Syndicate content

Archive - Mar 2014

Date

March 15th

Novel Approach to Treating Chronic Lymphocytic Leukemia (CLL)

Dartmouth researchers have developed a novel and unique approach to treating chronic lymphocytic leukemia (CLL), a form of blood cancer that often requires repeated chemotherapy treatments to which the cancer grows resistant. The researchers, led by Alexey V. Danilov, M.D., Ph.D., assistant professor at the Geisel School of Medicine at Dartmouth and hematologist-oncologist at the Norris Cotton Cancer Center, modeled in the laboratory the lymph node microenvironment where CLL cells are found. The scientists were able to disrupt the activity of a pathway (NF-kappa B) that ensures the survival and resistance of the CLL cells in such microenvironments. The study findings were published in the March 15, 2014 issue of Clinical Cancer Research. "In this in vitro microenvironment, we used MLN4924 to disrupt the activity of the NF-kappaB pathway by targeting Nedd8, which controls activation of NF-kappa B," said Dr. Danilov. "This decreased the survival of CLL cells and re-sensitized them to conventional chemotherapy as well as novel agents. Because the CLL cells used were obtained from patients with this disorder, these findings are immediately relevant to the clinic." Dr. Danilov says that unlike other novel therapies that have shown promise in the treatment of CLL, this approach is unique because it does not directly target proteins within the B-cell receptor pathway. He also notes that other research models that mimic the natural lymph node microenvironment have typically induced prolonged survival of CLL cells and made them resistant to in vitro chemotherapy. This research used novel model systems which reversed the pro-survival effects of the microenvironment. The researchers are now working to understand the intricate mechanisms of how MLN4924 decreased the survival of CLL cells.

Scientists Use Direct Coupling Analysis to Investigate Complex Molecular Machines

Open, feed, cut. Such is the humdrum life of a motor molecule, the subject of new research at Rice University, that eats and excretes damaged proteins and turns them into harmless peptides for disposal. The why is obvious: Without these trash bins, the Escherichia coli bacteria they serve would die. And thanks to Rice, the how is becoming clearer. Biophysicists at Rice used the miniscule machine – a protease called an FtsH-AAA hexameric peptidase – as a model to test calculations that combine genetic and structural data. Their goal is to solve one of the most compelling mysteries in biology: how proteins perform the regulatory mechanisms in cells upon which life depends. The Rice team of biological physicist Dr. José Onuchic and postdoctoral researchers Drs. Biman Jana and Faruck Morcos published a new paper on the work online on March 7, 2014 in a special issue of the Royal Society of Chemistry journal, Physical Chemistry Chemical Physics. The special issue edited by Rice biophysicist Dr. Peter Wolynes and Dr. Ruth Nussinov, a researcher at the National Cancer Institute and a professor at the Sackler School of Medicine at Tel Aviv University, pulls together current thinking on how an explosion of data combined with ever more powerful computers is bringing about a second revolution in molecular biology. The paper describes the Onuchic group’s first successful attempt to feed data through their computational technique to describe the complex activity of a large molecular machine formed by proteins. Ultimately, understanding these machines will help researchers design drugs to treat diseases like cancer, the focus of Rice’s Center for Theoretical Biological Physics. “Structural techniques like X-ray crystallography and nuclear magnetic resonance have worked quite well to help us understand how smaller proteins function,” Dr.

March 14th

Scientists Induce E. coli to Resist High-Dose Radiation Damage

Capitalizing on the ability of an organism to evolve in response to punishment from a hostile environment, scientists have coaxed the model bacterium Escherichia coli to dramatically resist ionizing radiation and, in the process, reveal the genetic mechanisms that make the feat possible. The study, published on March 4, 2014 in an open-access article in the online journal eLife, provides evidence that just a handful of genetic mutations give E. coli the capacity to withstand doses of radiation that would otherwise doom the microbe. The findings are important because they have implications for better understanding how organisms can resist radiation damage to cells and repair damaged DNA. "What our work shows is that the repair systems can adapt and those adaptations contribute a lot to radiation resistance," says University of Wisconsin-Madison biochemistry Professor Michael Cox, the senior author of the eLife report. In previous work, Dr. Cox and his group, working with Dr. John R. Battista, a professor of biological sciences at Louisiana State University, showed that E. coli could evolve to resist ionizing radiation by exposing cultures of the bacterium to the highly radioactive isotope cobalt-60. "We blasted the cultures until 99 percent of the bacteria were dead. Then we'd grow up the survivors and blast them again. We did that twenty times," explains Dr. Cox. The results were E. coli capable of enduring as much as four orders of magnitude more ionizing radiation, making them similar to Deinococcusradiodurans, a desert-dwelling bacterium found in the 1950s to be remarkably resistant to radiation. That bacterium is capable of surviving more than one thousand times the radiation dose that would kill a human. "Deinococcus evolved mainly to survive desiccation, not radiation," Dr.

March 13th

Five New Species of Armored Spiders Identified in Chinese Caves

Armored spiders are medium to small species that derive their name from the complex pattern of the plates covering their abdomen strongly resembling body armor. Lurking in the darkness of caves in Southeast China, scientists have discovered and described five new species of this exciting group of spiders. The study was published online on March 13, 2014 in the open-access journal ZooKeys. The common name “armored spiders” is given to the engaging family Tetrablemmidae. Distinguished by their peculiar armor-like abdominal pattern, these tropical and subtropical spiders are mainly collected from litter and soil, but like the newly described species some live in caves. Some cave species, but also some soil inhabitants, show typical adaptations of cave spiders, such as loss of eyes. The genus Tetrablemma, for example, to which two of the new species belong, is distinguished by having only four eyes. All these new spiders were collected from the South China Karst, a UNESCO World Heritage Site. The South China Karst spans the provinces of Guangxi, Guizhou, and Yunnan. It is noted for its karst features and landscapes, as well as rich biodiversity. UNESCO describes the South China Karst as "unrivalled in terms of the diversity of its karst features and landscapes." Colleagues from the Chinese Academy of Sciences under the leadership of Professor Shuqiang LI have investigated more than 2,000 caves in the South China Karst. Several hundred new species of cave spiders are reported by Dr. Li and colleagues. As a result, the total known spider species of China increased from 2,300 species to 4,300 species in the last ten years.

USP9X Gene Critical to Brain Development

Research from the University of Adelaide in Australia has confirmed that a gene linked to intellectual disability is critical to the earliest stages of the development of human brains. Known as USP9X, the gene has been investigated by Adelaide researchers for more than a decade, but in recent years scientists have begun to understand its particular importance to brain development. In a new paper published online on March 6, 2014 in the American Journal of Human Genetics, an international research team led by the University of Adelaide's Robinson Research Institute explains how mutations in USP9X are associated with intellectual disability. These mutations, which can be inherited from one generation to the next, have been shown to cause disruptions to normal brain cell functioning. Speaking during Brain Awareness Week, senior co-author Dr. Lachlan Jolly from the University of Adelaide's Neurogenetics Research Program says the USP9X gene has shed new light on the mysteries of brain development and disability. Dr. Jolly says the base framework for the brain's complex network of cells begins to form at the embryo stage. "Not surprisingly, disorders that cause changes to this network of cells, such as intellectual disabilities, epilepsy, and autism, are hard to understand, and treat," Dr. Jolly says. "By looking at patients with severe learning and memory problems, we discovered a gene - called USP9X - that is involved in creating this base network of nerve cells. USP9X controls both the initial generation of the nerve cells from stem cells, and also their ability to connect with one another and form the proper networks," he says. "This work is critical to understanding how the brain develops, and how it is altered in individuals with brain disorders.

Harvard Scientists Create DNA Polyhedra That Could Deliver Drugs, Perform Other Functions

Move over, nanotechnologists, and make room for the biggest of the small. Scientists at Harvard's Wyss Institute have built a set of self-assembling DNA cages one-tenth as wide as a bacterium. The structures are some of the largest and most complex structures ever constructed solely from DNA, the scientists reported online on March 13, 2014 in Science. Moreover, the scientists visualized the structures using a DNA-based super-resolution microscopy method -- and obtained the first sharp 3D optical images of intact synthetic DNA nanostructures in solution. In the future, scientists could potentially coat the DNA cages to enclose their contents, packaging drugs for delivery to tissues. And, like a roomy closet, the cage could be modified with chemical hooks that could be used to hang other components such as proteins or gold nanoparticles. This could help scientists build a variety of technologies, including tiny power plants, miniscule factories that produce specialty chemicals, or high-sensitivity photonic sensors that diagnose disease by detecting molecules produced by abnormal tissue. "I see exciting possibilities for this technology," said Peng Yin, Ph.D., a Core Faculty member at the Wyss Institute and Assistant Professor of Systems Biology at Harvard Medical School, and senior author of the paper. DNA is best known as a keeper of genetic information. But scientists in the emerging field of DNA nanotechnology are exploring ways to use it to build tiny structures for a variety of applications. These structures are programmable, in that scientists can specify the sequence of letters, or bases, in the DNA, and those sequences then determine the structure it creates.

March 13th

Plant Breakthrogh: Auxin Sensing and Signaling Complex Discovered on Plant Cell Surface

Auxin, a small molecule, is a plant hormone discovered by Charles Darwin about 100 years ago. Over the years that followed it became understood to be the most important and versatile plant hormone controlling nearly all aspects of plant growth and development, such as bending of shoots toward the source of light (as discovered by Darwin), formation of new leaves, flowers, and roots, growth of roots, and gravity-oriented growth. Just how a small molecule like auxin could play such a pivotal role in plants baffled plant biologists for decades. Then, about ten years ago, an auxin sensing and signaling system was discovered in the cell's nucleus, but it still could not explain all the diverse roles of auxin. Now, plant cell biologists at the University of California (UC), Riverside, have discovered a new auxin sensing and signaling complex, one that is localized on the cell surface rather than in the cell's nucleus. The discovery provides new insights into the mode of auxin action, the researchers say. "This is a new milestone in auxin biology and will ignite interest in the field," said Dr. Zhenbiao Yang, a professor of cell biology in the Department of Botany and Plant Sciences, and the leader of the research project. "Our findings conclusively demonstrate the existence of an extracellular auxin sensing system in plants, which had long been proposed but remained elusive. Further, we have uncovered the decades-long mystery of how ABP1, an auxin-binding protein, works to control plant developmental processes." ABP1 was identified more than 40 years ago, but its role was hotly debated among plant biologists because its mode of action remained unclear — until the recent discovery by Yang's team.

MicroRNA-34 Genes Cooperate with p53 to Suppress Prostate Cancer

Cornell researchers report they have discovered direct genetic evidence that a family of genes, called microRNA-34 (miR-34), are bona fide tumor suppressors. The study was published online in the journal Cell Reports on March 13, 2014. Previous research at Cornell and elsewhere has shown that another gene, called p53, acts to positively regulate miR-34. Mutations of p53 have been implicated in half of all cancers. Interestingly, miR-34 is also frequently silenced by mechanisms other than p53 in many cancers, including those with p53 mutations. The researchers showed in mice how interplay between genes p53 and miR-34 jointly inhibits another cancer-causing gene called MET. In absence of p53 and miR-34, MET overexpresses a receptor protein and promotes unregulated cell growth and metastasis. This is the first time this mechanism has been proven in a mouse model, said Dr. Alexander Nikitin, a professor of pathology in Cornell’s Department of Biomedical Sciences and the paper’s senior author. Chieh-Yang Cheng, a graduate student in Dr. Nikitin’s lab, is the paper’s first author. In a 2011 Proceedings of the National Academy of Sciences paper, Dr. Nikitin and colleagues showed that p53 and miR-34 jointly regulate MET in cell culture but it remained unknown if the same mechanism works in a mouse model of cancer (a special strain of mice used to study human disease). The findings suggest that drug therapies that target and suppress MET could be especially successful in cancers where both p53 and miR-34 are deficient. The researchers used mice bred to develop prostate cancer, then inactivated the p53 gene by itself, or miR-34 by itself, or both together, but only in epithelium tissue of the prostate, as global silencing of these genes may have produced misleading results.

Gene Variants Protect Against Relapse after Treatment for Hepatitis C

Researchers at the Sahlgrenska Academy in Sweden have identified a gene, which explains why certain patients with chronic hepatitis C do not experience relapse after treatment. The discovery may contribute to more effective treatment. More than 100 million humans around the world are infected with hepatitis C virus. The infection gives rise to chronic liver inflammation, which may result in reduced liver function, liver cirrhosis, and liver cancer. Even though anti-viral medications often efficiently eliminate the virus, the infection recurs in approximately one fifth of the patients. Dr. Martin Lagging and co-workers at the Sahlgrenska Academy have studied an enzyme called inosine trifosfatas (ITPase), which normally prevents the incorporation of defective building blocks into RNA and DNA. Unexpectedly, they found that the gene encoding for ITPase (ITPA) had significance for the treatment outcome in chronic hepatitis C virus infection. Earlier studies had shown that approximately one third of all people carry variants of the ITPA gene that result in reduced ITPase activity. The research team at the Sahlgrenska Academy showed that patients with these gene variants exhibited a more than a five times lower risk of experiencing relapse after treatment. The study encompassed over 300 patients and was carried out in cooperation with hepatitis researchers in several Nordic countries. “Relapse after completed treatment is a significant problem in chronic hepatitis C, and the results may contribute to explaining why the infection recurs in many patients. Our hypothesis is that a low ITPase activity results in defective nucleotides being incorporated into the virus RNA, which makes the virus unstable,” Dr. Lagging said. According to Dr. Lagging, the discovery may also have significance for other virus infections.

Relationship Between Gut Bacteria and Blood Cell Development Helps Immune System Fight Infection

The human relationship with microbial life is complicated. At almost any supermarket, you can pick up both antibacterial soap and probiotic yogurt during the same shopping trip. Although there are types of bacteria that can make us sick, Caltech professor of biology and biological engineering Dr. Sarkis Mazmanian and his team are most interested in the thousands of other bacteria—many already living inside our bodies—that actually keep us healthy. His past work in mice has shown that restoring populations of beneficial bacteria can help alleviate the symptoms of inflammatory bowel disease, multiple sclerosis, and even autism. Now, he and his team have found that these good bugs might also prepare the immune cells in our blood to fight infections from harmful bacteria. In the recent study, published on March 12, 2014 in the journal Cell Host & Microbe, the researchers found that beneficial gut bacteria were necessary for the development of innate immune cells—specialized types of white blood cells that serve as the body's first line of defense against invading pathogens. In addition to circulating in the blood, reserve stores of immune cells are also kept in the spleen and in the bone marrow. When the researchers looked at the immune cell populations in these areas in so-called germ-free mice, born without gut bacteria, and in healthy mice with a normal population of microbes in the gut, they found that germ-free mice had fewer immune cells—specifically macrophages, monocytes, and neutrophils—than healthy mice. Germ-free mice also had fewer granulocyte and monocyte progenitor cells, stemlike cells that can eventually differentiate into a few types of mature immune cells. And the innate immune cells that were in the spleen were defective—never fully reaching the proportions found in healthy mice with a diverse population of gut microbes.