Properties of developmental gene regulatory networks

The modular components, or subcircuits, of developmental gene regulatory networks (GRNs) execute specific developmental functions, such as the specification of cell identity. We survey examples of such subcircuits and relate their structures to corresponding developmental functions. These relations transcend organisms and genes, as illustrated by the similar structures of the subcircuits controlling the specification of the mesectoderm in the Drosophila embryo and the endomesoderm in the sea urchin, even though the respective subcircuits are composed of nonorthologous regulatory genes

Assessment of the effect of esterified propoxylated glycerol (EPG) on the status of fat-soluble vitamins and select water-soluble nutrients following dietary administration to humans for 8weeks

AbstractThis double-blind, randomized, controlled study assessed the effect of esterified propoxylated glycerol (EPG) on fat-soluble vitamins and select nutrients in human subjects. For 8weeks, 139 healthy volunteers consumed a core diet providing adequate caloric and nutrient intakes. The diet included items (spread, muffins, cookies, and biscuits) providing EPG (10, 25, and 40g/day) vs. margarine alone (control). EPG did not significantly affect circulating retinol, α-tocopherol, or 25-OH D2, but circulating β-carotene and phylloquinone were lower in the EPG groups, and PIVKA-II levels were higher; 25-OH D3 increased but to a lesser extent than the control. The effect might be related to EPG acting as a lipid “sink” during gastrointestinal transit. No effects were seen in secondary endpoint measures (physical exam, clinical pathology, serum folate, RBC folate, vitamin B12, zinc, iron, calcium, phosphorus, osteocalcin, RBP, intact PTH, PT, PTT, cholesterol, HDL-C, LDL-C, triglycerides). Gastrointestinal adverse events (gas with discharge; diarrhea; oily spotting; oily evacuation; oily stool; liquid stool; soft stool) were reported more frequently by subjects receiving 25 or 40g/day of EPG. In general, the incidence and duration of these symptoms correlated directly with EPG dietary concentration. The results suggest 10g/day of EPG was reasonably well tolerated

SpMyb functions as an intramodular repressor to regulate spatial expression of CyIIIa in sea urchin embryos

The CyIIIa actin gene of Strongylocentrotus purpuratus is transcribed exclusively in the embryonic aboral ectoderm, under the control of 2.3 kb cis-regulatory domain that contains a proximal module that controls expression in early embryogenesis, and a middle module that controls expression in later embryogenesis. Previous studies demonstrated that the SpRunt-1 target site within the middle module is required for the sharp increase in CyIIIa transcription which accompanies differentiation of the aboral ectoderm, and that a negative regulatory region near the SpRunt-1 target site is required to prevent ectopic transcription in the oral ectoderm and skeletogenic mesenchyme. This negative regulatory region contains a consensus binding site for the myb family of transcription factors. In vitro DNA-binding experiments reveal that a protein in blastula-stage nuclei interacts specifically with the myb target site. Gene transfer experiments utilizing CyIIIa reporter constructs containing oligonucleotide substitutions indicate that this site is both necessary and sufficient to prevent ectopic expression of CyIIIa. Synthetic oligonucleotides containing the myb target site were used to purify a protein from sea urchin embryo nuclear extracts by affinity chromatography. This protein is immunoprecipitated by antibodies specific to the evolutionarily conserved myb domain, and amino acid sequences obtained from the purified protein were found to be identical to sequences within the myb domain. Sequence information was used to obtain cDNA clones of SpMyb, the S. purpuratus member of the myb family of transcription factors. Through interactions within the middle module, SpMyb functions to repress activation of CyIIIa in the oral ectoderm and skeletogenic mesenchyme

Studies on Nucleic Acid Reassociation Kinetics: Retarded Rate of Hybridization of RNA with Excess DNA

The rate of reaction of excess double-stranded bacteriophage phi X174 and plasmid RSF2124 DNA drivers with enzymatically synthesized asymmetric RNA tracers was measured. Other reactions were carried out with excess Escherichia coli DNA and E. coli RNA labeled in vivo. RNA and DNA fragment lengths were held approximately equal. For each case it was shown that in DNA excess the rate constant for RNA· DNA hybridization is 3- to 4.5-fold lower than that of the renaturation rate constant for the driver DNA. This retardation was also observed in pseudo-first-order hybridization reactions driven by excess strand-separated RSF2124 DNA. It was concluded that the rate constant for RNA· DNA hybridization depends partially on which species is in excess

Safety of Aggressive Lipid Management

Data from recent clinical trials of high- versus moderate-dose statin therapy support the recommendation to achieve a low-density lipoprotein (LDL) <100 mg/dl in high-risk patients and reveal that many patients will require a high-dose statin to achieve this goal. Overall, low rates of serious musculoskeletal (<0.6%) and hepatic (<1.3%) toxicity have been observed with high-dose statin therapy. In the long-term trials, atorvastatin 80 mg had higher rates of persistent transaminase elevations but rates of myopathy and rhabdomyolysis similar to lower doses of statins. The rate of myopathy and rhabdomyolysis for simvastatin 80 mg, although still low, was about 4× higher than for atorvastatin 80 mg and lower doses of statin. A similar margin of safety would be expected in properly selected patients with characteristics similar to those who participated in the clinical trials. High-dose statin therapy or combination therapy will be required for the large majority of very high-risk patients to achieve the optional LDL goal of <70 mg/dl. While the combination of ezetimibe, bile-acid sequestering agents, niacin, and fenofibrate with moderate dose statins appears to be reasonably safe, the long-term safety of combination with high-dose statins remains to be established. In order to optimize patient outcomes, clinicians should be aware of specific patient characteristics, such as advancing age, gender, body mass index, or glomerular filtration rate, which predict muscle and hepatic statin toxicity

Negotiated Development Denial Meets People\u27s Court: Del Monte Dunes Brings New Wildcards to Exactions Law

The United States Supreme Court Answered YES to the $1.45 million over exaction question for 1999. In City of Monterey v. Del Monte Dunes at Monterey Ltd., a unanimous court extended the scope of compensatory takings review beyond land dedication conditions into the realm of regulatory denial. Justice Kennedy\u27s opinion vitalized the legitimate state interests test from Agins v. City of Tiburon to sustain an inverse condemnation conclusion and damage award to the frustrated developer. A majority of the court also concurred that the trial court may delegate this takings conclusion to the jury under federal civil rights law. The activation of Agins\u27 substantive takings test in such challenges and the prospect of continued lay application of constitutional law to development restrictions add uncertain dimensions to exactions litigation at the millennium. In Del Monte Dunes, the Court also distinguished the instant development denial of an inverse condemnation claim from the land dedication conditions at issue in Dolan v. City of Tigard. This distinction enabled the unanimous Court to uphold the trial verdict based on Agins and avoid elements of the Ninth Circuit\u27s reasoning invoking the Dolan rough proportionality test. Other recent federal and state decisions also decline to extend Dolan\u27s applicability beyond individual land dedication development conditions to other forms of economic exactions. This year\u27s exactions and impact fee report focuses on Del Monte Dunes, namely its effects on negotiated development, trial practice, and on regulatory takings doctrine as defined by judges and juries in civil rights litigation

Negotiated Development Denial Meets People\u27s Court: Del Monte Dunes Brings New Wildcards to Exactions Law

The United States Supreme Court Answered YES to the $1.45 million over exaction question for 1999. In City of Monterey v. Del Monte Dunes at Monterey Ltd., a unanimous court extended the scope of compensatory takings review beyond land dedication conditions into the realm of regulatory denial. Justice Kennedy\u27s opinion vitalized the legitimate state interests test from Agins v. City of Tiburon to sustain an inverse condemnation conclusion and damage award to the frustrated developer. A majority of the court also concurred that the trial court may delegate this takings conclusion to the jury under federal civil rights law. The activation of Agins\u27 substantive takings test in such challenges and the prospect of continued lay application of constitutional law to development restrictions add uncertain dimensions to exactions litigation at the millennium. In Del Monte Dunes, the Court also distinguished the instant development denial of an inverse condemnation claim from the land dedication conditions at issue in Dolan v. City of Tigard. This distinction enabled the unanimous Court to uphold the trial verdict based on Agins and avoid elements of the Ninth Circuit\u27s reasoning invoking the Dolan rough proportionality test. Other recent federal and state decisions also decline to extend Dolan\u27s applicability beyond individual land dedication development conditions to other forms of economic exactions. This year\u27s exactions and impact fee report focuses on Del Monte Dunes, namely its effects on negotiated development, trial practice, and on regulatory takings doctrine as defined by judges and juries in civil rights litigation

Leczenie dużymi dawkami statyn: korzyści i bezpieczeństwo intensywnej terapii hipolipemizującej

Cholesterol frakcji LDL (LDL-C) jest biomarkerem miażdżycy. Zmniejszenie stężenia LDL-C wiąże się ze zmniejszeniem ryzyka niepożądanych punktów końcowych o etiologii sercowo-naczyniowej. W ostatnich badaniach wykazano korzyści z obniżenia stężenia LDL-C poniżej 100 mg/dl, a nawet poniżej 70 mg/dl. Na ich podstawie dokonano aktualizacji zaleceń, sugerując niższe docelowe stężenia LDL-C u niektórych pacjentów należących do grupy wysokiego ryzyka. U pacjentów bez potwierdzonej choroby wieńcowej lub ekwiwalentu choroby wieńcowej z co najmniej 2 czynnikami ryzyka, należy obliczyć 10-letnie ryzyko według skali Framingham w celu ustalenia docelowej wartości LDL-C. Wydaje się, że optymalne stężenie LDL-C u wszystkich pacjentów z chorobą sercowo-naczyniową wynosi poniżej 70 mg/dl. U pacjentów bez choroby sercowo-naczyniowej celowe jest zmniejszenie stężenia LDL-C o co najmniej 50% w stosunku do stężenia wyjściowego. Stężenie LDL-C poniżej 70 mg/dl można osiągnąć w bezpieczny sposób u większości pacjentów z chorobą sercowo-naczyniową, o ile stosuje się wysoce skuteczne leki hipolipemizujące. W ciągu ponad 20 lat stosowania statyn przez miliony pacjentów udowodniono, że taka terapia jest bezpieczna i dobrze tolerowana. Lekarze powinni wybrać lek, który pozwoli osiągnąć odpowiednie stężenie LDL-C, na podstawie danych dotyczących klinicznych punktów końcowych, wybrać odpowiednio dużą dawkę początkową oraz modyfikować dawkę tak, aby osiągnąć docelowe stężenie