The Transforming Growth Factor-Beta (TGF-β) family is involved in regulating a variety of cellular processes such as apoptosis, differentiation, and proliferation. TGF-β binding to a Serine/Threonine ...kinase receptor complex causes the recruitment and subsequent activation of transcription factors known as smad2 and smad3. These proteins subsequently translocate into the nucleus to negatively or positively regulate gene expression. In this study, we define a second signaling pathway leading to TGF-β receptor activation of Extracellular Signal Regulated Kinase (Erk) in a cell-type dependent manner. TGF-β induced Erk activation was found in phenotypically normal mesenchymal cells, but not normal epithelial cells. By activating phosphotidylinositol 3-kinase (PI3K), TGF-β stimulates p21-activated kinase2 (Pak2) to phosphorylate c-Raf, ultimately resulting in Erk activation. Activation of Erk was necessary for TGF-β induced fibroblast replication. In addition, Erk phosphorylated the linker region of nuclear localized smads, resulting in increased half-life of C-terminal phospho-smad 2 and 3 and increased duration of smad target gene transcription. Together, these data show that in mesenchymal cell types the TGF-β/PI3K/Pak2/Raf/MEK/Erk pathway regulates smad signaling, is critical for TGF-β-induced growth and is part of an integrated signaling web containing multiple interacting pathways rather than discrete smad/non-smad pathways.
Endurance exercise (i.e. running), by up‐regulating brain‐derived neurotrophic factor (BDNF) and other modulators of synaptic plasticity, improves attention and learning, both critical components of ...stroke rehabilitation. We hypothesized that, following middle cerebral artery occlusion in male Sprague‐Dawley rats, endurance exercise would act synergistically with a challenging skilled forelimb task to facilitate motor recovery. Animals were randomly assigned to one of four rehabilitation conditions: no rehabilitation, running only, reach training only, and reach training preceded by running (run/reach training) for 5 weeks beginning 5 days after stroke. The behavioral outcome, morphological change and mRNA expression of proteins implicated in neuroplasticity (BDNF, synapsin I and microtubule‐associated protein 2) were compared. Endurance exercise on a motorized running wheel, prior to reach training, enhanced recovery of skilled reaching ability but did not transfer to gross motor skills such as postural support (forelimb asymmetry test) and gait (ladder rung walking test). Microtubule‐associated protein 2 staining density in the run/reach group was slightly enhanced in the contralateral motor cortex compared with the contralateral sensory and ipsilateral cingulate cortices, suggesting that running preceding reach training may have resulted in more dendritic branching within the motor cortex in this group. No significant differences in mRNA levels were detected among the training paradigms; however, there was a trend toward greater BDNF and synapsin I mRNA in the reaching groups. These findings suggest that exercise facilitates learning of subsequent challenging reaching tasks after stroke, which has the potential to optimize outcomes in patients with stroke.
Background
Paratuberculosis has a worldwide distribution and many countries have implemented control programs to prevent transmission among and within herds. For these programs to be efficient, ...knowledge of the risk factors involved in transmission is essential.
Objectives
Systematically review the scientific literature concerning risk factors associated with Mycobacterium avium subsp. paratuberculosis (MAP) transmission to dairy calves.
Study Design
Systematic review.
Methods
An electronic search was done in PubMed and CAB to retrieve references relevant to answer at least 1 of the 5 questions concerning neonatal environment, colostrum, milk, housing of calves, and contact of calves with adult cow feces as risk factors in MAP transmission. A 1st screening was done using titles only, then s, and finally full‐length articles were reviewed for relevance. From the articles selected, risk factors and presence of a significant association between these risk factors and MAP transmission were recorded.
Results
Twenty‐three articles from 11 different countries and published in 12 different journals were reviewed. The most common study design was cross‐sectional (n = 16). The case definition and diagnostic tests used were very variable among studies, but serum ELISA was used in most studies (n = 14). The study unit was the herd in 18 studies.
Conclusions and Clinical Importance
The contact of calves with adult cow feces is the most important risk factor in MAP transmission. The 5 categories of risk factors are linked to one another.
The objectives of the current study were (1) to determine the gain in prognostic accuracy of preoperative l-lactate concentration (LAC) measured on farm on cows with right displaced abomasum (RDA) or ...abomasal volvulus (AV) for predicting negative outcome; and (2) to suggest clinically relevant thresholds for such use. A cohort of 102 cows with on-farm surgical diagnostic of RDA or AV was obtained from June 2009 through December 2011. Blood was drawn from coccygeal vessels before surgery and plasma LAC was immediately measured by using a portable clinical analyzer. Dairy producers were interviewed by phone 30d following surgery and the outcome was determined: a positive outcome if the owner was satisfied of the overall evolution 30d postoperatively, and a negative outcome if the cow was culled, died, or if the owner reported being unsatisfied 30d postoperatively. The area under the curve of the receiver operating characteristic curve for LAC was 0.92 and was significantly greater than the area under the curve of the receiver operating characteristic curve of heart rate (HR; 0.77), indicating that LAC, in general, performed better than HR to predict a negative outcome. Furthermore, the ability to predict a negative outcome was significantly improved when LAC measurement was considered in addition to the already available HR data (area under the curve: 0.93 and 95% confidence interval: 0.87, 0.99). Important inflection points of the misclassification cost term function were noted at thresholds of 2 and 6mmol/L, suggesting the potential utility of these cut-points. The 2 and 6mmol/L thresholds had a sensitivity, specificity, positive predictive value, and negative predictive value for predicting a negative outcome of 76.2, 82.7, 53.3, and 93.1%, and of 28.6, 97.5, 75, and 84%, respectively. In terms of clinical interpretation, LAC ≤2mmol/L appeared to be a good indicator of positive outcome and could be used to support a surgical treatment decision. The treatment decision for cows with LAC between 2 and 6mmol/L, however, would depend on the economic context and the owner’s attitude to risk in regard to potential return on its investment. Finally, performing a surgical correction on commercial cows with RDA or AV and a LAC ≥6mmol/L appeared to be unjustified and these animals should be culled based on their high probability of negative outcome.
•Perceived energy expenditure is the main driver for energy intake in elite youth.•Post-exercise appetite feelings and energy intake is uncoupled in elite youth.•Energy expenditure does not drive ...subsequent energy intake in elite youth.
Background: Acute exercise has been shown to induce nutritional adaptations in obese and lean inactive youth but it remains unclear whether youth with a high level of physical activity experience such exercise-induced energy intake and appetite modifications. Methods: 14 (15- to 16-year-old) male elite rugby players completed sessions on three separate occasions: (1) a control session (CON); (2) an exercise session (EX) and; (3) a rugby session (RUGBY). The energy induced by the rugby and exercise sessions was matched (Polar Team2 pro technology), and participants' energy intake, food preferences (ad libitum buffet meals) and appetite feelings (Visual Analogue Scales) were assessed throughout the experimental days. Results: The energy intake during lunch and snack time was not different between conditions. Dinner time energy intake was significantly increased after RUBGY compared to CON with respectively 969 ± 145 kcal and 777 ± 183 kcal (p < 0.05). The energy intake at dinner time was significantly increased during EX (1185 ± 199 kcal) compared to both CON (p < 0.001) and RUGBY (p < 0.01). None of the appetite feelings investigated were modified between sessions. Conclusion: Adolescent elite rugby players regulate their energy intake differently depending on the nature of their training; independently of the energy expended. This demonstrates the need for energetic and nutritional education to optimize their physical fitness and performance.
Biodegradable elastomeric controlled-release poly (decane-co-tricarballylate) (PDET) based matrices capable of maintaining the stability and bioactivity of Interleukin-2 (IL-2) through the ...utilization of visible-light curing and solvent-free loading of the cytokine are reported. The elastomeric devices were fabricated by intimately mixing lyophilized IL-2 powder with the acrylated prepolymer before photocrosslinking. The bioactivity of the released protein was assessed by its ability to stimulate the proliferation of the C57BL/6 mouse cytotoxic T lymphocyte, and its concentration was analysed using ELISA. The influence of changes in the polymer's physicochemical and mechanical properties on IL-2 release kinetics and bioactivity were also studied. The increase in the device's surface area and the incorporation of trehalose in the loaded lyophilized mix increased the IL-2 release rate with drug release proceeding via typical zero-order release kinetics. Moreover, the decrease in the degree of acrylation of the prepared devices increased the IL-2 release rate. The bioactivity assay showed that IL-2 retained over 94% of its initial bioactivity throughout 28 days of the release period. A new protein delivery vehicle composed of biodegradable PDET elastomers was demonstrated to be promising and effective for linear, constant, and sustained osmotic-driven release of bioactive IL-2 and other sensitive proteins and hormones.
The human kallikrein-related peptidase family consists of 15 genes. Twelve of these genes are overexpressed in ovarian cancer and may represent potential markers for diagnosis, prognosis, and/or ...response to treatment. The aim of this study was to determine the prognostic significance of kallikrein-related peptidase 6 (KLK6) and kallikrein-related peptidase 13 (KLK13) in epithelial ovarian cancer by quantifying gene expression levels with tumour pathology and patient survival data.
Total RNA was isolated from 106 patients diagnosed with primary ovarian cancer, as well as 8 normal ovary controls. Samples were analysed by quantitative real-time PCR for KLK6 and KLK13 expression. Correlation between kallikrein gene expression and clinical characteristics was evaluated with the chi(2)-test. Survival analysis was performed using Kaplan-Meier and Cox proportional hazards regression models.
Expression levels of both KLK6 and KLK13 mRNA were significantly increased in invasive cancers relative to normal ovaries (P=0.002 and 0.039 respectively). High KLK6 and KLK13 expression was an indicator of poor prognosis, with patients having a shorter recurrence-free survival (P=0.002 and 0.027 respectively). High KLK6 expression was also significantly associated with lower overall survival (P=0.011). When subjected to multivariate analysis, patients with either high KLK6 or KLK13 were 3- and 2.2-fold, respectively, more likely to have a recurrence than patients with low kallikrein expression.
These data show increased mRNA expression of KLK6 and KLK13 in ovarian cancer compared to normal ovarian tissues. High KLK6 or KLK13 expression in primary ovarian tumours can significantly predict prognosis in terms of recurrence-free survival and overall survival. In all, this study shows KLK6 and KLK13 as potential biomarkers and may be therapeutic targets for treatment of ovarian cancer.
Background Obesity is increasing worldwide, reaching alarming proportions. Eating habits have changed over time and nowadays children and adolescents' environment favours the adoption of unhealthy ...eating behaviours leading to metabolic impairment.
Objective To explore the impact of eating risk factors and their cumulative effect on anthropometric characteristics in French primary school children.
Methods A total of 278 healthy French children (7.50 ± 0.67 years old) and their legal representatives agreed to take part in this study. Parents were asked to fill in an eating habits clinical questionnaire with questions about skipping breakfast, snacking between meals, eating in front of the TV and sugar‐sweetened beverage consumption. On the basis of the answers, children were classified into four categories as a function of the number of eating risk factors they presented. Body mass index (BMI), the sum of four skinfolds (Σ4 skinfolds: tricipital, bicipital, sub‐scapular and supra‐iliac) and waist circumference (WC) were measured. BMI was transformed into z‐BMI for each child.
Results anova and unpaired t‐test provided significantly higher z‐BMI, Σ4 skinfolds and WC in children who were used to skipping breakfast, snacking, watching TV while eating and consuming sugar‐sweetened beverages. The more children accumulated eating risk factors, the higher were their z‐BMI, Σ4 skinfolds and WC (manova: P < 0.001).
Conclusions Eating habits appear to be associated with anthropometric characteristics in French primary school children. Anthropometric values (z‐BMI, Σ4 skinfolds and WC) increased with the number of eating risk factors they presented.
Histone deacetylase (HDAC) plays a role in synaptic plasticity and long-term memory formation. We hypothesized that trichostatin-A (TSA), an HDAC inhibitor, would promote long-term odor preference ...memory and maintain enhanced GluA1 receptor levels that have been hypothesized to support memory. We used an early odor preference learning model in neonate rat pups that normally produces only 24-h memory to test behavior and examine receptor protein expression. Our behavioral studies showed that intrabulbar infusion of TSA, prior to pairing of the conditioned stimulus (peppermint odor) with the unconditioned stimulus (tactile stimulation), prolonged 24-h odor preference memory for at least 9 d. The prolonged odor preference memory was selective for the paired odor and was also observed using a specific HDAC6 inhibitor, tubacin, supporting a role for histone acetylation in associative memory. Immunoblot analysis showed that GluA1 receptor membrane expression in the olfactory bulbs of the TSA-treated group was significantly increased at 48 h unlike control rats without TSA. Immunohistochemistry revealed significant increase of GluA1 expression in olfactory bulb glomeruli 5 d after training. These results extend previous evidence for a close relationship between enhanced GluA1 receptor membrane expression and memory expression. Together, these findings provide a new single-trial appetitive model for understanding the support and maintenance of memories of varying duration.
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