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Archive - Sep 2014

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September 10th

LC-MS Analysis Shows That Timing of Food Intake Could Impact Effectiveness of TB Treatment

The timing of food intake in the early phase of TB treatment could have a negative impact on the effectiveness of TB treatment. A new study, presented at the European Respiratory Society (ERS) International Congress in Munich on September 7, 2014, suggests that eating food just before taking a TB drug could reduce the effectiveness of the medicine. Researchers conducted a small study looking at 20 patients who were about to begin treatment for TB for the first time. The patients were given the usual course of TB drugs, including isoniazid, rifampicin, pyrazinamide, and ethambutol. The drugs were administered by injection on day one and given orally on days two and three, either while fasting or with a high-carbohydrate meal. Blood samples were taken from each participant and an analytical chemistry technique, called liquid chromatography-tandem mass spectrometry, was used to separate the sample and give information about the chemicals present. This technique allows the researchers to assess concentration levels of the drug and fraction of the unchanged drug that reaches the circulation. Blood samples were taken from the same individual and in the same environment while changing the food intake. The results showed that when the drugs were given with a high-carbohydrate meal, there were lower concentrations of isoniazid, rifampicin, and pyrazinamide in the blood compared with when they were given the drugs in a fasting state. This suggests that eating a high-carbohydrate meal, before taking the drugs can make the drugs less effective. Antonia Morita Iswari, lead author from the Universitas Gadjah Mada in Indonesia and currently completing her Ph.D.

Fungal Leucinostatins Identified Using LC-MS/MS

The fungus Paecilomyces lilacinus (image) produces leucinostatins, which are peptaibiotics that exert a range of biological activities, including antimalarial, antiviral, antitumor, and phytotoxic activities. In an article published online on September 3, 2014 in The Journal of Antibiotics, Dr. Ana Martinez and Dr. Luiz Moraes, of the University of Sao Paulo in Brazil, report the development of an analytic method utilizing LC-MS/MS in the precurson ion and product ion modes to identify five new leucinostatins from this fungus. The scientists used Direct Infusion-MS (DI-MS) to help identify the most abundant leucinostatins (F, D, B2, S, A, and K). They noted that MS/MS analysis using a triple quadrupole operating at different scan modes is a versatile tool with which to study natural products, especially peptaibiotics. They commented that although DI-MS full-scan analysis is both rapid and sensitive, it cannot distinguish between peptide isomers. On the other hand, although LC-MS/MS operated in the precursor ion and product ion modes is time-consuming, it does allow the identification of the structures of isomers or isobars in a crude extract. [The Journal of Antibiotics abstract]

AB Sciex and Dalton Collaborate to Develop Antibody-Drug Conjugate Analysis Capabilities

In an August 26, 2014 press release, AB Sciex announced that it has established a research collaboration with Dalton Pharma Services (Dalton) to develop Antibody-Drug Conjugate (ADC) analysis capabilities. This will include development of a more definitive and comprehensive method for the identification of drug loading and position of conjugation on macromolecules. This collaboration is part of AB SCIEX's commitment to support the growing movement to bring targeted antibody-based therapies to market. The collective goal is to help our customers bring drugs from concept to market faster. The collaboration provides AB SCIEX, a global leader in life science analytical technologies, with the specialized synthetic conjugation capabilities of Dalton. The research includes the preparation and characterization of ADC’s by Dalton scientists working with AB SCIEX experts to develop standardized analytical procedures on the TripleTOF® 5600+ system with SelexION™ technology and the new TripleTOF® 6600 platform (image) for determining the chemical structures of conjugated molecules. "A key challenge for developing successful Antibody-Drug Conjugate medicines is understanding the structure and payload of the final molecule. Determining where the drug attaches to a particular antibody early in its development and the number of drug molecules on the antibody are important indicators of the likely success of a new ADC," explained Dr. Tan Quach, Chemistry Manager at Dalton Pharma Services. "Recent advances in mass spectrometry (MS) have provided a solution to answer the challenging questions in terms of understanding ADC drug development and working within a biological matrix,” said Dr. Chris Radloff, Vice President, LC/ MS Business at AB SCIEX.

September 9th

Scientists Discover Bacteria That Consume Hazardous Waste

Although bacteria with waste-eating properties have been discovered in relatively pristine soils before, this is the first time that microbes that can survive in the very harsh conditions expected in radioactive waste disposal sites have been found. The findings are published online on July 25, 2014 in the ISME (Multidisciplinary Journal of Microbial Ecology) journal by a team of researchers affiliated with the University of Manchester (UK), the National Council for Scientific Research–Lebanon, and the National Nuclear Laboratory (UK). The disposal of nuclear waste is very challenging, with very large volumes destined for burial deep underground. The largest volume of radioactive waste in the UK, termed 'intermediate level' and comprising of 364,000 cubic meters will be encased in concrete prior to disposal into underground vaults. When ground waters eventually reach these waste materials, they will react with the cement and become highly alkaline. This change drives a series of chemical reactions, triggering the breakdown of the various 'cellulose' based materials that are present in these complex wastes. One such product linked to these activities, isosaccharinic acid (ISA), causes much concern as it can react with a wide range of radionuclides - unstable and toxic elements that are formed during the production of nuclear power and make up the radioactive component of nuclear waste. If the ISA binds to radionuclides, such as uranium, then the radionuclides will become far more soluble and more likely to flow out of the underground vaults to surface environments, where they could enter drinking water or the food chain. However, the researchers’ new findings indicate that microorganisms may prevent this from becoming a problem.

Formation of an Ultra-Thin, Self-Hydrated Artificial Membrane

Artificial membranes mimicking those found in living organisms have many potential applications, ranging from detecting bacterial contaminants in food to toxic pollution in the environment to dangerous diseases in people. Now a group of scientists in Chile has developed a way to create these delicate, ultra-thin constructs through a "dry" process, by evaporating two commercial, off-the-shelf chemicals onto silicon surfaces. Described online on September 9, 2014 in The Journal of Chemical Physics, from AIP Publishing, this is the first time anyone has ever made an artificial membrane without mixing liquid solvents together. And because the new process creates membranes on silicon surfaces, it is a significant step toward creating bio-silicon interfaces, where biological "sensor" molecules can be printed onto cheap silicon chip holding integrated electronic circuits. "Our idea is to create a biosensor that can transmit electrical signals through the membrane," said María José Retamal, a Ph.D. student at Pontificia Universidad Católica de Chile and first author of the paper. The importance of lipid membranes to life is hard to overstate. They are a principal component of the cell, as fundamental as DNA or proteins, and all known organisms on Earth, from the tiniest bacteria to the biggest blue whales, use membranes in a multitude of ways. They separate distinct spaces within cells and define walls between neighboring cells -- a functional compartmentalization that serves many physiological processes, protecting genetic material, regulating what comes in and out of cells, and maintaining the function of separate organs.

Discovery of Nerve-Cell-Protective Molecular Target May Lead to Improved Memory and Cognitive Function in Alzheimer’s Patients

As Alzheimer's disease progresses, it kills brain cells mainly in the hippocampus and cortex, leading to impairments in "neuroplasticity," the mechanism that affects learning, memory, and thinking. Targeting these areas of the brain, scientists hope to stop or slow the decline in brain plasticity, providing a novel way to treat Alzheimer's. Ground-breaking new research has discovered a new way to preserve the flexibility and resilience of the brain. The study, led by Tel Aviv University's (TAU’s) Professor Illana Gozes and published online on September 2, 2014 in Molecular Psychiatry, reveals a nerve-cell-protective molecular target that is essential for brain plasticity. According to Professor Gozes, "This discovery offers the world a new target for drug design and an understanding of mechanisms of cognitive enhancement." Professor Gozes is the incumbent of the Lily and Avraham Gildor Chair for the Investigation of Growth Factors and Director of the Adams Super Center for Brain Studies at the Sackler Faculty of Medicine and a member of TAU's Sagol School of Neuroscience. Also contributing to the study were Dr. Saar Oz, Oxana Kapitansky, Yanina Ivashco-Pachima, Anna Malishkevich, Dr. Joel Hirsch, Dr. Rina Rosin-Arbersfeld, and their students, all from TAU. TAU staff scientists Dr. Eliezer Gildai and Dr. Leonid Mittelman provided the state-of-the-art molecular cloning and cellular protein imaging necessary for the study. The new finding is based on Professor Gozes' earlier discovery of NAP, a snippet of a protein essential for brain formation (activity-dependent neuroprotective protein [ADNP]). As a result of this discovery, a drug candidate that showed efficacy in mild cognitive impairment patients, a precursor to Alzheimer's disease, is being developed.

High-Speed Analysis of Ebola Virus-Related Epitope Data Seeks to ID Therapeutic Targets and Aid Vaccine Development

The effort to develop therapeutics and a vaccine against the deadly Ebola virus disease (EVD) requires a sophisticated understanding of the microorganism and its interaction with the host, especially the host’s immune response. Adding to the challenge, EVD can be caused by any one of five known species within the genus Ebolavirus (EBOV), in the Filovirus family. In a September 9, 2014 press release, it was announced that researchers at the La Jolla Institute for Allergy and Immunology (La Jolla Institute) and the San Diego Supercomputer Center (SDSC) at the University of California, San Diego are now assisting the scientific community by running high-speed online publications of analysis of EBOV-related epitope data being curated in the Immune Epitope Data Base (IEDB), and predicting epitopes using the IEDB Analysis Resource. Dr. Sebastian Maurer-Stroh of Bioinformatics Institute, A*STAR, Singapore is also assisting with analysis of the latest outbreak sequences of Ebola proteins. “These results are the first installment of a series of analysis, whose ultimate goal is to provide a comprehensive overview of the molecular targets of the immune responses to Ebola virus,” said Dr. Julia Ponomarenko, a senior research scientist at SDSC and UCSD PI of IEDB. The recent Ebola outbreak in West Africa has now reached historic proportions, surpassing 1,900 deaths from 3,500 confirmed or probable cases, prompting the World Health Organization (WHO) to declare an international public health emergency, according to recent news reports. Outbreaks of EVD have occurred in Africa in the past; however the current epidemic, caused by Zaire Ebolavirus, has been characterized by its unprecedented breadth and rapid spread.

Study Finds miRNA Mutations Linked With Ethnic Disparities in Cancer

One of the goals of genome sequencing is to identify genetic mutations associated with increased susceptibility to disease. Yet by and large these discoveries have been made in people of European or Asian ancestry, resulting in an incomplete picture of global genetic variation in disease vulnerability. In a new study published in the journal BMC Medical Genomics, researchers at the University of Pennsylvania (Penn) have addressed this omission. Their investigation identified more than 30 previously undescribed mutations in important regulatory molecules called microRNAs. Many of these mutations influence whether a person develops cancer or the severity of the disease. One variant has been associated with breast cancer mortality, and the team’s discovery could help explain why, once diagnosed with breast cancer, women with African ancestry are more likely to die from the disease than other women. Knowing about these differences could inform efforts to develop diagnostic tests or even treatments for diseases like cancer. Dr. Renata A. Rawlings-Goss, a postdoctoral fellow in the Department of Genetics in Penn’s Perelman School of Medicine, led the work, collaborating with the department’s Dr. Michael C. Campbell. Dr. Sarah Tishkoff, a Penn Integrates Knowledge professor with appointments in Penn Medicine’s Department of Genetics and the School of Arts & Sciences’ Department of Biology, was the study’s senior author. MicroRNAs, or miRNAs, are small molecules that are not translated into proteins, but rather, serve to regulate gene expression, usually by blocking protein production. A single miRNA can govern the expression of as many as 6,000 different genes, so a change in the way these molecules function can have significant biological effects.

Growth Factors in Breast Milk May Protect Against Serious GI Disease Seen in 10 Percent of Premature Infants

Necrotizing enterocolitis (NEC) is a devastating gastrointestinal illness affecting up to 10% of premature infants, with a 30% mortality rate, and formula feeding has been identified as a risk factor for NEC. A study published online on September 8, 2014 in The American Journal of Pathology found that growth factors present in human breast milk, but not in formula, may explain the protection against intestinal damage. Further, supplementing the diet of newborn NEC-affected rodents with these growth factors promotes epithelial cell survival. "NEC is a highly morbid disease that can lead to multiple complications, including intestinal strictures, short gut syndrome, repeated surgeries, and extended hospital stays. Advances in understanding the growth factor signaling cascades that maintain the healthy developing intestine could lead to new methods for treating or preventing this devastating illness," says Mark R. Frey, Ph.D., The Saban Research Institute of Children's Hospital Los Angeles and the Keck School of Medicine of the University of Southern California. Driving this research is the quest to understand how human breast milk protects infants from NEC. Soluble growth factors found in breast milk, such as epidermal growth factor (EGF) and heparin-binding EGF-like growth factor (HB-EGF), are thought to be possible protective molecules. Although both EGF and HB-EGF primarily activate the EGF receptor (EGFR), a member of the ErbB receptor tyrosine kinase family, HB-EGF also activates ErbB4 receptors. "We have recently demonstrated that NRG4, an ErbB4-specific ligand that does not bind or activate other family members, specifically promotes survival but not migration or proliferation of mouse colon epithelial cells," says Dr. Frey. Thus, NRG4 is a potentially unique and selective target for new therapies.

Activation of AMPK Gene May Slow Aging Process

UCLA biologists have identified a gene that can slow the aging process throughout the entire body when activated remotely in key organ systems. Working with fruit flies, the life scientists activated a gene called AMPK that is a key energy sensor in cells; it is activated when cellular energy levels are low. Increasing the amount of AMPK (image of AMPK protein) in fruit flies' intestines increased their lifespans by about 30 percent — to roughly eight weeks from the typical six — and the flies stayed healthier longer as well. The research, published online on September 4, 2014 in the open-source journal Cell Reports, could have important implications for delaying aging and disease in humans, said Dr. David Walker, an associate professor of integrative biology and physiology at UCLA and senior author of the research. "We have shown that when we activate the gene in the intestine or the nervous system, we see the aging process is slowed beyond the organ system in which the gene is activated," Dr. Walker said. Dr. Walker noted that the findings are important because extending the healthy life of humans would presumably require protecting many of the body's organ systems from the ravages of aging — but delivering anti-aging treatments to the brain or other key organs could prove technically difficult. The study suggests that activating AMPK in a more accessible organ such as the intestine, for example, could ultimately slow the aging process throughout the entire body, including the brain. Humans have AMPK, but it is usually not activated at a high level, Dr. Walker said.