Rosetta FlexPepDock web server—high resolution modeling of peptide–protein interactions

Peptide–protein interactions are among the most prevalent and important interactions in the cell, but a large fraction of those interactions lack detailed structural characterization. The Rosetta FlexPepDock web server (http://flexpepdock.furmanlab.cs.huji.ac.il/) provides an interface to a high-resolution peptide docking (refinement) protocol for the modeling of peptide–protein complexes, implemented within the Rosetta framework. Given a protein receptor structure and an approximate, possibly inaccurate model of the peptide within the receptor binding site, the FlexPepDock server refines the peptide to high resolution, allowing full flexibility to the peptide backbone and to all side chains. This protocol was extensively tested and benchmarked on a wide array of non-redundant peptide–protein complexes, and was proven effective when applied to peptide starting conformations within 5.5 Å backbone root mean square deviation from the native conformation. FlexPepDock has been applied to several systems that are mediated and regulated by peptide–protein interactions. This easy to use and general web server interface allows non-expert users to accurately model their specific peptide–protein interaction of interest

Orbital Magnetism in the Ballistic Regime: Geometrical Effects

We present a general semiclassical theory of the orbital magnetic response of noninteracting electrons confined in two-dimensional potentials. We calculate the magnetic susceptibility of singly-connected and the persistent currents of multiply-connected geometries. We concentrate on the geometric effects by studying confinement by perfect (disorder free) potentials stressing the importance of the underlying classical dynamics. We demonstrate that in a constrained geometry the standard Landau diamagnetic response is always present, but is dominated by finite-size corrections of a quasi-random sign which may be orders of magnitude larger. These corrections are very sensitive to the nature of the classical dynamics. Systems which are integrable at zero magnetic field exhibit larger magnetic response than those which are chaotic. This difference arises from the large oscillations of the density of states in integrable systems due to the existence of families of periodic orbits. The connection between quantum and classical behavior naturally arises from the use of semiclassical expansions. This key tool becomes particularly simple and insightful at finite temperature, where only short classical trajectories need to be kept in the expansion. In addition to the general theory for integrable systems, we analyze in detail a few typical examples of experimental relevance: circles, rings and square billiards. In the latter, extensive numerical calculations are used as a check for the success of the semiclassical analysis. We study the weak-field regime where classical trajectories remain essentially unaffected, the intermediate field regime where we identify new oscillations characteristic for ballistic mesoscopic structures, and the high-field regime where the typical de Haas-van Alphen oscillations exhibit finite-size corrections. We address the comparison with experimental data obtained in high-mobility semiconductor microstructures discussing the differences between individual and ensemble measurements, and the applicability of the present model.Comment: 88 pages, 15 Postscript figures, 3 further figures upon request, to appear in Physics Reports 199

Lactobacillus rhamnosus GG-supplemented formula expands butyrate-producing bacterial strains in food allergic infants.

Dietary intervention with extensively hydrolyzed casein formula supplemented with Lactobacillus rhamnosus GG (EHCF+LGG) accelerates tolerance acquisition in infants with cow's milk allergy (CMA). We examined whether this effect is attributable, at least in part, to an influence on the gut microbiota. Fecal samples from healthy controls (n=20) and from CMA infants (n=19) before and after treatment with EHCF with (n=12) and without (n=7) supplementation with LGG were compared by 16S rRNA-based operational taxonomic unit clustering and oligotyping. Differential feature selection and generalized linear model fitting revealed that the CMA infants have a diverse gut microbial community structure dominated by Lachnospiraceae (20.5±9.7%) and Ruminococcaceae (16.2±9.1%). Blautia, Roseburia and Coprococcus were significantly enriched following treatment with EHCF and LGG, but only one genus, Oscillospira, was significantly different between infants that became tolerant and those that remained allergic. However, most tolerant infants showed a significant increase in fecal butyrate levels, and those taxa that were significantly enriched in these samples, Blautia and Roseburia, exhibited specific strain-level demarcations between tolerant and allergic infants. Our data suggest that EHCF+LGG promotes tolerance in infants with CMA, in part, by influencing the strain-level bacterial community structure of the infant gut

Operational Research in Education

Operational Research (OR) techniques have been applied, from the early stages of the discipline, to a wide variety of issues in education. At the government level, these include questions of what resources should be allocated to education as a whole and how these should be divided amongst the individual sectors of education and the institutions within the sectors. Another pertinent issue concerns the efficient operation of institutions, how to measure it, and whether resource allocation can be used to incentivise efficiency savings. Local governments, as well as being concerned with issues of resource allocation, may also need to make decisions regarding, for example, the creation and location of new institutions or closure of existing ones, as well as the day-to-day logistics of getting pupils to schools. Issues of concern for managers within schools and colleges include allocating the budgets, scheduling lessons and the assignment of students to courses. This survey provides an overview of the diverse problems faced by government, managers and consumers of education, and the OR techniques which have typically been applied in an effort to improve operations and provide solutions

Tim50’s presequence receptor domain is essential for signal driven transport across the TIM23 complex

The Tim50 subunit of the mitochondrial TIM23 complex contains a presequence-binding domain that is essential for viability and precursor transport across the inner membrane

Motion Planning via Manifold Samples

We present a general and modular algorithmic framework for path planning of robots. Our framework combines geometric methods for exact and complete analysis of low-dimensional configuration spaces, together with practical, considerably simpler sampling-based approaches that are appropriate for higher dimensions. In order to facilitate the transfer of advanced geometric algorithms into practical use, we suggest taking samples that are entire low-dimensional manifolds of the configuration space that capture the connectivity of the configuration space much better than isolated point samples. Geometric algorithms for analysis of low-dimensional manifolds then provide powerful primitive operations. The modular design of the framework enables independent optimization of each modular component. Indeed, we have developed, implemented and optimized a primitive operation for complete and exact combinatorial analysis of a certain set of manifolds, using arrangements of curves of rational functions and concepts of generic programming. This in turn enabled us to implement our framework for the concrete case of a polygonal robot translating and rotating amidst polygonal obstacles. We demonstrate that the integration of several carefully engineered components leads to significant speedup over the popular PRM sampling-based algorithm, which represents the more simplistic approach that is prevalent in practice. We foresee possible extensions of our framework to solving high-dimensional problems beyond motion planning.Comment: 18 page

Cardiac remodeling and dysfunction in nephrotic syndrome

There is an increased incidence of heart disease in patients with chronic nephrotic syndrome (NS), which may be attributable to the malnutrition and activated inflammatory state accompanying the sustained proteinuria. In this study, we evaluated renal function, cardiac morphometry, contractile function, and myocardial gene expression in the established puromycin aminonucleoside nephrosis rat model of NS. Two weeks after aminonucleoside injection, there was massive proteinuria, decreased creatinine clearance, and a negative sodium balance. Skeletal and cardiac muscle atrophy was present and was accompanied by impaired left ventricular (LV) hemodynamic function along with decreased contractile properties of isolated LV muscle strips. The expression of selected cytokines and proteins involved in calcium handling in myocardial tissue was evaluated by real time polymerase chain reaction. This revealed that the expression of interleukin-1beta, tumor necrosis factor-alpha, and phospholamban were elevated, whereas that of cardiac sarco(endo)plasmic reticulum calcium pump protein was decreased. We suggest that protein wasting and systemic inflammatory activation during NS contribute to cardiac remodeling and dysfunction

Human SHBG mRNA Translation Is Modulated by Alternative 5′-Non-Coding Exons 1A and 1B

BACKGROUND: The human sex hormone-binding globulin (SHBG) gene comprises at least 6 different transcription units (TU-1, -1A, -1B, -1C, -1D and -1E), and is regulated by no less than 6 different promoters. The best characterized are TU-1 and TU-1A: TU-1 is responsible for producing plasma SHBG, while TU-1A is transcribed and translated in the testis. Transcription of the recently described TU-1B, -1C, and -1D has been demonstrated in human prostate tissue and prostate cancer cell lines, as well as in other human cell lines such as HeLa, HepG2, HeK 293, CW 9019 and imr 32. However, there are no reported data demonstrating their translation. In the present study, we aimed to determine whether TU-1A and TU-1B are indeed translated in the human prostate and whether 5' UTR exons 1A and 1B differently regulate SHBG translation. RESULTS: Cis-regulatory elements that could potentially regulate translation were identified within the 5'UTRs of SHBG TU-1A and TU-1B. Although full-length SHBG TU-1A and TU-1B mRNAs were present in prostate cancer cell lines, the endogenous SHBG protein was not detected by western blot in any of them. LNCaP prostate cancer cells transfected with several SHBG constructs containing exons 2 to 8 but lacking the 5'UTR sequence did show SHBG translation, whereas inclusion of the 5'UTR sequences of either exon 1A or 1B caused a dramatic decrease in SHBG protein levels. The molecular weight of SHBG did not vary between cells transfected with constructs with or without the 5'UTR sequence, thus confirming that the first in-frame ATG of exon 2 is the translation start site of TU-1A and TU-1B. CONCLUSIONS: The use of alternative SHBG first exons 1A and 1B differentially inhibits translation from the ATG situated in exon 2, which codes for methionine 30 of transcripts that begin with the exon 1 sequence

Legionella DotM structure reveals a role in effector recruiting to the Type 4B secretion system

Legionella pneumophila, a causative agent of pneumonia, utilizes the Type 4B secretion (T4BS) system to translocate over 300 effectors into the host cell during infection. T4BS systems are encoded by a large gene cluster termed dot/icm, three components of which, DotL, DotM, and DotN, form the “coupling complex”, which serves as a platform for recruitment of effector proteins. One class of effectors includes proteins containing Glu-rich/E-block sequences at their C terminus. However, the protein or region of the coupling complex mediating recruitment of such effectors is unknown. Here we present the crystal structure of DotM. This all alpha-helical structure exhibits patches of positively charged residues. We show that these regions form binding sites for acidic Glu-rich peptides and that mutants targeting these patches are defective in vivo in the translocation of acidic Glu-rich motif-containing effectors. We conclude that DotM forms the interacting surface for recruitment of acidic Glu-rich motif-containing Legionella effectors