Roles for a lipid phosphatase in the activation of its opposing lipid kinase.

Fig4 is a phosphoinositide phosphatase that converts PI3,5P2 to PI3P. Paradoxically, mutation of Fig4 results in lower PI3,5P2, indicating that Fig4 is also required for PI3,5P2 production. Fig4 promotes elevation of PI3,5P2, in part, through stabilization of a protein complex that includes its opposing lipid kinase, Fab1, and the scaffold protein Vac14.

The ATPase Fap7 Tests the Ability to Carry Out Translocation-like Conformational Changes and Releases Dim1 during 40S Ribosome Maturation.

Late in their maturation, nascent small (40S) ribosomal subunits bind 60S subunits to produce 80S-like ribosomes. Because of the analogy of this translation-like cycle to actual translation, and because 80S-like ribosomes do not produce any protein, it has been suggested that this represents a quality control mechanism for subunit functionality. Here we use genetic and biochemical experiments to show that the essential ATPase Fap7 promotes formation of the rotated state, a key intermediate in translocation, thereby releasing the essential assembly factor Dim1 from pre-40S subunits.

PI5P and PI(3,5)P: Minor, but Essential Phosphoinositides.

In most eukaryotes, phosphoinositides (PIs) have crucial roles in multiple cellular functions. Although the cellular levels of phosphatidylinositol 5-phosphate (PI5P) and phosphatidylinositol 3,5-bisphosphate (PI(3,5)P) are extremely low relative to some other PIs, emerging evidence demonstrates that both lipids are crucial for the endocytic pathway, intracellular signaling, and adaptation to stress. Mutations that causes defects in the biosynthesis of PI5P and PI(3,5)P are linked to human diseases including neurodegenerative disorders.

An intramolecular interaction within the lipid kinase Fab1 regulates cellular phosphatidylinositol 3,5-bisphosphate lipid levels.

Phosphorylated phosphoinositide lipids (PPIs) are low-abundance signaling molecules that control signal transduction pathways and are necessary for cellular homeostasis. The PPI phosphatidylinositol (3,5)-bisphosphate (PI(3,5)P) is essential in multiple organ systems. PI(3,5)P is generated from PI3P by the conserved lipid kinase Fab1/PIKfyve.

Close encounters of the lysosome-peroxisome kind.

Lysosomes provide a major source for cellular cholesterol; however, most of this cholesterol is trafficked to the plasma membrane via unknown mechanisms. Chu et al. identify an unexpected role for peroxisomes in the transport of cholesterol from the lysosome to the plasma membrane via a lysosome-peroxisome membrane contact site.

Activity-dependent PI(3,5)P2 synthesis controls AMPA receptor trafficking during synaptic depression.

Dynamic regulation of phosphoinositide lipids (PIPs) is crucial for diverse cellular functions, and, in neurons, PIPs regulate membrane trafficking events that control synapse function. Neurons are particularly sensitive to the levels of the low abundant PIP, phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2], because mutations in PI(3,5)P2-related genes are implicated in multiple neurological disorders, including epilepsy, severe neuropathy, and neurodegeneration. Despite the importance of PI(3,5)P2 for neural function, surprisingly little is known about this signaling lipid in neurons, or any cell type.

A translation-like cycle is a quality control checkpoint for maturing 40S ribosome subunits.

Assembly factors (AFs) prevent premature translation initiation on small (40S) ribosomal subunit assembly intermediates by blocking ligand binding. However, it is unclear how AFs are displaced from maturing 40S ribosomes, if or how maturing subunits are assessed for fidelity, and what prevents premature translation initiation once AFs dissociate. Here we show that maturation involves a translation-like cycle whereby the translation factor eIF5B, a GTPase, promotes joining of large (60S) subunits with pre-40S subunits to give 80S-like complexes, which are subsequently disassembled by the termination factor Rli1, an ATPase.

Ribosome assembly factors prevent premature translation initiation by 40S assembly intermediates.

Ribosome assembly in eukaryotes requires approximately 200 essential assembly factors (AFs) and occurs through ordered events that initiate in the nucleolus and culminate in the cytoplasm. Here, we present the electron cryo-microscopy (cryo-EM) structure of a late cytoplasmic 40S ribosome assembly intermediate from Saccharomyces cerevisiae at 18 angstrom resolution. We obtained cryo-EM reconstructions of preribosomal complexes lacking individual components to define the positions of all seven AFs bound to this intermediate.

SET7/9 catalytic mutants reveal the role of active site water molecules in lysine multiple methylation.

SET domain lysine methyltransferases (KMTs) methylate specific lysine residues in histone and non-histone substrates. These enzymes also display product specificity by catalyzing distinct degrees of methylation of the lysine ε-amino group. To elucidate the molecular mechanism underlying this specificity, we have characterized the Y245A and Y305F mutants of the human KMT SET7/9 (also known as KMT7) that alter its product specificity from a monomethyltransferase to a di- and a trimethyltransferase, respectively.

Loss of the SIN3 transcriptional corepressor results in aberrant mitochondrial function.

Background: SIN3 is a transcriptional repressor protein known to regulate many genes, including a number of those that encode mitochondrial components.

Results: By monitoring RNA levels, we find that loss of SIN3 in Drosophila cultured cells results in up-regulation of not only nuclear encoded mitochondrial genes, but also those encoded by the mitochondrial genome. The up-regulation of gene expression is accompanied by a perturbation in ATP levels in SIN3-deficient cells, suggesting that the changes in mitochondrial gene expression result in altered mitochondrial activity.

Powering through ribosome assembly.

Ribosome assembly is required for cell growth in all organisms. Classic in vitro work in bacteria has led to a detailed understanding of the biophysical, thermodynamic, and structural basis for the ordered and correct assembly of ribosomal proteins on ribosomal RNA. Furthermore, it has enabled reconstitution of active subunits from ribosomal RNA and proteins in vitro.

Integration of pre-hospital electrocardiograms and ST-elevation myocardial infarction receiving center (SRC) networks: impact on Door-to-Balloon times across 10 independent regions.

Objectives: The aim of this study was to evaluate the rate of timely reperfusion for ST-elevation myocardial infarction (STEMI) with primary percutaneous coronary intervention (PPCI) in regional STEMI Receiving Center (SRC) networks.

Background: The American College of Cardiology Door-to-Balloon (D2B) Alliance target is a >75% rate of D2B View Article and Find Full Text PDF

A retrospective study of the association between megestrol acetate administration and mortality among nursing home residents with clinically significant weight loss.

Background: Megestrol acetate (MA) is a progestin widely used to treat weight loss and cachexia in patients suffering from AIDS or cancer. Although MA is also frequently prescribed for similarly malnourished elderly individuals, the efficacy and morbidity of MA treatment in this patient population remain unclear.

Objective: The goal of this study was to examine the effects of MA therapy on weight and overall mortality in elderly nursing home residents.

Tracking health care costs: continued stability but at high rates in 2005.

Health care spending per privately insured person increased 7.4 percent in 2005, marking the third year that the cost trend hovered between 7 and 8 percent following double-digit trends in 2001 and 2002. Data for the first quarter of 2006 suggest continued stability.

High incidence of focal left ventricular wall motion abnormalities and normal coronary arteries in patients with myocardial infarctions presenting to a community hospital.

Background: Myocardial infarction with normal coronary arteries (MINCA) is a well-documented syndrome often associated with global left ventricular wall motion abnormalities (LVWMAs). Recent literature has emphasized the occurrence of Takotsubo cardiomyopathy associated with MINCA. What has not been reported is the incidence of MINCA in the general population and the relative frequency of other types of associated LVWMAs.

Why employer-sponsored insurance coverage changed, 1997-2003.

Four and a half million Americans gained employer-sponsored health insurance coverage during 1997-2001, while nearly nine million lost coverage in the ensuing economic downturn (2001-2003), after population growth was accounted for. Macroeconomic trends affecting employment, job quality, and incomes drove most of the coverage changes, although key factors varied during the two periods. Take-up rates affected coverage, mostly reflecting the interaction of premium cost trends and labor-market tightness, but take-up also was influenced by the implementation of the State Children's Health Insurance Program (SCHIP) during 1997-2001.

The effect of population aging on future hospital demand.

This analysis examines how shifts in the age distribution of the U.S. population, reflecting both the aging of the baby-boom generation and increased longevity, will affect demand for hospital inpatient services during the next ten years.

Gastrointestinal adverse events in a general population sample of nursing home residents taking cholinesterase inhibitors.

Objective: To assess the occurrence of gastrointestinal (GI) adverse events in a national sample of nursing home residents taking donepezil, galantamine, or rivastigmine.

Design: A retrospective analysis of the Minimum Data Set (MDS) was performed.

Setting: Four hundred-fifty-two nursing facilities across the United States.

Antipsychotic drug use among nursing home residents taking rivastigmine.

Objective: To evaluate whether or not rivastigmine use is associated with a decrease in the initiation of antipsychotic drug therapy among nursing home residents in the United States.

Methods: A retrospective analysis was performed using Minimum Data Set data and physician order files for newly admitted residents of 452 US nursing facilities from 2000 through 2002. The rivastigmine group included those who were diagnosed with Alzheimers disease (AD) and began rivastigmine treatment within 30 days of diagnosis.

Geography and destiny: local-market perspectives on developing Medicare Advantage regional plans.

The Medicare Prescription Drug, Improvement, and Modernization Act (MMA) of 2003 established regional preferred provider organizations (PPOs) as a new private-plan option for beneficiaries in the Medicare Advantage (MA) program, starting in 2006. Developing network-based Medicare products uniformly priced across statewide or multistate regions presents unprecedented challenges and opportunities for health insurers. We held discussions with local health plan and hospital informants in six of the twelve Community Tracking Study (CTS) communities to obtain their perspectives on key considerations in evaluating whether they can and will offer regional PPO products under the MA program.

Tracking health care costs: declining growth trend pauses in 2004.

Health care spending increased 8.2 percent in 2004. This was virtually unchanged from 2003, which suggests that health care cost trends have stabilized.

Comparison of pressure ulcer treatments in long-term care facilities: clinical outcomes and impact on cost.

This study compared clinical outcomes and nursing labor costs associated with (a) balsam Peru, hydrogenated castor oil, and trypsin (BCT) ointment; (b) BCT + Other; and (c) Other treatments in 2014 wound episodes occurring in 861 patients (mean 2.34 wounds/patient). Treatment with BCT ointment or BCT + Other was associated with a higher healing rate (P < .

Tracking health care costs: trends turn downward in 2003.

Health care spending per privately insured person increased 7.4 percent in 2003. While lower than the 2002 increase, it still outpaced growth in the overall economy by a margin that exceeds the historical average.