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Archive - 2014

January 30th

Scientists Determine the ARF-Related Effects of Auxins on DNA in Plants

A joint study published in Cell by the teams headed by Dr. Miquel Coll at the Institute for Research in Biomedicine (IRB Barcelona) and the Institute of Molecular Biology of the CSIC (Consejo Superior de Investigationes Cientificas), both in Barcelona, and Dr. Dolf Weijers at the University of Wageningen, in the Netherlands, has unravelled the mystery behind how the plant hormones called auxins activate multiple vital plant functions through various gene transcription factors. Auxins are plant hormones that control growth and development, that is to say, they determine the size and structure of the plant. Among their many activities, auxins favor cell growth, root initiation, flowering, fruit setting, and delay ripening. Auxins have practical applications and are used in agriculture to produce seedless fruit, to prevent fruit drop, and to promote rooting, in addition to being used as herbicides. The biomedical applications of these hormones as anti-tumor agents and to facilitate somatic cell reprogramming (the cells that form tissues) to stem cells are also being investigated. The effects of auxins in plants were first observed by Darwin in 1881, and since then this hormone has been the focus of many studies. However, although it was known how and where auxin is synthesized in the plant, how it is transported, and the receptors on which it acts, it was unclear how a hormone could trigger such diverse processes. At the molecular level, the hormone serves to unblock a transcription factor, a DNA-binding protein, which in turn activates or represses a specific group of genes. Some plants have more than 20 distinct auxin-regulated transcription factors.

Cal Tech Researchers Use Optogenetics to Show Activation of Inhibitory Neurons in Brain's Lateral Septum Increases Anxiety

According to the National Institute of Mental Health, over 18 percent of American adults suffer from anxiety disorders, characterized as excessive worry or tension that often leads to other physical symptoms. Previous studies of anxiety in the brain have focused on the amygdala, an area known to play a role in fear. But a team of researchers led by biologists at the California Institute of Technology (Caltech) had a hunch that understanding a different brain area, the lateral septum (LS), could provide more clues into how the brain processes anxiety. Their instincts paid off—using mouse models, the team has found a neural circuit that connects the LS with other brain structures in a manner that directly influences anxiety. "Our study has identified a new neural circuit that plays a causal role in promoting anxiety states," says David Anderson, the Seymour Benzer Professor of Biology at Caltech, and corresponding author of the study. "Part of the reason we lack more effective and specific drugs for anxiety is that we don't know enough about how the brain processes anxiety. This study opens up a new line of investigation into the brain circuitry that controls anxiety." The team's findings are described in the January 30, 2014 issue version of Cell. Led by Dr. Todd Anthony, a senior research fellow at Caltech, the researchers decided to investigate the so-called septohippocampal axis because previous studies had implicated this circuit in anxiety, and had also shown that neurons in a structure located within this axis—the LS—lit up, or were activated, when anxious behavior was induced by stress in mouse models. But does the fact that the LS is active in response to stressors mean that this structure promotes anxiety, or does it mean that this structure acts to limit anxiety responses following stress?

Some Lung Diseases Reversed in Mice by Manipulating Natural Pathway and Thrombospondin-1 Protein

It may be possible one day to treat several lung diseases by introducing proteins that direct lung stem cells to grow the specific cell types needed to repair the lung injuries involved in the conditions, according to new research by scientists at Boston Children's Hospital and collaborating institutions. Reporting in the January 30, 2014 issue ofCell, the researchers, led by Carla Kim, Ph.D., and Joo-Hyeon Lee, Ph.D., of the Stem Cell Research Program at Boston Children's, describe a new pathway in the lung, activated by injury, that directs stem cells to transform into specific types of cells. By enhancing this natural pathway in a mouse model, they successfully increased production of alveolar epithelial cells, which line the small sacs (alveoli) where gas exchange takes place. These cells are irreversibly damaged in diseases like pulmonary fibrosis and emphysema. By inhibiting the same pathway, the researchers ramped up production of airway epithelial cells, which become damaged in diseases affecting the lung's airways, such as asthma and bronchiolitis obliterans. Using a novel 3D culture model that mimics the environment of the lung, the researchers showed that even a single lung stem cell could be coaxed into producing alveolar and bronchiolar epithelial cells. By adding a protein known as thrombospondin-1 (TSP-1) to these cultures, they prodded the stem cells to generate alveolar cells. Dr. Kim and Dr. Lee conducted experiments using a live mouse model of fibrosis. By simply taking the endothelial cells that line the lung's many small blood vessels—which naturally produce TSP-1—and directly injecting the liquid surrounding the cultured cells into the mice, they were able to reverse the lung damage.

January 29th

RETRACTION URGED--Possibly Simpler and Faster Method of Creating Pluripotent Stem Cells Is Discovered

TEAM RESEARCHER ASKS FOR PAPER TO BE WITHDRAWN DUE TO LACK OF REPRODUCIBILITY. Breakthrough findings by Dr. Haruko Obokata (image) and colleagues at the RIKEN Center for Developmental Biology (CDB) in Japan look to upset the canonical views on the fundamental definitions of cellular differentiation and pluripotency. In a pair of reports published online on January 29, 2014 in Nature, Dr. Obokata shows that ordinary somatic cells from newborn mice can be stripped of their differentiation memory, reverting to a state of pluripotency in many ways resembling that seen in embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). The conversion process, which Obokata has named STAP (stimulus-triggered acquisition of pluripotency), requires only that the cells be shocked with a dose of sublethal stress, such as low pH or mechanical force, in order to trigger a remarkable transformation, in which the cells shrink, lose the functional characteristics specific to their somatic cell type, and enter a state of stem cell-like pluripotency. Such STAP cells show all the hallmarks of pluripotency, and contribute to chimeric mice and germline transmission when injected into early stage embryos. Even more interestingly, STAP cells show a level of plasticity that exceeds that even of ESCs and iPSCs, in that they can give rise to cells of both embryonic and extraembryonic lineages; other pluripotent stem cells typically only generate embryonic lineage cells. STAP cells also differ from stem cells in their lower ability to proliferate in culture, but Dr.

Puzzle of Bacteria’s CRISPR RNA-Guided Cas9-Based Destruction of Foreign DNA Solved

A central question has been answered regarding a protein that plays an essential role in the bacterial immune system and is fast becoming a valuable tool for genetic engineering. A team of researchers with the Lawrence Berkeley National Laboratory (Berkeley Lab) and the University of California (UC) Berkeley has determined how the bacterial enzyme known as Cas9, guided by RNA, is able to identify and degrade foreign DNA during viral infections, as well as induce site-specific genetic changes in animal and plant cells. Through a combination of single-molecule imaging and bulk biochemical experiments, the research team has shown that the genome-editing ability of Cas9 is made possible by the presence of short DNA sequences known as “PAM,” for protospacer adjacent motif. “Our results reveal two major functions of the PAM that explain why it is so critical to the ability of Cas9 to target and cleave DNA sequences matching the guide RNA,” says Dr. Jennifer Doudna, the biochemist who led this study. “The presence of the PAM adjacent to target sites in foreign DNA and its absence from those targets in the host genome enables Cas9 to precisely discriminate between non-self DNA that must be degraded and self DNA that may be almost identical. The presence of the PAM is also required to activate the Cas9 enzyme.” With genetically engineered microorganisms, such as bacteria and fungi, playing an increasing role in the green chemistry production of valuable chemical products including therapeutic drugs, advanced biofuels, and biodegradable plastics from renewables, Cas9 is emerging as an important genome-editing tool for practitioners of synthetic biology.

MMP-9 Protein Presence or Absence Explains Differing Motor Neuron Susceptibility in ALS, Points to Potential Therapeutic Target

Columbia University Medical Center (CUMC) researchers have identified a gene, called matrix metalloproteinase-9 (MMP-9), that appears to play a major role in motor neuron degeneration in amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. The findings, made in mice, explain why most, but not all, motor neurons are affected by the disease and identify a potential therapeutic target for this still-incurable neurodegenerative disease. The study was published online on January 22, 2014 in Neuron. “One of the most striking aspects of ALS is that some motor neurons—specifically, those that control eye movement and eliminative and sexual functions—remain relatively unimpaired in the disease,” said study leader Christopher E. Henderson, Ph.D., the Gurewitsch and Vidda Foundation Professor of Rehabilitation and Regenerative Medicine, professor of pathology & cell biology and neuroscience (in neurology), and co-director of Columbia’s Motor Neuron Center. “We thought that if we could find out why these neurons have a natural resistance to ALS, we might be able to exploit this property and develop new therapeutic options.” To understand why only some motor neurons are vulnerable to ALS, the researchers used DNA microarray profiling to compare the activity of tens of thousands of genes in neurons that resist ALS (oculomotor neurons/eye movement and Onuf’s nuclei/continence) with neurons affected by ALS (lumbar 5 spinal neurons/leg movement). The neurons were taken from normal mice. “We found a number of candidate ‘susceptibility’ genes—genes that were expressed only in vulnerable motor neurons. One of those genes, MMP-9, was strongly expressed into adulthood. That was significant, as ALS is an adult-onset disease,” said co-lead author Dr. Krista J. Spiller, a former graduate student in Dr.

Engineered Molecule May Protect Brain from Detrimental Effects Linked to Diabetes

Researchers at the Hebrew University of Jerusalem have created a molecule that could potentially lower diabetic patients' higher risk of developing dementia or Alzheimer's disease. Recent studies indicate that high levels of sugar in the blood in diabetics and non-diabetics are a risk factor for the development of dementia, impaired cognition, and a decline of brain function. Diabetics have also been found to have twice the risk of developing Alzheimer's disease compared to non-diabetics. Now, researchers from the Hebrew University of Jerusalem have found a potential neuro-inflammatory pathway that could be responsible for the increases of diabetics' risk of Alzheimer's and dementia. They also reveal a potential treatment to reverse this process. The research group led by Professor Daphne Atlas, of the Department of Biological Chemistry in the Alexander Silberman Institute of Life Sciences at the Hebrew University, experimented with diabetic rats to examine the mechanism of action that may be responsible for changes in the brain due to high sugar levels. The researchers found that diabetic rats displayed high activity of enzymes called MAPK kinases, which are involved in facilitating cellular responses to a variety of stimuli, leading to inflammatory activity in brain cells and the early death of cells. The study shows that the diabetic rats given a daily injection of the sugar-lowering drug rosiglitazone for a month enjoyed a significant decrease in MAPK enzyme activity accompanied by a decrease in the inflammatory processes in the brain. According to the authors, this finding represents the first unequivocal evidence of a functional link between high blood sugar and the activation of this specific inflammatory pathway in the brain.

Nanophotonic System of “Chameleon of the Sea” May Inspire Improved Paints, Cosmetics, Electronics, and Military Camouflage

Scientists at Harvard University in Boston and the Marine Biological Laboratory (MBL) in Woods Hole, Massachusetts, hope new understanding of the natural nanoscale photonic device that enables a small marine animal to dynamically change its colors will inspire improved protective camouflage for soldiers on the battlefield. The cuttlefish, known as the "chameleon of the sea," can rapidly alter both the color and pattern of its skin, helping it blend in with its surroundings and avoid predators. In a paper published online on January 29, 2014 in the Journal of the Royal Society Interface, the Harvard-MBL team reports new details on the sophisticated biomolecular nanophotonic system underlying the cuttlefish’s color-changing ways. "Nature solved the riddle of adaptive camouflage a long time ago," said Dr. Kevin Kit Parker, Tarr Family Professor of Bioengineering and Applied Physics at the Harvard School of Engineering and Applied Sciences (SEAS) and core faculty member at the Wyss Institute for Biologically Inspired Engineering at Harvard. “Now the challenge is to reverse-engineer this system in a cost-efficient, synthetic system that is amenable to mass manufacturing." In addition to textiles for military camouflage, the findings could also have applications in materials for paints, cosmetics, and consumer electronics. The cuttlefish (Sepia officinalis) is a cephalopod, like squid and octopuses. Neurally controlled, pigmented organs called chromatophores allow it to change its appearance in response to visual clues, but scientists have had an incomplete understanding of the biological, chemical, and optical functions that make this adaptive coloration possible.

January 28th

Scientists ID Protein Crucial to the First Step of Cilium Formation, May Aid Understanding of Ciliopathies Like PKD

A team of researchers from Penn State University and the University of California-San Francisco has discovered a protein that is required for the growth of tiny, but critical, hair-like structures called cilia on cell surfaces. The discovery has important implications for human health because lack of cilia or problems with them can lead to serious diseases such as polycystic kidney disease PKD), blindness, and neurological disorders. "If we want to better understand and treat diseases related to cilium development, we need to identify important regulators of cilium growth and learn how those regulators function," said co-author Dr. Aimin Liu, Associate Professor of Biology at Penn State. "This work gives us significant insight into one of the earliest steps in cilium formation." The researchers describe their findings in a paper that was published online on January 27, 2014 in PNAS. In addition to Dr. Liu, article authors include Penn State cellular biologists Dr. Xuan Ye, Dr. Huiqing Zeng, and Dr. Gang Ning, as well as Dr. Jeremy F. Reiter, a biophysicist at the University of California-San Francisco. Cilia, which are present on the surface of almost all mammalian cells, are responsible for sending, receiving, and processing information within the body. "You could think of cilia as the cells' antennae," Dr. Liu said. "Without cilia, the cells can't sense what's going on around them, and they can't communicate." Cilia also perform important filtering and cleansing functions. For example, cilia inside the trachea, or windpipe, trap and prevent bacteria from entering the lungs. In a previous study, Dr. Liu and his colleagues learned that a protein called C2cd3 is important for cilium formation because mice that lacked this protein exhibited severe developmental problems typically associated with the lack of cilia.

Gone Today, Hair Tomorrow !

One potential approach to reversing hair loss uses stem cells to regenerate the missing or dying hair follicles. But it hasn't been possible to generate sufficient number of hair-follicle-generating stem cells – until now. Xiaowei "George" Xu, M.D., Ph.D., Associate Professor of Pathology and Laboratory Medicine and Dermatology at the Perelman School of Medicine, University of Pennsylvania (Penn), and colleagues published online on January 26, 2014 in Nature Communications a method for converting adult cells into epithelial stem cells (EpSCs), the first time anyone has achieved this in either humans or mice. The epithelial stem cells, when implanted into immunocompromised mice, regenerated the different cell types of human skin and hair follicles, and even produced structurally recognizable hair shaft, raising the possibility that they may eventually enable hair regeneration in people. Dr. Xu and his team, which includes researchers from Penn's Departments of Dermatology and Biology, as well as the New Jersey Institute of Technology, started with human skin cells called dermal fibroblasts. By adding three genes, they converted those cells into induced pluripotent stem cells (iPSCs), which have the capability to differentiate into any cell types in the body. They then converted the iPS cells into epithelial stem cells, normally found at the bulge of hair follicles. Starting with procedures other research teams had previously worked out to convert iPSCs into keratinocytes, Dr. Xu's team demonstrated that by carefully controlling the timing of the growth factors the cells received, they could force the iPSCs to generate large numbers of epithelial stem cells. In the Xu study, the team's protocol succeeded in turning over 25% of the iPSCs into epithelial stem cells in 18 days.