RNF12 controls embryonic stem cell fate and morphogenesis in zebrafish embryos by targeting Smad7 for degradation

TGF-β members are of key importance during embryogenesis and tissue homeostasis. Smad7 is a potent antagonist of TGF-β family/Smad-mediated responses, but the regulation of Smad7 activity is not well understood. We identified the RING domain-containing E3 ligase RNF12 as a critical component of TGF-β signaling. Depletion of RNF12 dramatically reduced TGF-β/Smad-induced effects in mammalian cells, whereas ectopic expression of RNF12 strongly enhanced these responses. RNF12 specifically binds to Smad7 and induces its polyubiquitination and degradation. Smad7 levels were increased in RNF12-deficient mouse embryonic stem cells, resulting in mitigation of both BMP-mediated repression of neural induction and activin-induced anterior mesoderm formation. RNF12 also antagonized Smad7 during Nodal-dependent and BMP-dependent signaling and morphogenic events in early zebrafish embryos. The gastrulation defects induced by ectopic and depleted Smad7 were rescued in part by RNF12 gain and loss of function, respectively. These findings demonstrate that RNF12 plays a critical role in TGF-β family signaling.     

Deficiency of a Glycogen Synthase-associated Protein,Epm2aip1, Causes Decreased Glycogen Synthesis and Hepatic Insulin Resistance

Glycogen synthesis is a major component of the insulin response, and defective glycogen synthesis is a major portion of insulin resistance. Insulin regulates glycogen synthase (GS) through incompletely defined pathways that activate the enzyme through dephosphorylation and, more potently, allosteric activation. We identify Epm2aip1 as a GS-associated protein. We show that the absence of Epm2aip1 in mice impairs allosteric activation of GS by glucose 6-phosphate, decreases hepatic glycogen synthesis, increases liver fat, causes hepatic insulin resistance, and protects against age-related obesity. Our work identifies a novel GS-associated GS activity-modulating component of insulin resistance.     

Field Trial Evaluating the Influence of Prophylactic and Therapeutic Antimicrobial Administration on Antimicrobial Resistance of Fecal Escherichia coli in Dairy Calves

The objective of this study was to describe the influence of in-feed and therapeutic antimicrobials on resistance in commensal fecal Escherichia coli isolated from preweaned calves. Four groups of 30, day-old calf-ranch calves were enrolled and raised until 4 weeks of age. Groups 1 to 3 were raised without antimicrobials in the feed. Group 1 was isolated from the other groups and received no antimicrobial therapy. Group 2 was housed on the calf ranch and did not receive antimicrobial therapy, whereas groups 3 and 4 could be treated with antimicrobials. Group 4 was fed neomycin and tetracycline HCl in the milk replacer. Fecal samples were collected from calves on days 1, 14, and 28. Three E. coli isolates per sample were evaluated for susceptibility to 12 antimicrobials. Cluster analysis was used to group isolates having similar susceptibility patterns. Cumulative logistic regression was used to evaluate factors associated with increasing levels of multiple antimicrobial resistance. In-feed antimicrobials were associated with higher levels of multiple antimicrobial resistance in fecal E. coli.f In calves not receiving in-feed antimicrobials, older calves had higher levels of resistance compared to day-old calves. Individual antimicrobial therapy increased resistance in these calves but appeared to be transient. There was no environmental influence on resistance in E. coli populations among study groups.     

Comparison of the Efficacies of Disinfectants To Control Microbial Contamination in Dental Unit Water Systems in General Dental Practices across the European Union

Water delivered by dental unit water systems (DUWS) in general dental practices can harbor high numbers of bacteria, including opportunistic pathogens. Biofilms on tubing within DUWS provide a reservoir for microorganisms and should be controlled. This study compared disinfection products for their ability to meet the American Dental Association's guideline of <200 CFU · ml⁻¹ for DUWS water. Alpron, BioBlue, Dentosept, Oxygenal, Sanosil, Sterilex Ultra, and Ster4Spray were tested in DUWS (n = 134) in Denmark, Germany, Greece, Ireland, The Netherlands, Spain, and the United Kingdom. Weekly water samples were tested for total viable counts (TVCs) on yeast extract agar, and, where possible, the effects of products on established biofilm (TVCs) were measured. A 4- to 5-week baseline measurement period was followed by 6 to 8 weeks of disinfection (intermittent or continuous product application). DUWS water TVCs before disinfection ranged from 0 to 5.41 log CFU · ml⁻¹. Disinfectants achieved reductions in the median water TVC ranging from 0.69 (Ster4Spray) to 3.11 (Dentosept) log CFU · ml⁻¹, although occasional high values (up to 4.88 log CFU · ml⁻¹) occurred with all products. Before treatment, 64% of all baseline samples exceeded American Dental Association guidelines, compared to only 17% following commencement of treatment; where tested, biofilm TVCs were reduced to below detectable levels. The antimicrobial efficacies of products varied (e.g., 91% of water samples from DUWS treated with Dentosept or Oxygenal met American Dental Association guidelines, compared to 60% of those treated with Ster4Spray). Overall, the continuously applied products performed better than those applied intermittently. The most effective products were Dentosept and Oxygenal, although Dentosept gave the most consistent and sustained antimicrobial effect over time.     

Subjects with Low Plasma HDL Cholesterol Levels Are Characterized by an Inflammatory and Oxidative Phenotype

Background

Epidemiological studies have shown that low plasma levels of high-density lipoprotein (HDL) cholesterol are associated with increased risk of cardiovascular disease, but the mechanisms for the possible atheroprotective effects of HDL cholesterol have still not been fully clarified, in particular in relation to clinical studies.

Objective

To examine the inflammatory, anti-oxidative and metabolic phenotype of subjects with low plasma HDL cholesterol levels.

Methods and Results

Fifteen subjects with low HDL cholesterol levels (eleven males and four females) and 19 subjects with high HDL (three males and 16 females) were recruited. Low HDL cholesterol was defined as ≤10th age/sex specific percentile and high HDL-C was defined as ≥90 age/sex specific percentile. Inflammatory markers in circulation and PBMC gene expression of cholesterol efflux mediators were measured. Our main findings were: (i) subjects with low plasma HDL cholesterol levels were characterized by increased plasma levels of CRP, MMP-9, neopterin, CXCL16 and ICAM-1 as well as low plasma levels of adiponectin, suggesting an inflammatory phenotype; (ii) these individuals also had reduced paraoxonase (PON)1 activity in plasma and PON2 gene expression in peripheral blood mononuclear cells (PBMC) accompanied by increased plasma levels of oxidized LDL suggesting decreased anti-oxidative capacity; and (iii) PBMC from low HDL subjects also had decreased mRNA levels of ABCA1 and ABCG1, suggesting impaired reverse cholesterol transport.

Conclusion

Subjects with low plasma HDL cholesterol levels are characterized by an inflammatory and oxidative phenotype that could contribute to the increased risk of atherosclerotic disorders in these subjects with low HDL levels.     

Insulin-like growth factor 1 enhances bile-duct proliferation and fibrosis in Abcb4−/− mice

Adamant progression of chronic cholangiopathies towards cirrhosis and limited therapeutic options leave a liver transplantation the only effective treatment. Insulin-like growth factor 1 (IGF1) effectively blocks fibrosis in acute models of liver damage in mice, and a phase I clinical trial suggested an improved liver function. IGF1 targets the biliary epithelium, but its potential benefit in chronic cholangiopathies has not been studied. To investigate the possible therapeutic effect of increased IGF1 expression, we crossed Abcb4^?/? mice (a model for chronic cholangiopathy), with transgenic animals that overexpress IGF1. The effect on disease progression was studied in the resulting IGF1-overexpressing Abcb4^?/? mice, and compared to that of Abcb4^?/? littermates. The specificity of this effect was further studied in an acute model of fibrosis. The overexpression of IGF1 in transgenic Abcb4^?/? mice resulted in stimulation of fibrogenic processes — as shown by increased expression of Tgfß, and collagens 1, 3 and 4, and confirmed by Sirius red staining and hydroxyproline measurements. Excessive extracellular matrix deposition was favored by raise in Timp1 and Timp2, while a reduction of tPA expression indicated lower tissue remodeling. These effects were accompanied by an increase in expression of inflammation markers like Tnfα, and higher presence of infiltrating macrophages. Finally, increased number of Ck19-expressing cells indicated proliferation of biliary epithelium. In contrast to liver fibrosis associated with hepatocellular damage, IGF1 overexpression does not inhibit liver fibrogenesis in chronic cholangiopathy.     

Predictors of clinical response to extrafine and non-extrafine particle inhaled corticosteroids in smokers and ex-smokers with asthma

We performed a post-hoc analysis of the OLiVIA-study investigating whether current and ex-smoking asthmatics with small airways dysfunction (SAD) show a better response in airway hyperresponsiveness (AHR) to small particle adenosine after treatment with extrafine compared to non-extrafine particle inhaled corticosteroids (ICS), and to investigate which clinical parameters predict a favorable response to both treatments. We show that smoking and ex-smoking asthmatics with and without SAD have a similar treatment response with either extrafine or non-extrafine particle ICS. We also found that lower blood neutrophils are associated with a smaller ICS-response in smokers and ex-smokers with asthma, independent from the level of blood eosinophils.     

Effect of UV‐B radiation on the content of UV‐B absorbing compounds and photosynthetic parameters in Parmotrema austrosinense from two contrasting habitats

• We studied the resistance of Parmotrema austrosinense to UV‐B stress. We focused on the effects of a high dose UV‐B radiation on the content of chlorophylls, carotenoids and UV‐B screening compounds.
• Photosynthetic parameters were measured by chlorophyll fluorescence (potential and effective quantum yields, photochemical and non‐photochemical quenching) and evaluated in control and UV‐B‐treated lichens. Lichens from two different locations in Cordoba, Argentina, were selected: (i) high altitude and dry plots at (Los Gigantes) and (ii) lowland high salinity plots (Salinas Grandes).
• UV‐B treatment led to a decrease in the content of photosynthetic pigments and UV‐B screens (absorbance decrease in 220–350 nm) in the samples from Salinas Grandes, while in Los Gigantes samples, an increase in UV‐B screen content was observed. Chlorophyll fluorescence parameters showed a UV‐B‐induced decline in F_V/F_M, Φ_PSII and qP indicating limitation of primary photosynthetic processes in photosystem II (PSII) of symbiotic alga, more pronounced in Salinas Grandes samples. Protective mechanism of PSII were activated by the UV‐B treatment to a higher extent in samples from Salinas Grandes (NPQ 0.48) than in Los Gigantes samples (NPQ 0.26).
• We concluded that site‐related characteristics, and in particular different UV‐B radiation regimen, had a strong effect on resistance of the photosynthetic apparatus of P. austrosinense to UV‐B radiation.

     

Threshold model for clustered firing of neurons

Two probabilistic threshold models for burst activity of cortical neurons are proposed. In model I every input impulse increases the summed effect of previous input impulses by one unit. The decay of the summed effect takes place in discrete steps of one unit. A response occurs on arrival of an input impulse, when a threshold value is attained.Although after a response the summed effect is not reset to zero, it cannot exceed the threshold either. The distribution of intervals can be resolved in two components, one for long and one for short intervals. In model II intervals of the short component are terminated by a multiple response instead of one response.