Estrogen receptor regulates MyoD gene expression by preventing AP-1-mediated repression.

Cell growth and differentiation are opposite events in the myogenic lineage. Growth factors block the muscle differentiation program by inducing the expression of transcription factors that negatively regulate the expression of muscle regulatory genes like MyoD. In contrast, extracellular clues that induce cell cycle arrest promote MyoD expression and muscle differentiation. Thus, the regulation of MyoD expression is critical for muscle differentiation. Here we show that estrogen induces MyoD expression in mouse skeletal muscle in vivo and in dividing myoblasts in vitro by relieving the MyoD promoter from AP-1 negative regulation through a mechanism involving estrogen receptor/AP-1 protein-protein interactions but independent of the estrogen receptor DNA binding activity.

Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism.

Neuronal development is the result of a multitude of neural migrations, which require extensive cell-cell communication. These processes are modulated by extracellular matrix components, such as heparan sulfate (HS) polysaccharides. HS is molecularly complex as a result of nonrandom modifications of the sugar moieties, including sulfations in specific positions. We report here mutations in HS 6-O-sulfotransferase 1 (HS6ST1) in families with idiopathic hypogonadotropic hypogonadism (IHH). IHH manifests as incomplete or absent puberty and infertility as a result of defects in gonadotropin-releasing hormone neuron development or function. IHH-associated HS6ST1 mutations display reduced activity in vitro and in vivo, suggesting that HS6ST1 and the complex modifications of extracellular sugars are critical for normal development in humans. Genetic experiments in Caenorhabditis elegans reveal that HS cell-specifically regulates neural branching in vivo in concert with other IHH-associated genes, including kal-1, the FGF receptor, and FGF. These findings are consistent with a model in which KAL1 can act as a modulatory coligand with FGF to activate the FGF receptor in an HS-dependent manner.

A single mutation in enzyme I of the sugar phosphotransferase system confers penicillin tolerance to Streptococcus gordonii.

Tolerance is a poorly understood phenomenon that allows bacteria exposed to a bactericidal antibiotic to stop their growth and withstand drug-induced killing. This survival ability has been implicated in antibiotic treatment failures. Here, we describe a single nucleotide mutation (tol1) in a tolerant Streptococcus gordonii strain (Tol1) that is sufficient to provide tolerance in vitro and in vivo. It induces a proline-to-arginine substitution (P483R) in the homodimerization interface of enzyme I of the sugar phosphotransferase system, resulting in diminished sugar uptake. In vitro, the susceptible wild-type (WT) and Tol1 cultures lost 4.5 and 0.6 log(10) CFU/ml, respectively, after 24 h of penicillin exposure. The introduction of tol1 into the WT (WT P483R) conferred tolerance (a loss of 0.7 log(10) CFU/ml/24 h), whereas restitution of the parent sequence in Tol1 (Tol1 R483P) restored antibiotic susceptibility. Moreover, penicillin treatment of rats in an experimental model of endocarditis showed a complete inversion in the outcome, with a failure of therapy in rats infected with WT P483R and the complete disappearance of bacteria in animals infected with Tol1 R483P.

Schistosomiasis control based on repeated chemotherapy in a rural village of the sugar-cane zone in Northeast Brazil

A schedule of repeated chemotherapy with oxamniquine, consisting of biannual treatment of school-aged (7-13 years) children and annual treatment of all other age groups, was used in a representative rural village from a highly endemic area of schistosomiasis in Pernambuco. Significant reductions in infection were obtained only after two cycles of treatment, as the overall prevalence decreased from 72.6% to 41.7% and the geometric mean egg counts per gram of faeces among positives fell from 188.4 to 76. In a school-aged cohort (n=29) three treatments at six-month intervals were necessary to significantly reduce the proportion of positives (from 75.9% to 51.7%). In a cohort of children under 7 years of age (n=20) the proportion of positives actually increased (from 30% to 45%) despite two annual treatments. Water contact was intense and host snail density was relatively high. As there is no short-term perspective of improved sanitation, auxiliary measures such as focal mollusciciding are needed for an adequate control of schistosomiasis in this and alike areas.

A 35.7 kb DNA fragment from the Bacillus subtilis chromosome containing a putative 12.3 kb operon involved in hexuronate catabolism and a perfectly symmetrical hypothetical catabolite-responsive element.

The Bacillus subtilis strain 168 chromosomal region extending from 109 degrees to 112 degrees has been sequenced. Among the 35 ORFs identified, cotT and rapA were the only genes that had been previously mapped and sequenced. Out of ten ORFs belonging to a single putative transcription unit, seven are probably involved in hexuronate catabolism. Their sequences are homologous to Escherichia coli genes exuT, uidB, uxaA, uxaB, uxaC, uxuA and uxuB, which are all required for the uptake of free D-glucuronate, D-galacturonate and beta-glucuronide, and their transformation into glyceraldehyde 3-phosphate and pyruvate via 2-keto-3-deoxygluconate. The remaining three ORFs encode two dehydrogenases and a transcriptional regulator. The operon is preceded by a putative catabolite-responsive element (CRE), located between a hypothetical promoter and the RBS of the first gene. This element, the longest and the only so far described that is fully symmetrical, consists of a 26 bp palindrome matching the theoretical B. subtilis CRE sequence. The remaining predicted amino acid sequences that share homologies with other proteins comprise: a cytochrome P-450, a glycosyltransferase, an ATP-binding cassette transporter, a protein similar to the formate dehydrogenase alpha-subunit (FdhA), protein similar to NADH dehydrogenases, and three homologues of polypeptides that have undefined functions.

Proposed Sugar Sweetened Drinks Tax: Health Impact Assessment

The Institute of Public Health in Ireland (IPH) was requested by the Department of Health (RoI) to undertake a Health Impact Assessment (HIA) of a proposed tax on sugar sweetened drinks (SSDs) in 2012. The public health priority for this proposal was to consider the potential of such a tax to address the problem of overweight and obesity in Ireland. The HIA was overseen by the Special Action Group on Obesity (SAGO) and guided by a steering group. The HIA process involved a population profile, a stakeholder consultation event and a literature review. This information, paralleled by a modelling exercise undertaken by Dr. Mike Rayner and his team in the University of Oxford was presented to the steering group to inform their conclusions.

Proposed Sugar Sweetened Drinks Tax: Health Impact Assessment Technical Report

The Institute of Public Health in Ireland (IPH) was requested by the Department of Health to undertake a Health Impact Assessment (HIA) of a proposed tax on sugar sweetened drinks (SSDs) in 2012. The public health priority for this proposal was to consider the potential of such a tax to address the problem of overweight and obesity in Ireland. The HIA was overseen by the Special Action Group on Obesity (SAGO) and guided by a steering group. The HIA process involved a population profile, a stakeholder consultation event and a literature review. This information, paralleled by a modelling exercise undertaken by Dr. Mike Rayner and his team in the University of Oxford was presented to the steering group to inform their conclusions.  This is the Technical Report.

Replacing oxamniquine by praziquantel against Schistosoma mansoni infection in a rural community from the sugar-cane zone of Northeast Brazil: an epidemiological follow-up

A group of 52 villagers was followed-up for three years regarding Schistosoma mansoni infection. All villagers were periodically surveyed by the Kato-Katz method. In March 1997 and March 1998 the positives were treated with oxamniquine (15-20 mg/kg), and in March 1999, with praziquantel (60 mg/kg). All infection indices decreased substantially between March 1999 and March 2000: prevalence of infection (from 32.7% to 21.2%), prevalence of moderate/heavy infection (from 7.7% to 1.9%), intensity of infection (from 23.1 epg to 7.4 epg) and reinfection (from 35.7% to 14.3%). Negativation increased from 53.8 to 82.4. An optimistic prognostic is assumed in the short term for the introduction of praziquantel in the study area.

Proposed Sugar Sweetened Drinks Tax: Health Impact Assessment (HIA)

Proposed Sugar Sweetened Drinks Tax: Health Impact Assessment (HIA)   Click here to download Background to the Health Impact Assessment on Sugar Sweetened Drink PDF 49KB Click here to download Proposed Sugar Sweetened Drinks Tax: Health Impact Assessment (HIA) PDF 9.22MB Click here to download Proposed Sugar Sweetened Drinks Tax: Health Impact Assessment (HIA) Technical Report PDF 19.2MB

Sugar Reduction: Responding to the Challenge

In ‘Sugar Reduction: Responding to the Challenge’, PHE is calling on charities, non-governmental organisations (NGOs), academics, businesses, retailers and consumers to work together to reduce the amount of sugar we eat as a nation. By analysing dietary data and discussing food habits with stakeholders, we have identified a range of areas that need exploring further. PHE already runs successful marketing campaigns designed to promote healthy living. To build on this, we also want to look at the way foods are being advertised to children, financial measures that relate to sugar sweetened drinks, food procurement across the public sector and education and training. Today, PHE received a draft report from the Scientific Advisory Committee on Nutrition (SACN): ‘Carbohydrates and Health’. PHE is particularly interested in SACN’s research because it is clear that the nation is consuming more sugar than the UK’s current recommendations. Diets high in sugar can contribute to excess calorie intake, which can lead to weight gain and obesity.

Sublingual sugar for hypoglycaemia in children with severe malaria: a pilot clinical study.

BACKGROUND: Hypoglycaemia is a poor prognostic indicator in severe malaria. Intravenous infusions are rarely feasible in rural areas. The efficacy of sublingual sugar (SLS) was assessed in a pilot randomized controlled trial among hypoglycaemic children with severe malaria in Mali. METHODS: Of 151 patients with presumed severe malaria, 23 children with blood glucose concentrations < 60 mg/dl (< 3.3 mmol/l) were assigned randomly to receive either intravenous 10% glucose (IVG; n = 9) or sublingual sugar (SLS; n = 14). In SLS, a teaspoon of sugar, moistened with a few drops of water, was gently placed under the tongue every 20 minutes. The child was put in the recovery position. Blood glucose concentration (BGC) was measured every 5-10 minutes for the first hour. All children were treated for malaria with intramuscular artemether. The primary outcome measure was treatment response, defined as reaching a BGC of >or= 3.3 mmol/l (60 mg/dl) within 40 minutes after admission. Secondary outcome measures were early treatment response at 20 minutes, relapse (early and late), maximal BGC gain (CGmax), and treatment delay. RESULTS: There was no significant difference between the groups in the primary outcome measure. Treatment response occurred in 71% and 67% for SLS and IVG, respectively. Among the responders, relapses occurred in 30% on SLS at 40 minutes and in 17% on IVG at 20 minutes. There was one fatality in each group. Treatment failures in the SLS group were related to children with clenched teeth or swallowing the sugar, whereas in the IVG group, they were due to unavoidable delays in beginning an infusion (median time 17.5 min (range 3-40).Among SLS, the BGC increase was rapid among the nine patients who really kept the sugar sublingually. All but one increased their BGC by 10 minutes with a mean gain of 44 mg/dl (95%CI: 20.5-63.4). CONCLUSION: Sublingual sugar appears to be a child-friendly, well-tolerated and effective promising method of raising blood glucose in severely ill children. More frequent repeated doses are needed to prevent relapse. Children should be monitored for early swallowing which leads to delayed absorption, and in this case another dose of sugar should be given. Sublingual sugar could be proposed as an immediate "first aid" measure while awaiting intravenous glucose. In many cases it may avert the need for intravenous glucose.

The repressor element silencing transcription factor (REST)-mediated transcriptional repression requires the inhibition of Sp1.

The terminal differentiation of neuronal and pancreatic beta-cells requires the specific expression of genes that are targets of an important transcriptional repressor named RE-1 silencing transcription factor (REST). The molecular mechanism by which these REST target genes are expressed only in neuronal and beta-cells and are repressed by REST in other tissues is a central issue in differentiation program of neuronal and beta-cells. Herein, we showed that the transcriptional factor Sp1 was required for expression of most REST target genes both in insulin-secreting cells and neuronal-like cells where REST is absent. Inhibition of REST in a non-beta and a non-neuronal cell model restored the transcriptional activity of Sp1. This activity was also restored by trichostatin A indicating the requirement of histone deacetylases for the REST-mediated silencing of Sp1. Conversely, exogenous introduction of REST blocked Sp1-mediated transcriptional activity. The REST inhibitory effect was mediated through its C-terminal repressor domain, which could interact with Sp1. Taken together, these data show that the inhibition of Sp1 by REST is required for the silencing of its target genes expression in non-neuronal and in non-beta-cells. We conclude that the interplay between REST and Sp1 determines the cell-specific expression of REST target genes.

A missing sugar prevents glucose entry: a new twist on insulin secretion.

The signaling pathway that regulates glucose-stimulated insulin secretion depends on glucose metabolism, which is itself controlled by glucokinase. In a recent issue of Cell, show that altering N-glycosylation of the GLUT2 glucose transporter prevents its anchoring and retention at the cell surface; this impairs glucose uptake and insulin secretion.