Circadian enhancers coordinate multiple phases of rhythmic gene transcription in vivo.

Mammalian transcriptomes display complex circadian rhythms with multiple phases of gene expression that cannot be accounted for by current models of the molecular clock. We have determined the underlying mechanisms by measuring nascent RNA transcription around the clock in mouse liver. Unbiased examination of enhancer RNAs (eRNAs) that cluster in specific circadian phases identified functional enhancers driven by distinct transcription factors (TFs). We further identify on a global scale the components of the TF cistromes that function to orchestrate circadian gene expression. Integrated genomic analyses also revealed mechanisms by which a single circadian factor controls opposing transcriptional phases. These findings shed light on the diversity and specificity of TF function in the generation of multiple phases of circadian gene transcription in a mammalian organ.

Modulation of spectrokinetic properties of o-quinonoid reactive intermediates by electronic factors: time-resolved laser flash and steady-state photolysis investigations of photochromic 6- and 7-arylchromenes.

A ready synthetic accessibility of a series of 6- and 7-arylchromenes via Pd(0)-catalyzed Suzuki coupling protocol has permitted a comprehensive investigation of the thermal decay behavior of a broad set of photogenerated o-quinonoid reactive intermediates. It is shown that substantial mesomeric effect between the benzopyran nucleus and the aryl ring at C6 or C7 position of the former renders significant absorption beyond 350 nm such that they are readily photoactivated to yield colored o-quinonoid intermediates. The absorption spectra of the latter are found to be strongly influenced by the substituents on C2-, C6- and C7-aryl rings; indeed the colored absorptions can be conveniently tuned by appropriate choice of substituents. The thermal decay (bleaching phenomenon), which is important from the point of view of their application in ophthalmic lenses, was investigated in each case by micros-ms as well as real-time absorption spectroscopy. By careful experimentation, we have extracted the decay rate constants for Z,E and E,E o-quinonoid isomers of all 6- and 7-arylchromenes in an attempt to establish a correlation between the electronic attributes with their thermokinetic behavior. From a combined analysis of micros-ms (laser flash) and real-time kinetic data, it is shown that the colored o-quinonoid intermediates decay faster when the C2-aryl and C6-/C7-aryl rings contain electron-donating and electron-accepting groups, respectively. In the same vein, the decay was found to occur slowly for the reversed scenario, while intermediate decay rates are observed when both substituents are electron-donating. Thus, any substituent on the C2-aryl ring that contributes mesomerically to the development of charge on the quinonoid oxygen, and any substituent on the C6-/C7-aryl ring that exerts -I effect appear to expedite thermal decay. Furthermore, evidence is obtained for the first time from mus time-resolved laser-flash spectroscopy for the formation and characterization of the trans,cis (E,Z) o-quinonoid isomer, which has heretofore eluded spectral characterization in the photochromic phenomena of pyrans.

Prevalence of Nonalcoholic Fatty Liver Disease in Normal-weight and Overweight Preadolescent Children in Haryana, India.

OBJECTIVE: To document the prevalence of non-alcoholic fatty liver disease (NAFLD) and metabolic parameters among normal-weight and overweight schoolchildren. STUDY DESIGN: Cross-sectional study. SETTING: Thirteen private schools in urban Faridabad, Haryana. PARTICIPANTS: 961 school children aged 5-10 years. METHODS: Ultrasound testing was done, and 215 with fatty liver on ultrasound underwent further clinical, biochemical and virological testing. OUTCOME MEASURES: Prevalence of fatty liver on ultrasound, and NAFLD and its association with biochemical abnormalities and demographic risk factors. RESULTS: On ultrasound, 215 (22.4%) children had fatty liver; 18.9% in normal-weight and 45.6% in overweight category. Presence and severity of fatty liver disease increased with body mass index (BMI) and age. Among the children with NAFLD, elevated SGOT and SGPT was observed in 21.5% and 10.4% children, respectively. Liver enzyme derangement was significantly higher in overweight children (27% vs 19.4% in normal-weight) and severity of fatty liver (28% vs 20% in mild fatty liver cases). Eleven (8.1%) children with NAFLD had metabolic syndrome. Higher BMI (OR 35.9), severe fatty liver disease (OR 1.7) and female sex (OR 1.9) had strong association with metabolic syndrome. CONCLUSION: 22.4% of normal-weight and overweight children aged 5-10 years had fatty liver. A high proportion (18.9%) of normal-weight children with fatty liver on ultrasound indicates the silent burden in the population.