May 20, 2011 - Search Search. Go to top of page Toggle menu. Institution: Google Indexer .... and chromatin remodeling.
EDITORS’CHOICE EDIT ED ITEE D BY KR KR KRISTEN MUELLER AND JAKE KE Y ES E TON EVOLUTION
Nitrogenase’s Nascence On early Earth, abiotic processes formed the initial supply of fixed (bioavailable) nitrogen necessary to maintain basic metabolic functions. As life began to flourish, this supply probably couldn’t meet demand, and evolutionary pressures selected for a means of biological nitrogen fixation. How did the requisite enzymatic machinery—nitrogenase proteins that catalyze the reduction of N2 into bioavailable ammonium—develop, and which microorganisms possessed it? By examining phylogenetic relationships between nitrogenases and other related proteins from modern bacteria and archaea (such as the one at left), Boyd et al. show that molybdenum (Mo)–dependent nitrogenases, which are currently the most common form of nitrogen-fixing enzymes, originated after vanadium- and purely iron-based variants. The first Mo-nitrogenase probably appeared 1.5 to 2.2 billion years ago in an ancestor of methanogenic archaea, and later transferred to bacteria through lateral gene transfer. At that time, the ocean was still adjusting to widespread oxygenation from oxygenic photosynthesis. Because the N2 reduction is an anaerobic process, however, it must have occurred in anoxic layers of a stratified ocean, where fixed nitrogen was limited and Mo was available from oxidative weathering of the continents. — NW Geobiology 9, 221 (2011).
Finding NEMO in the Clock Living organisms have intrinsic clocks that have an approximately 24-hour period. The specific biochemical mechanism that sets the pace of the clock, however, has not been fully described. Chiu et al. expand on earlier indications that changes in daily cycles of phosphorylation of PER (which recruits transcriptional repressors controlling the central transcriptional clock mechanism) can alter the period of the clock. Studies using cultured cells and genetically altered Drosophila showed that complex interactions of sequential phosphorylation of multiple clusters of phosphorylation sites on PER by multiple protein kinases dictated the rate at which PER became fully phosphorylated and thus targeted for degradation. The protein kinase NEMO was identified as being critical for an initial phosphorylation event that was permissive for further phosphorylation by the protein kinase DOUBLETIME. Intriguingly, NEMO functions (as do several regulators of the circadian clock) in the Wnt or Wingless signaling pathway. Yu et al.
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also implicate NEMO in pacing the Drosophila clock and found that NEMO is present in nuclear protein complexes with clock components PER, TIM, and CLK, and appears to influence phosphorylation and abundance of the transcriptional activator CLK. — LBR Cell 145, 357 (2011); Curr. Biol. 21, 756 (2011). PSYCHOLOGY
Ambiguous Evidence Two of the methodologies used to compare the efficacies of treatments are randomized placement of participants in experimental studies and statistical or propensity matching of participants on confounding variables in observational studies. Both approaches have their proponents and might plausibly carry comparable weight in evidentiary assessments. Bastardi et al. developed a scenario in which a matching study (in comparison to a randomized one) was described as favoring home care of children to one group of participants, whereas a second group of participants received the information that the matching study favored day care. All of the participants were soon
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to become parents, and their preexisting belief was that home care was superior, although half of them were intending to use day care. When confronted with these scenarios in a crossed design, those who intended to use home care for their children did not judge one methodology to be more reliable than the other and maintained their stance about the superiority of home care. On the other hand, the internally conflicted participants (that is, those who intended to use day care) did regard the matching protocol as better when it favored day care, and this sufficed to shift their belief to the point where home care and day care were viewed as equivalent. — GJC Psychol. Sci. 22, 10.1077/ 0956797611406447 (2011). B I O M AT E R I A L S
TREEting Rheumatoid Arthritis Rheumatoid arthritis is an autoimmune inflammatory disorder that can cause swelling of the joints, cartilage degradation, and eventual bone erosion. The immunological processes are controlled by a set of cytokines (cell signaling
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CREDIT: DR. RACHEL A. FOSTER
CELL SIGNALING
EDITORS’CHOICE molecules) that trigger an inflammatory response, diminish anti-inflammatory responses, and promote the differentiation of monocytes into osteoclasts. Current treatments, based on monoclonal antibodies and soluble receptors, typically target only the proinflammatory cytokines. Hayder et al. synthesized dendrimers—highly branched tree-like polymers— in which the outer branches were capped with azabisphosphonate (ABP), which has been shown to selectively target monocytes in culture. These dendrimers were tested in mice with a deficiency in the interleukin-1 receptor antagonist and in mice undergoing K/BxN serum transfer, which are two established inflammatory arthritis models. At the highest doses tested (1 and 10 mg/kg), intravenous injections completely suppressed inflammation, as evidenced by a decrease in paw swelling and little or no damage to the synovial fluid and cartilage in the ankle joints. Further tests using ex vivo human synovial tissue and human peripheral blood monocytes in vitro showed that the ABP dendrimers prevented the conversion of monocytes into osteoclasts. Because the dendrimers promote anti-inflammatory responses in addition to preventing bone loss, they may prove more effective than current treatments for rheumatoid arthritis. — MSL Sci. Transl. Med. 3, 81ra35 (2011). CELL BIOLOGY
Actin bound to RNA polymerase and the chromatin complex BAF, suggesting that it may regulate gene expression by promoting transcription and chromatin remodeling. — BAP Genes Dev. 25, 946 (2011). GENETICS
Pseudo Regulators No More For many years, pseudogenes were thought to just be “junk” DNA: present in the genome but noncoding and therefore without function. Many recent studies now indicate that this is not the case, and studies in mice and rice suggest that pseudogenes generate small RNAs that have regulatory function. Wen et al. investigated pseudogene expression in the ancient eukaryote Trypanosoma brucei, a significant human pathogen. Earlier studies suggested that T. brucei pseudogenes were important for generating chimeric genes for antigenic variation and immune escape, but it appears that by pairing with the complementary coding gene, pseudogenes in T. brucei generate small RNAs that modulate the expression of the coding gene by RNA interference. The pseudogene-derived siRNAs appear to regulate genes of diverse functions, including genes involved in metabolic processes. This discovery in an ancient protist, as well as in mice and plants, indicates that pseudogene-RNAi regulation is widespread among eukaryotes. — CA Proc. Natl. Acad. Sci. U.S.A. 108, 10.1073/ pnas.1103894108 (2011).
CREDIT: MIYAMOTO ET AL., GENES DEV. 25, 946 (2011)
New Actions for Actin Actin is a major component of the cytoskeleton and regulates fundamental cellular processes such as cell motility, cell division, and organelle movement. Actin is also present in the nucleus, participating in transcription, chromatin remodeling, and nuclear export, although additional roles for nuclear actin are still being defined. In a search for factors that regulate cellular reprogramming of differentiated cells into pluripotent cells, Miyamoto et al. identified nuclear actin as a candidate cell reprogramming factor. When somatic nuclei were transplanted into amphibian oocytes, filamentous actin localized to the nuclear envelope. One day after nuclear transfer, filamentous actin was detected in the transplanted nucleus. Polymerized nuclear actin was required for the transcriptional reactivation of Oct4, which is critical for cellular reprogramming. The actin signaling protein Toca-1 enhanced polymerization of actin and stimulated Oct4 reactivation. www.sciencemag.org
PHYSICS
Focusing On Disorder The ability of high-end optical microscopes to image the smallest of features is very much dependent on the quality of the lenses. However, the preparation and milling of the best-quality lenses add a hefty premium to the cost. In a somewhat counterintuitive approach to improving resolving capability, van Putten et al. explore the use of lenses that are completely disordered. Laser light hitting such a disordered lens creates a random pattern, or speckle, of intense, highly focused spots. By manipulating the wavefront of the laser beam with a spatial light modulator before it hits the lens, the authors show that the multiple spots can be made coincident, thereby forming a spot smaller than that from a conventional lens. They then go on to demonstrate imaging of gold particles with sub–100-nm resolution. Such an adaptive optics approach might prove a useful and ultimately cheaper method of high-resolution microscopy. — ISO
SCIENCE
Phys. Rev. Lett. 106, 193905 (2011).
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The National Library of Medicine, Friends of the National Library of Medicine, and The American Association for the Advancement of Science
2011 CONFERENCE
“Clinical Trials: New Challenges & Opportunities”
The 2011 NLM/FNLM Conference will convene major figures in government, industry, and academia, including
NIH Director Francis Collins
to discuss pressing issues in clinical trials: • Roles of NIH and ClinicalTrials.gov, the FDA, industry, and academia • Effects of social media, Web 2.0, and patient-driven networks on clinical research • Clinical research’s response to public health needs • New ways to improve trials’ efficiency and quality • Forging government-industry partnerships • Using clinical trials to improve patient care The keynote address will be delivered by
Robert Califf, MD, MACC
MONDAY–TUESDAY, JUNE 6–7, 2011 Natcher Conference Center, National Institutes of Health Bethesda, Maryland
More information and online registration, please visit www.fnlm.org.
