A Genetic Dissection of Mitochondrial Respiratory Chain Biogenesis

Mitochondria house the mitochondrial respiratory chain (MRC), the main site for cellular respiration and energy production. The MRC consists of five large protein complexes (I-V) in the inner mitochondrial membrane. Despite the fundamental role of the MRC in cellular energy generation and its involvement in several human diseases, we still do not know all the proteins required for its formation. To address this gap in our knowledge, we have developed an integrative approach based on clues from evolutionary history and protein localization to shortlist 56 uncharacterized proteins that are physically localized to the mitochondria of yeast and humans. A recent study on mitochondrial disease patients identified potential pathogenic mutations in one of our prioritized candidate genes, C1orf31, suggesting its involvement in MRC biogenesis. Due to the lack of an assigned function to C1orf31, it was not possible to prove the pathogenicity of the patient mutations. Therefore, our study focused on determining the role of C1orf31 in MRC biogenesis. We identified a yeast, Saccharomyces cerevisiae, ortholog of C1orf31, named Coa6, by BLAST analysis, allowing us to use this genetically tractable model system to quickly decipher the protein’s function. Using coa6Δ yeast cells, we show that Coa6 is required for respiratory growth, cellular respiration, and MRC complex IV biogenesis. A sequence analysis of Coa6 identified a conserved, non-canonical, putative copper-binding motif, suggesting its role in copper delivery to MRC complex IV, the only copper-containing MRC complex. Indeed, copper supplementation rescues the respiratory defect of coa6Δ yeast cells, while copper starvation exacerbates the respiratory growth phenotype. Furthermore, we show that conserved residues in the putative copper-binding motif, including the residues mutated in the human mitochondrial disease patient, are essential for Coa6 function, thus confirming the pathogenicity of the patient mutations. Based on these results, we hypothesize that Coa6 is a mitochondrial copper metallochaperone required for delivery of copper to MRC complex IV. In support of this hypothesis, we show that the coa6Δ phenotype is exacerbated when the gene for another known copper metallochaperone, Sco2, is deleted, indicating that these two proteins have an overlapping function in delivering copper to MRC complex IV

A Primer for the Act-1 Language

This document is intended to describe the current design for computer programming language, Act-1. It describes the Actor computational model, which Act-1 was designed to support. A perspective is provided from which to view the language, with respect to existing computer language systems and to the computer system and environment under development for support of the language. The language is informally introduced in a tutorial fashion and demonstrated through examples. A programming strategy for the language is described, further illustrating its use.MIT Artificial Intelligence Laborator

Hormonal regulation of apolipoproteins synthesis and secretion in human hepatocytes.

Faulty regulation of various apolipoproteins by the human liver may be an important contributor in the development of coronary heart disease. The factors that regulate hepatic apolipoprotein production are largely unknown. In cell culture, insulin appeared to reduce the secretion of apolipoprotein B, whereas thyroid hormone stimulated apolipoprotein B secretion. Both of these effects were found to be dose-dependent. In order to understand the mechanisms underlying the regulation of hepatic apolipoprotein B secretion, a cell-free translation system derived from a human hepatoma cell-line, HepG2, was developed to investigate the rate of apolipoprotein B synthesis. Extracts of HepG2 cells were found to have high in vitro protein synthesizing activity, and were shown to efficiently synthesize in vitro a number of liver specific proteins, including the unusually large apolipoprotein B molecule. This in vitro system along with whole-cell pulse labeling experiments were used to study the effects of insulin and thyroid hormone on apolipoproteins B, E and A-I synthesis and secretion in HepG2 cells. Source: Dissertation Abstracts International, Volume: 56-01, Section: B, page: 0226. Adviser: Khosrow Adeli. Thesis (Ph.D.)--University of Windsor (Canada), 1994

Effects of statins on the secretion of human serum albumin in cultured HepG2 cells

Statins reduce cholesterol biosynthesis by inhibiting HMG-CoA reductase and thereby lower total cholesterol and LDL cholesterol levels in serum, which in turn lower the incidence of cardiovascular disease (CVD). Statins are also known to modulate various cellular functions such as gene expression, cell proliferation, and programmed cell death through inhibition of downstream intermediates in cholesterol synthesis. In this study, we have investigated the possible effects of statins on the secretion of serum albumin from cultured HepG2 cells since high levels of serum albumin are associated with reduced risks for CVD and statins are effective in lowering the risk of CVD through other effects in addition to their effects on serum total cholesterol and LDL cholesterol levels, known as pleiotropic effects. Our results showed that simvastatin increased HSA secretion up to 32.3% compared to the control group. Among 3 statin analogs we tested, simvastatin exhibited the highest stimulatory effects on HSA secretion compared to the control group. Our study also showed that the increased HSA secretions from HepG2 cells by simvastatin treatments were due to the increased rate of HSA synthesis, not due to the reduced posttranslational degradation rate of HSA. Our finding suggests another added benefit of statins' treatments in preventing CVD through stimulation of HSA biosynthesis

Breast Cancer and Pregnancy: Current Concepts in Diagnosis and Treatment

This review evaluates the available data to help guide patients and caregivers when developing treatment plans for women diagnosed with breast cancer during pregnancy

Multidetector cardiac tomography: A useful tool before cardiac resynchronization therapy

Background: Left ventricular lead placement in a suitable coronary vein is a key determi­nant of responsiveness to cardiac resynchronization therapy (CRT). Multidetector cardiac tomography (MDCT) is a non-invasive alternative to depict cardiac venous anatomy although coronary sinus (CS) retrograde venography (RV) is the gold standard. The aim of this study was to evaluate the accuracy of MDCT to determine the presence of CS tributaries before CRT. Methods: A retrospective analysis of 41 consecutive patients eligible to CRT was performed. MDCT was assessed in all patients before CRT and RV was achieved in 39 patients. Both methods evaluated the presence of the inferior interventricular vein (IIV), posterior vein (PV) and lateral main vein (LMV). CS ostium diameter and distance between the CS ostium and right atrium (RA) lateral wall were also measured. Results: The IIV was identified in 100% of MDCT and in 43.6% of RV. In comparison to RV, the MDCT’s sensitivity to identify PV and LMV was 100% for both, kappa coefficient of 0.792 (CI 95% 0.46–0.93) and 0.69 (CI 95% 0.46–0.91), respectively. There was no significant difference between ischemic and non-ischemic patients regarding the presence of PV or LMV. Median CS antero-posterior diameter was 10.3 mm (IQR 7.5–13) and supero-inferior was 14.1 mm (IQR 11.5–17) (p < 0.01). A positive correlation (p < 0.001) between echocardiographic RA area and the distance from CS ostium to the RA lateral wall in the MDCT was observed. Conclusions: MDCT is as accurate as RV to depict CS and its tributaries (IIV, PV, LMV), and it could be useful as a non-invasive technique before CRT

High-g accelerometer based on an in-fiber bragg grating sensor

An accelerometer based on an in-fiber Bragg grating sensor has been fabricated and demonstrated. The grating sensor operates linearly up to accelerations of 170,000gn. The design, testing and performance of the accelerometer are discussed

The establishment and utility of Sweha-Reg: a Swedish population-based registry to understand hereditary angioedema

<p>Abstract</p> <p>Background</p> <p>The importance of acquiring comprehensive epidemiological and clinical data on hereditary angioedema has increasingly caught the attention of physicians and scientists around the world. The development of networks and creation of comprehensive policies to improve care of people suffering from rare diseases, such as hereditary angioedema, is a stated top priority of the European Union.</p> <p>Hereditary angioedema is a rare disease, that it may be life-threatening. Although the exact prevalence is unknown, current estimates suggest that it is 1/10,000–1/150,000 individuals. The low prevalence requires combined efforts to gain accurate epidemiological data on the disease and so give us tools to reduce morbidity and mortality, and improve quality of life of sufferers.</p> <p>Methods</p> <p>Sweha-Reg is a population-based registry of hereditary angioedema in Sweden with the objectives of providing epidemiological data, and so creates a framework for the study of this disease. The registry contains individual-based data on diagnoses, treatments and outcomes.</p> <p>Conclusion</p> <p>The present manuscript seeks to raise awareness of the existence of Sweha-Reg to stimulate the international collaboration of registries. A synthesis of data from similar registries across several countries is required to approach an inclusive course understanding of HAE.</p

Pain outcomes in patients with bone metastases from advanced cancer: assessment and management with bone-targeting agents

Bone metastases in advanced cancer frequently cause painful complications that impair patient physical activity and negatively affect quality of life. Pain is often underreported and poorly managed in these patients. The most commonly used pain assessment instruments are visual analogue scales, a single-item measure, and the Brief Pain Inventory Questionnaire-Short Form. The World Health Organization analgesic ladder and the Analgesic Quantification Algorithm are used to evaluate analgesic use. Bone-targeting agents, such as denosumab or bisphosphonates, prevent skeletal complications (i.e., radiation to bone, pathologic fractures, surgery to bone, and spinal cord compression) and can also improve pain outcomes in patients with metastatic bone disease. We have reviewed pain outcomes and analgesic use and reported pain data from an integrated analysis of randomized controlled studies of denosumab versus the bisphosphonate zoledronic acid (ZA) in patients with bone metastases from advanced solid tumors. Intravenous bisphosphonates improved pain outcomes in patients with bone metastases from solid tumors. Compared with ZA, denosumab further prevented pain worsening and delayed the need for treatment with strong opioids. In patients with no or mild pain at baseline, denosumab reduced the risk of increasing pain severity and delayed pain worsening along with the time to increased pain interference compared with ZA, suggesting that use of denosumab (with appropriate calcium and vitamin D supplementation) before patients develop bone pain may improve outcomes. These data also support the use of validated pain assessments to optimize treatment and reduce the burden of pain associated with metastatic bone disease