Detailed Structure of a CDW in a Quenched Random Field

Using high resolution x-ray scattering, we have measured the structure of the Q_1 CDW in Ta-doped NbSe_3. Detailed line shape analysis of the data demonstrates that two length scales are required to describe the phase-phase correlation function. Phase fluctuations with wavelengths less than a new length scale $a$ are suppressed and this $a$ is identified with the amplitude coherence length. We find that xi_a* = 34.4 \pm 10.3 angstroms. Implications for the physical mechanisms responsible for pinning are discussed.Comment: revtex 3.0, 3 postscript uuencoded figure

Comparison of symptomatic and functional responses to vagus nerve stimulation in ANTHEM-HF, INOVATE-HF, and NECTAR-HF

AIMS: Clinical studies of vagal nerve stimulation (VNS) for heart failure with reduced ejection fraction have had mixed results to date. We sought to compare VNS delivery and associated changes in symptoms and function in autonomic regulation therapy via left or right cervical vagus nerve stimulation in patients with chronic heart failure (ANTHEM-HF), increase of vagal tone in heart failure (INOVATE-HF), and neural cardiac therapy for heart failure (NECTAR-HF) for hypothesis generation. METHODS AND RESULTS: Descriptive statistics were used to analyse data from the public domain for differences in proportions using Pearson\u27s chi-square test, differences in mean values using Student\u27s unpaired t-test, and differences in changes of mean values using two-sample t-tests. Guideline-directed medical therapy recommendations were similar across studies. Fewer patients were in New York Heart Association 3, and baseline heart rate (HR) was higher in ANTHEM-HF. In INOVATE-HF, VNS was aimed at peripheral neural targets, using closed-loop delivery that required synchronization of VNS to R-wave sensing by an intracardiac lead. Pulse frequency was low (1-2 Hz) because of a timing schedule allowing ≤3 pulses of VNS following at most 25% of detected R waves. NECTAR-HF and ANTHEM-HF used open-loop VNS delivery (i.e. independent of any external signal) aimed at both central and peripheral targets. In NECTAR-HF, VNS delivery at 20 Hz caused off-target effects that limited VNS up-titration in a majority of patients. In ANTHEM-HF, VNS delivery at 10 Hz allowed up-titration until changes in HR dynamics were confirmed. Six months after VNS titration, significant improvements in both HR and HR variability occurred only in ANTHEM-HF. When ANTHEM-HF and NECTAR-HF were compared, greater improvements from baseline were observed in ANTHEM-HF in standard deviation in normal-to-normal R-R intervals (94 ± 26 to 111 ± 50 vs. 146 ± 48 to 130 ± 52 ms; P \u3c 0.001), left ventricular ejection fraction (32 ± 7 to 37 ± 0.4 vs. 31 ± 6 to 33 ± 6; P \u3c 0.05), and Minnesota Living with Heart Failure mean score (40 ± 14 to 21 ± 10 vs. 44 ± 22 to 36 ± 21; P \u3c 0.002). When compared with INOVATE-HF, greater improvement in 6-min walk distance was observed in ANTHEM-HF (287 ± 66 to 346 ± 78 vs. 304 ± 111 to 334 ± 111 m; P \u3c 0.04). CONCLUSIONS: In this post-hoc analysis, differences in patient demographics were seen and may have caused the differential responses in symptoms and function observed in association with VNS. Major differences in technology platforms, neural targets, VNS delivery, and HR and HR variability responses could have also potentially played a very important role. Further study is underway in a randomized controlled trial with these considerations in mind

Advances in our clinical understanding of autonomic regulation therapy using vagal nerve stimulation in patients living with heart failure

The ANTHEM-HF, INOVATE-HF, and NECTAR-HF clinical studies of autonomic regulation therapy (ART) using vagus nerve stimulation (VNS) systems have collectively provided dose-ranging information enabling the development of several working hypotheses on how stimulation frequency can be utilized during VNS for tolerability and improving cardiovascular outcomes in patients living with heart failure (HF) and reduced ejection fraction (HFrEF). Changes in heart rate dynamics, comprising reduced heart rate (HR) and increased HR variability, are a biomarker of autonomic nerve system engagement and cardiac control, and appear to be sensitive to VNS that is delivered using a stimulation frequency that is similar to the natural operating frequency of the vagus nerve. Among prior studies, the ANTHEM-HF Pilot Study has provided the clearest evidence of autonomic engagement with VNS that was delivered using a stimulation frequency that was within the operating range of the vagus nerve. Achieving autonomic engagement was accompanied by improvement from baseline in six-minute walk duration (6MWD), health-related quality of life, and left ventricular EF (LVEF), over and above those achieved by concomitant guideline-directed medical therapy (GDMT) administered to counteract harmful neurohormonal activation, with relative freedom from deleterious effects. Autonomic engagement and positive directional changes have persisted over time, and an exploratory analysis suggests that improvement in autonomic tone, symptoms, and physical capacity may be independent of baseline NT-proBNP values. Based upon these encouraging observations, prospective, randomized controlled trials examining the effects on symptoms and cardiac function as well as natural history have been warranted. A multi-national, large-scale, randomized, controlled trial is well underway to determine the outcomes associated with ART using autonomic nervous system engagement as a guide for VNS delivery

A Microcosm of the Biomedical Research Experience for Upper-level Undergraduates

The skill set required of biomedical researchers continues to grow and evolve as biology matures as a natural science. Science necessitates creative yet critical thinking, persuasive communication skills, purposeful use of time, and adeptness at the laboratory bench. Teaching these skills can be effectively accomplished in an inquiry-based, active-learning environment at a primarily undergraduate institution. Cell Biology Techniques, an upper-level cell biology laboratory course at St. John Fisher College, features two independent projects that take advantage of the biology of the nematode Caenorhabditis elegans, a premier yet simple model organism. First, students perform a miniature epigenetic screen for novel phenotypes using RNA interference. The results of this screen combined with literature research direct students toward a singe gene that they attempt to subclone in the second project. The biology of the chosen gene/protein also becomes an individualized focal point with respect to the content of the laboratory. Progress toward course goals is evaluated using written, oral, and group-produced assignments, including a concept map. Pre- and postassessment indicates a significant increase in the understanding of broad concepts in cell biological research

Optics and Quantum Electronics

Contains table of contents for Section 3 and reports on eighteen research projects.Defense Advanced Research Projects Agency/MIT Lincoln Laboratory Contract MDA972-92-J-1038Joint Services Electronics Program Grant DAAH04-95-1-0038National Science Foundation Grant ECS 94-23737U.S. Air Force - Office of Scientific Research Contract F49620-95-1-0221U.S. Navy - Office of Naval Research Grant N00014-95-1-0715MIT Center for Material Science and EngineeringNational Center for Integrated Photonics Technology Contract DMR 94-00334National Center for Integrated Photonics TechnologyU.S. Navy - Office of Naval Research (MFEL) Contract N00014-94-1-0717National Institutes of Health Grant 9-R01-EY11289MIT Lincoln Laboratory Contract BX-5098Electric Power Research Institute Contract RP3170-25ENEC

Corrigendum to "Overview: oxidant and particle photochemical processes above a south-east Asian tropical rainforest (the OP3 project): introduction, rationale, location characteristics and tools" published in Atmos. Chem. Phys., 10, 169–199, 2010

Author(s): Hewitt, CN; Lee, JD; MacKenzie, AR; Barkley, MP; Carslaw, N; Carver, GD; Chappell, NA; Coe, H; Collier, C; Commane, R; Davies, F; Davison, B; DiCarlo, P; Di Marco, CF; Dorsey, JR; Edwards, PM; Evans, MJ; Fowler, D; Furneaux, KL; Gallagher, M; Guenther, A; Heard, DE; Helfter, C; Hopkins, J; Ingham, T; Irwin, M; Jones, C; Karunaharan, A; Langford, B; Lewis, AC; Lim, SF; MacDonald, SM; Mahajan, AS; Malpass, S; McFiggans, G; Mills, G; Misztal, P; Moller, S; Monks, PS; Nemitz, E; Nicolas-Perea, V; Oetjen, H; Oram, DE; Palmer, PI; Phillips, GJ; Pike, R; Plane, JMC; Pugh, T; Pyle, JA; Reeves, CE; Robinson, NH; Stewart, D; Stone, D; Whalley, LK; Yang,

Machine learning identification of thresholds to discriminate osteoarthritis and rheumatoid arthritis synovial inflammation

Background We sought to identify features that distinguish osteoarthritis (OA) and rheumatoid arthritis (RA) hematoxylin and eosin (H&E)-stained synovial tissue samples. Methods We compared fourteen pathologist-scored histology features and computer vision-quantified cell density (147 OA and 60 RA patients) in H&E-stained synovial tissue samples from total knee replacement (TKR) explants. A random forest model was trained using disease state (OA vs RA) as a classifier and histology features and/or computer vision-quantified cell density as inputs. Results Synovium from OA patients had increased mast cells and fibrosis (p < 0.001), while synovium from RA patients exhibited increased lymphocytic inflammation, lining hyperplasia, neutrophils, detritus, plasma cells, binucleate plasma cells, sub-lining giant cells, fibrin (all p < 0.001), Russell bodies (p = 0.019), and synovial lining giant cells (p = 0.003). Fourteen pathologist-scored features allowed for discrimination between OA and RA, producing a micro-averaged area under the receiver operating curve (micro-AUC) of 0.85±0.06. This discriminatory ability was comparable to that of computer vision cell density alone (micro-AUC = 0.87±0.04). Combining the pathologist scores with the cell density metric improved the discriminatory power of the model (micro-AUC = 0.92±0.06). The optimal cell density threshold to distinguish OA from RA synovium was 3400 cells/mm2, which yielded a sensitivity of 0.82 and specificity of 0.82. Conclusions H&E-stained images of TKR explant synovium can be correctly classified as OA or RA in 82% of samples. Cell density greater than 3400 cells/mm2 and the presence of mast cells and fibrosis are the most important features for making this distinction

Optics and Quantum Electronics

Contains table of contents for Section 3 and reports on twenty research projects.Charles S. Draper Laboratories Contract DL-H-467138Joint Services Electronics Program Contract DAAL03-92-C-0001Joint Services Electronics Program Grant DAAH04-95-1-0038U.S. Air Force - Office of Scientific Research Contract F49620-91-C-0091MIT Lincoln LaboratoryNational Science Foundation Grant ECS 90-12787Fujitsu LaboratoriesNational Center for Integrated PhotonicsHoneywell Technology CenterU.S. Navy - Office of Naval Research (MFEL) Contract N00014-94-1-0717U.S. Navy - Office of Naval Research (MFEL) Grant N00014-91-J-1956National Institutes of Health Grant NIH-5-R01-GM35459-09U.S. Air Force - Office of Scientific Research Grant F49620-93-1-0301MIT Lincoln Laboratory Contract BX-5098Electric Power Research Institute Contract RP3170-25ENEC

Evaluating Gene Drive Approaches for Public Benefit

Gene drive approaches—those which bias inheritance of a genetic element in a population of sexually reproducing organisms—have the potential to provide important public benefits. The spread of selected genetic elements in wild populations of organisms may help address certain challenges, such as transmission of vector-borne human and animal diseases and biodiversity loss due to invasive animals. Adapting various naturally occurring gene drive mechanisms to these aims is a long-standing research area, and recent advances in genetics have made engineering gene drive systems significantly more technically feasible. Gene drive approaches would act through changes in natural environments, thus robust methods to evaluate potential research and use are important. Despite the fact that gene drive approaches build on existing paradigms, such as genetic modification of organisms and conventional biological control, there are material challenges to their evaluation. One challenge is the inherent complexity of ecosystems, which makes precise prediction of changes to the environment difficult. For gene drive approaches that are expected to spread spatially and/or persist temporally, responding to this difficulty with the typical stepwise increases in the scale of studies may not be straightforward after studies begin in the natural environment. A related challenge is that study or use of a gene drive approach may have implications for communities beyond the location of introduction, depending on the spatial spread and persistence of the approach and the population biology of the target organism. This poses a particular governance challenge when spread across national borders is plausible. Finally, community engagement is an important element of responsible research and governance, but effective community engagement for gene drive approaches requires addressing complexity and uncertainty and supporting representative participation in decision making. These challenges are not confronted in a void. Existing frameworks, processes, and institutions provide a basis for effective evaluation of gene drive approaches for public benefit. Although engineered gene drive approaches are relatively new, the necessities of making decisions despite uncertainty and governing actions with potential implications for shared environments are well established. There are methodologies to identify potential harms and assess risks when there is limited experience to draw upon, and these methodologies have been applied in similar contexts. There are also laws, policies, treaties, agreements, and institutions in place across many jurisdictions that support national and international decision making regarding genetically modified organisms and the potential applications of gene drive approaches, such as public health and biodiversity conservation. Community engagement is an established component of many decision-making processes, and related experience and conceptual frameworks can inform engagement by researchers. The existence of frameworks, processes, and institutions provides an important foundation for evaluating gene drive approaches, but it is not sufficient by itself. They must be rigorously applied, which requires resources for risk assessment, research, and community engagement and diligent implementation by governance institutions. The continued evolution of the frameworks, processes, and institutions is important to adapt to the growing understanding of gene drive approaches. With appropriate resources and diligence, it will be possible to responsibly evaluate and make decisions on gene drive approaches for public benefit

Highly-efficient Cas9-mediated transcriptional programming

The RNA-guided nuclease Cas9 can be reengineered as a programmable transcription factor. However, modest levels of gene activation have limited potential applications. We describe an improved transcriptional regulator obtained through the rational design of a tripartite activator, VP64-p65-Rta (VPR), fused to nuclease-null Cas9. We demonstrate its utility in activating endogenous coding and noncoding genes, targeting several genes simultaneously and stimulating neuronal differentiation of human induced pluripotent stem cells (iPSCs).National Human Genome Research Institute (U.S.) (Grant P50 HG005550)United States. Dept. of Energy (Grant DE-FG02-02ER63445)Wyss Institute for Biologically Inspired EngineeringNational Science Foundation (U.S.). Graduate Research FellowshipMassachusetts Institute of Technology. Department of Biological EngineeringHarvard Medical School. Department of Genetic