in the farm fields was 3.4 times larger on the LP than on HP. The possible origin of SV in relation to electric distribution systems within and to farms is discussed. Relations between SV and rho are analyzed. Conditions are specified under which SV in the barn must be related to rho measured in the field, rather than the rho of the concrete floor of the barn. It is suggested that laboratory research is necessary to establish the significance for cow health and milk production of long term exposure to low SV levels.     

Antenatal glucocorticoids alter premature newborn lamb neuroendocrine and endocrine responses to hypoxia

Glucocorticoids are administered for preterm labor to improve postnatal adaptation. We assessed the effect of antenatal betamethasone (Beta) treatment on preterm newborn lamb neuroendocrine [catecholamine, arginine vasopressin (AVP)] and endocrine [triiodothyronine (T(3)), ANG II, and atrial natriuretic factor (ANF)] adaptive responses following delivery and a hypoxic challenge. Beta treatment included direct fetal injection at 0.2 (F(0.2); n = 8) or 0.5 (F(0.5); n = 7) mg/kg estimated fetal body weight or maternal injection with 0.2 (n = 8) or 0.5 mg/kg (M(0.5); n = 8). Control animals received fetal and maternal intramuscular injections of saline (n = 8). After 24 h, lambs were delivered by cesarean section, surfactant treated, and ventilated for 4 h. Relative to the control lambs, 3 h after delivery, there was a marked suppression of plasma cortisol, epinephrine, norepinephrine, and ANG II levels and elevated plasma T(3) and ANF levels, systolic blood pressure, and left ventricular contractility (dP/dt; F(0.5) and M(0.5)) values in F(0.5) and both maternal Beta-treated groups. However, Beta treatment augmented the cardiac output, cortisol, norepinephrine, AVP, and ANF responses to 20 min of hypoxia (PO(2) = 25-30 mmHg). We concluded that short-term (24 h) antenatal glucocorticoid exposure 1) alters preterm newborn postnatal blood pressure regulation in the face of marked depression of plasma cortisol, catecholamine, and ANG II levels and 2) augments the postnatal neuroendocrine and endocrine responses to a hypoxic challenge.     

Species-specific shifts in centromere sequence composition are coincident with breakpoint reuse in karyotypically divergent lineages

Background  

It has been hypothesized that rapid divergence in centromere sequences accompanies rapid karyotypic change during speciation. However, the reuse of breakpoints coincident with centromeres in the evolution of divergent karyotypes poses a potential paradox. In distantly related species where the same centromere breakpoints are used in the independent derivation of karyotypes, centromere-specific sequences may undergo convergent evolution rather than rapid sequence divergence. To determine whether centromere sequence composition follows the phylogenetic history of species evolution or patterns of convergent breakpoint reuse through chromosome evolution, we examined the phylogenetic trajectory of centromere sequences within a group of karyotypically diverse mammals, macropodine marsupials (wallabies, wallaroos and kangaroos).