Inverse folding of RNA pseudoknot structures

Background: RNA exhibits a variety of structural configurations. Here we consider a structure to be tantamount to the noncrossing Watson-Crick and \pairGU-base pairings (secondary structure) and additional cross-serial base pairs. These interactions are called pseudoknots and are observed across the whole spectrum of RNA functionalities. In the context of studying natural RNA structures, searching for new ribozymes and designing artificial RNA, it is of interest to find RNA sequences folding into a specific structure and to analyze their induced neutral networks. Since the established inverse folding algorithms, {\tt RNAinverse}, {\tt RNA-SSD} as well as {\tt INFO-RNA} are limited to RNA secondary structures, we present in this paper the inverse folding algorithm {\tt Inv} which can deal with 3-noncrossing, canonical pseudoknot structures. Results: In this paper we present the inverse folding algorithm {\tt Inv}. We give a detailed analysis of {\tt Inv}, including pseudocodes. We show that {\tt Inv} allows to design in particular 3-noncrossing nonplanar RNA pseudoknot 3-noncrossing RNA structures-a class which is difficult to construct via dynamic programming routines. {\tt Inv} is freely available at \url{http://www.combinatorics.cn/cbpc/inv.html}. Conclusions: The algorithm {\tt Inv} extends inverse folding capabilities to RNA pseudoknot structures. In comparison with {\tt RNAinverse} it uses new ideas, for instance by considering sets of competing structures. As a result, {\tt Inv} is not only able to find novel sequences even for RNA secondary structures, it does so in the context of competing structures that potentially exhibit cross-serial interactions.Comment: 20 pages, 26 figure

Thermal Starch Properties in Corn Belt and Exotic Corn Inbred Lines and Their Crosses

More knowledge is needed about variability of starch functional traits in adapted and exotic germplasm and possible genetic effects of these traits before conducting rigorous inheritance studies and breeding programs for starch quality. We studied and compared the range of variability for starch functional traits in a set of Corn Belt inbred lines with a set of exotic inbred lines from Argentina, Uruguay, and South Africa. Reciprocal hybrids of some of the lines within each set were compared with their parents. Functional traits were examined by using differential scanning calorimetry on starch extracted from single kernels of genotypes. The set of Corn Belt lines had a wider range of values for most traits than did the set of exotic lines. For both sets of lines, the maximum value for peak height index was as high as that previously reported for the waxy endosperm mutant. Although the Corn Belt lines exhibited a wider range of values for range of retrogradation than the exotic lines, the exotic lines showed a wider range of values for percentage retrogradation. Hybrid values were not consistently higher, lower, midpoint, or similar with respect to the values of their parents. This was true regardless of germplasm type or functional trait. Reciprocal cross values showed trends suggesting reciprocal differences, although there was no trend suggesting greater effect of the female parent. These traits seem to be controlled by many modifying effects in addition to major effects. Results indicate that sufficient variability exists in Corn Belt germplasm to conduct breeding and inheritance studies effectively and that there should be potential for breeding for functional traits

Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma.

Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell- and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor

Chemotactic response and adaptation dynamics in Escherichia coli

Adaptation of the chemotaxis sensory pathway of the bacterium Escherichia coli is integral for detecting chemicals over a wide range of background concentrations, ultimately allowing cells to swim towards sources of attractant and away from repellents. Its biochemical mechanism based on methylation and demethylation of chemoreceptors has long been known. Despite the importance of adaptation for cell memory and behavior, the dynamics of adaptation are difficult to reconcile with current models of precise adaptation. Here, we follow time courses of signaling in response to concentration step changes of attractant using in vivo fluorescence resonance energy transfer measurements. Specifically, we use a condensed representation of adaptation time courses for efficient evaluation of different adaptation models. To quantitatively explain the data, we finally develop a dynamic model for signaling and adaptation based on the attractant flow in the experiment, signaling by cooperative receptor complexes, and multiple layers of feedback regulation for adaptation. We experimentally confirm the predicted effects of changing the enzyme-expression level and bypassing the negative feedback for demethylation. Our data analysis suggests significant imprecision in adaptation for large additions. Furthermore, our model predicts highly regulated, ultrafast adaptation in response to removal of attractant, which may be useful for fast reorientation of the cell and noise reduction in adaptation.Comment: accepted for publication in PLoS Computational Biology; manuscript (19 pages, 5 figures) and supplementary information; added additional clarification on alternative adaptation models in supplementary informatio

The effects of bending speed on the lumbo-pelvic kinematics and movement pattern during forward bending in people with and without low back pain

Abstract Background Impaired lumbo-pelvic movement in people with low back pain during bending task has been reported previously. However, the regional mobility and the pattern of the lumbo-pelvic movement were found to vary across studies. The inconsistency of the findings may partly be related to variations in the speed at which the task was executed. This study examined the effects of bending speeds on the kinematics and the coordination lumbo-pelvic movement during forward bending, and to compare the performance of individuals with and without low back pain. Methods The angular displacement, velocity and acceleration of the lumbo-pelvic movement during the repeated forward bending executed at five selected speeds were acquired using the three dimensional motion tracking system in seventeen males with low back pain and eighteen males who were asymptomatic. The regional kinematics and the degree of coordination of the lumbo-pelvic movement during bending was compared and analysed between two groups. Results Significantly compromised performance in velocity and acceleration of the lumbar spine and hip joint during bending task at various speed levels was shown in back pain group (p < 0.01). Both groups displayed a high degree of coordination of the lumbo-pelvic displacement during forward bending executed across the five levels of speed examined. Significant between-group difference was revealed in the coordination of the lumbo-pelvic velocity and acceleration (p < 0.01). Asymptomatic group moved with a progressively higher degree of lumbo-pelvic coordination for velocity and acceleration while the back pain group adopted a uniform lumbo-pelvic pattern across all the speed levels examined. Conclusions The present findings show that bending speed imposes different levels of demand on the kinematics and pattern of the lumbo-pelvic movement. The ability to regulate the lumbo-pelvic movement pattern during the bending task that executed at various speed levels was shown only in pain-free individuals but not in those with low back pain. Individuals with low back pain moved with a stereotyped strategy at their lumbar spine and hip joints. This specific aberrant lumbo-pelvic movement pattern may have a crucial role in the maintenance of the chronicity in back pain

Genetic ablation or chemical inhibition of phosphatidylcholine transfer protein attenuates diet?induced hepatic glucose production†‡

 Phosphatidylcholine transfer protein (PC?TP, synonym StARD2) is a highly specific intracellular lipid binding protein that is enriched in liver. Coding region polymorphisms in both humans and mice appear to confer protection against measures of insulin resistance. The current study was designed to test the hypotheses that Pctp?/? mice are protected against diet?induced increases in hepatic glucose production and that small molecule inhibition of PC?TP recapitulates this phenotype. Pctp?/? and wildtype mice were subjected to high?fat feeding and rates of hepatic glucose production and glucose clearance were quantified by hyperinsulinemic euglycemic clamp studies and pyruvate tolerance tests. These studies revealed that high?fat diet?induced increases in hepatic glucose production were markedly attenuated in Pctp?/? mice. Small molecule inhibitors of PC?TP were synthesized and their potencies, as well as mechanism of inhibition, were characterized in vitro. An optimized inhibitor was administered to high?fat?fed mice and used to explore effects on insulin signaling in cell culture systems. Small molecule inhibitors bound PC?TP, displaced phosphatidylcholines from the lipid binding site, and increased the thermal stability of the protein. Administration of the optimized inhibitor to wildtype mice attenuated hepatic glucose production associated with high?fat feeding, but had no activity in Pctp?/? mice. Indicative of a mechanism for reducing glucose intolerance that is distinct from commonly utilized insulin?sensitizing agents, the inhibitor promoted insulin?independent phosphorylation of key insulin signaling molecules. Conclusion: These findings suggest PC?TP inhibition as a novel therapeutic strategy in the management of hepatic insulin resistance

The Complete Chloroplast and Mitochondrial Genome Sequences of Boea hygrometrica: Insights into the Evolution of Plant Organellar Genomes

The complete nucleotide sequences of the chloroplast (cp) and mitochondrial (mt) genomes of resurrection plant Boea hygrometrica (Bh, Gesneriaceae) have been determined with the lengths of 153,493 bp and 510,519 bp, respectively. The smaller chloroplast genome contains more genes (147) with a 72% coding sequence, and the larger mitochondrial genome have less genes (65) with a coding faction of 12%. Similar to other seed plants, the Bh cp genome has a typical quadripartite organization with a conserved gene in each region. The Bh mt genome has three recombinant sequence repeats of 222 bp, 843 bp, and 1474 bp in length, which divide the genome into a single master circle (MC) and four isomeric molecules. Compared to other angiosperms, one remarkable feature of the Bh mt genome is the frequent transfer of genetic material from the cp genome during recent Bh evolution. We also analyzed organellar genome evolution in general regarding genome features as well as compositional dynamics of sequence and gene structure/organization, providing clues for the understanding of the evolution of organellar genomes in plants. The cp-derived sequences including tRNAs found in angiosperm mt genomes support the conclusion that frequent gene transfer events may have begun early in the land plant lineage

Improving ionospheric predictability requires accurate simulation of the mesospheric polar vortex

The mesospheric polar vortex (MPV) plays a critical role in coupling the atmosphere-ionosphere system, so its accurate simulation is imperative for robust predictions of the thermosphere and ionosphere. While the stratospheric polar vortex is widely understood and characterized, the mesospheric polar vortex is much less well-known and observed, a short-coming that must be addressed to improve predictability of the ionosphere. The winter MPV facilitates top-down coupling via the communication of high energy particle precipitation effects from the thermosphere down to the stratosphere, though the details of this mechanism are poorly understood. Coupling from the bottom-up involves gravity waves (GWs), planetary waves (PWs), and tidal interactions that are distinctly different and important during weak vs. strong vortex states, and yet remain poorly understood as well. Moreover, generation and modulation of GWs by the large wind shears at the vortex edge contribute to the generation of traveling atmospheric disturbances and traveling ionospheric disturbances. Unfortunately, representation of the MPV is generally not accurate in state-of-the-art general circulation models, even when compared to the limited observational data available. Models substantially underestimate eastward momentum at the top of the MPV, which limits the ability to predict upward effects in the thermosphere. The zonal wind bias responsible for this missing momentum in models has been attributed to deficiencies in the treatment of GWs and to an inaccurate representation of the high-latitude dynamics. In the coming decade, simulations of the MPV must be improved

Enhancing Protease Activity Assay in Droplet-Based Microfluidics Using a Biomolecule Concentrator

We introduce an integrated microfluidic device consisting of a biomolecule concentrator and a microdroplet generator, which enhances the limited sensitivity of low-abundance enzyme assays by concentrating biomolecules before encapsulating them into droplet microreactors. We used this platform to detect ultralow levels of matrix metalloproteinases (MMPs) from diluted cellular supernatant and showed that it significantly (~10-fold) reduced the time required to complete the assay and the sample volume used.National Institutes of Health (U.S.) (Grant GM68762)National Institutes of Health (U.S.) (Grant U54-CA112967)National Institutes of Health (U.S.) (Grant R01-EB010246)National Institutes of Health (U.S.) (Grant R01-GM081336)National Science Foundation (U.S.) (Graduate Fellowship)United States. Defense Advanced Research Projects Agency (Cipher Program