bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Phosphatidyl-
myo
-Inositol Mannosyltransferase PimA Is Essential for Mycobacterium tuberculosis Growth
In Vitro
and
In Vivo
Authors: Boldrin Francesca , Ventura Marcello , Degiacomi Giulia , Ravishankar Sudha , Sala Claudia , Svetlikova Zuzana , Ambady Anisha , Dhar Neeraj , Kordulakova Jana , Zhang Ming , Serafini Agnese , Vishwas V. G. , Kolly Gaëlle S. , Kumar Naveen , Palù Giorgio , Guerin Marcelo E. , Mikusova Katarina , Cole Stewart T. , Manganelli Riccardo 
Published: July 2014

ABSTRACT

The cell envelope of
Mycobacterium tuberculosis
contains glycans and lipids of peculiar structure that play prominent roles in the biology and pathogenesis of tuberculosis. Consequently, the chemical structure and biosynthesis of the cell wall have been intensively investigated in order to identify novel drug targets. Here, we validate that the function of phosphatidyl-
myo
-inositol mannosyltransferase PimA is vital for
M. tuberculosis
in vitro
and
in vivo
. PimA initiates the biosynthesis of phosphatidyl-
myo
-inositol mannosides by transferring a mannosyl residue from GDP-Man to phosphatidyl-
myo
-inositol on the cytoplasmic side of the plasma membrane. To prove the essential nature of
pimA
in
M. tuberculosis
, we constructed a
pimA
conditional mutant by using the TetR-Pip off system and showed that downregulation of PimA expression causes bactericidality in batch cultures. Consistent with the biochemical reaction catalyzed by PimA, this phenotype was associated with markedly reduced levels of phosphatidyl-
myo
-inositol dimannosides, essential structural components of the mycobacterial cell envelope. In addition, the requirement of PimA for viability was clearly demonstrated during macrophage infection and in two different mouse models of infection, where a dramatic decrease in viable counts was observed upon silencing of the gene. Notably, depletion of PimA resulted in complete clearance of the mouse lungs during both the acute and chronic phases of infection. Altogether, the experimental data highlight the importance of the phosphatidyl-
myo
-inositol mannoside biosynthetic pathway for
M. tuberculosis
and confirm that PimA is a novel target for future drug discovery programs.
Subcellular Localization and Clues for the Function of the HetN Factor Influencing Heterocyst Distribution in Anabaena sp. Strain PCC 7120
Authors: Corrales-Guerrero Laura , Mariscal Vicente , Nürnberg Dennis J. , Elhai Jeff , Mullineaux Conrad W. , Flores Enrique , Herrero Antonia 
Published: July 2014

ABSTRACT

In the filamentous cyanobacterium
Anabaena
sp. strain PCC 7120, heterocysts are formed in the absence of combined nitrogen, following a specific distribution pattern along the filament. The PatS and HetN factors contribute to the heterocyst pattern by inhibiting the formation of consecutive heterocysts. Thus, inactivation of any of these factors produces the multiple contiguous heterocyst (Mch) phenotype. Upon N stepdown, a HetN protein with its C terminus fused to a superfolder version of green fluorescent protein (sf-GFP) or to GFP-mut2 was observed, localized first throughout the whole area of differentiating cells and later specifically on the peripheries and in the polar regions of mature heterocysts, coinciding with the location of the thylakoids. Polar localization required an N-terminal stretch comprising residues 2 to 27 that may represent an unconventional signal peptide.
Anabaena
strains expressing a version of HetN lacking this fragment from a mutant gene placed at the native
hetN
locus exhibited a mild Mch phenotype. In agreement with previous results, deletion of an internal ERGSGR sequence, which is identical to the C-terminal sequence of PatS, also led to the Mch phenotype. The subcellular localization in heterocysts of fluorescence resulting from the fusion of GFP to the C terminus of HetN suggests that a full HetN protein is present in these cells. Furthermore, the full HetN protein is more conserved among cyanobacteria than the internal ERGSGR sequence. These observations suggest that HetN anchored to thylakoid membranes in heterocysts may serve a function besides that of generating a regulatory (ERGSGR) peptide.
Crystal Structure of PhnF, a GntR-Family Transcriptional Regulator of Phosphate Transport in Mycobacterium smegmatis
Authors: Gebhard Susanne , Busby Jason N. , Fritz Georg , Moreland Nicole J. , Cook Gregory M. , Lott J. Shaun , Baker Edward N. , Money Victoria A. 
Published: July 2014

ABSTRACT

Bacterial uptake of phosphate is usually accomplished via high-affinity transporters that are commonly regulated by two-component systems, which are activated when the concentration of phosphate is low.
Mycobacterium smegmatis
possesses two such transporters, the widely distributed PstSCAB system and PhnDCE, a transporter that in other bacteria mediates the uptake of alternative phosphorus sources. We previously reported that the transcriptional regulator PhnF controls the production of the Phn system, acting as a repressor under high-phosphate conditions. Here we show that the
phnDCE
genes are common among environmental mycobacteria, where they are often associated with
phnF
-like genes. In contrast, pathogenic mycobacteria were not found to encode Phn-like systems but instead were found to possess multiple copies of the
pst
genes. A detailed biochemical analysis of PhnF binding to its identified binding sites in the
phnD-phnF
intergenic region of
M. smegmatis
has allowed us to propose a quantitative model for repressor binding, which shows that a PhnF dimer binds independently to each site. We present the crystal structure of
M. smegmatis
PhnF at 1.8-Å resolution, showing a homodimer with a helix-turn-helix N-terminal domain and a C-terminal domain with a UbiC transcription regulator-associated fold. The C-terminal domain crystallized with a bound sulfate ion instead of the so far unidentified physiological ligand, allowing the identification of residues involved in effector binding. Comparison of the positioning of the DNA binding domains in PhnF with that in homologous proteins suggests that its DNA binding activity is regulated via a conformational change in the linker region, triggering a movement of the N-terminal domains.
Factored axis-aligned filtering for rendering multiple distribution effects
Authors: Mehta Soham Uday , Yao JiaXian , Ramamoorthi Ravi , Durand Fredo 
Published: July 2014

Monte Carlo (MC) ray-tracing for photo-realistic rendering often requires hours to render a single image due to the large sampling rates needed for convergence. Previous methods have attempted to filter sparsely sampled MC renders but these methods have high reconstruction overheads. Recent work has shown fast performance for individual effects, like soft shadows and indirect illumination, using axis-aligned filtering. While some components of light transport such as indirect or area illumination are smooth, they are often multiplied by high-frequency components such as texture, which prevents their sparse sampling and reconstruction.
We propose an approach to adaptively sample and filter for simultaneously rendering primary (defocus blur) and secondary (soft shadows and indirect illumination) distribution effects, based on a multi-dimensional frequency analysis of the direct and indirect illumination light fields. We describe a novel approach of factoring texture and irradiance in the presence of defocus blur, which allows for pre-filtering noisy irradiance when the texture is not noisy. Our approach naturally allows for different sampling rates for primary and secondary effects, further reducing the overall ray count. While the theory considers only Lambertian surfaces, we obtain promising results for moderately glossy surfaces. We demonstrate 30x sampling rate reduction compared to equal quality noise-free MC. Combined with a GPU implementation and low filtering over-head, we can render scenes with complex geometry and diffuse and glossy BRDFs in a few seconds.
Provably good planar mappings
Authors: Poranne Roi , Lipman Yaron 
Published: July 2014

The problem of planar mapping and deformation is central in computer graphics. This paper presents a framework for adapting general, smooth, function bases for building provably good planar mappings. The term "good" in this context means the map has no fold-overs (injective), is smooth, and has low isometric or conformal distortion.
Existing methods that use mesh-based schemes are able to achieve injectivity and/or control distortion, but fail to create smooth mappings, unless they use a prohibitively large number of elements, which slows them down. Meshless methods are usually smooth by construction, yet they are not able to avoid fold-overs and/or control distortion.

Our approach constrains the linear deformation spaces induced by popular smooth basis functions, such as B-Splines, Gaussian and Thin-Plate Splines, at a set of collocation points, using specially tailored convex constraints that prevent fold-overs and high distortion at these points. Our analysis then provides the required density of collocation points and/or constraint type, which guarantees that the map is injective and meets the distortion constraints over the
entire
domain of interest.

We demonstrate that our method is interactive at reasonably complicated settings and compares favorably to other state-of-the-art mesh and meshless planar deformation methods.
Controlling singular values with semidefinite programming
Authors: Kovalsky Shahar Z. , Aigerman Noam , Basri Ronen , Lipman Yaron 
Published: July 2014

Controlling the singular values of
n
-dimensional matrices is often required in geometric algorithms in graphics and engineering. This paper introduces a convex framework for problems that involve singular values. Specifically, it enables the optimization of functionals and constraints expressed in terms of the extremal singular values of matrices.

Towards this end, we introduce a family of convex sets of matrices whose singular values are bounded. These sets are formulated using Linear Matrix Inequalities (LMI), allowing optimization with standard convex Semidefinite Programming (SDP) solvers. We further show that these sets are optimal, in the sense that there exist no larger convex sets that bound singular values.
A number of geometry processing problems are naturally described in terms of singular values. We employ the proposed framework to optimize and improve upon standard approaches. We experiment with this new framework in several applications: volumetric mesh deformations, extremal quasi-conformal mappings in three dimensions, non-rigid shape registration and averaging of rotations. We show that in all applications the proposed approach leads to algorithms that compare favorably to state-of-art algorithms.
Bridging the gap
Authors: Dumas Jérémie , Hergel Jean , Lefebvre Sylvain 
Published: July 2014

Fused Filament Fabrication (FFF) is the process of 3D printing objects from melted plastic filament. The hot plastic exits a nozzle and fuses with the part just below, adding a layer of material to the object being formed. However, filament can only be deposited
on top
of an existing surface. Therefore, overhangs require a disposable
support structure
to be printed, temporarily supporting the threads of plastic that would otherwise hang in empty space.

Existing techniques for support generation fall into two categories: The first allow for very reliable prints by enclosing the bottom of the object in a dense structure, at the expense of increased material usage and build times. The second generate thin hierarchical structures connecting to the surface in a sparse number of points. This uses less material, at the expense of reliability: the part might become unstable, the structure itself may become difficult to print, the bottom surface quality degrades. The user therefore has to correct the structure and its parameters for each new object.
We propose to exploit the ability of FFF printers to print bridges across gaps. Since bridges are always supported by pillars at their extremities, they are both stronger and more stable than hierarchical tree structures. Our technique first selects the points to support based on overhang and part stability during the entire print process. It then optimizes for a printable scaffolding composed of bridges and vertical pillars, supporting all points. The result is an automated support generation technique using little material while ensuring fine surface quality and stability during the printing process.
The Connect-The-Dots family of puzzles
Authors: Löffler Maarten , Kaiser Mira , van Kapel Tim , Klappe Gerwin , van Kreveld Marc , Staals Frank 
Published: July 2014

In this paper we introduce several innovative variants on the classic Connect-The-Dots puzzle. We study the underlying geometric principles and investigate methods for the automatic generation of high-quality puzzles from line drawings.
Specifically, we introduce three new variants of the classic Connect-The-Dots puzzle. These new variants use different rules for drawing connections, and have several advantages: no need for printed numbers in the puzzle (which look ugly in the final drawing), and perhaps more challenging "game play", making the puzzles suitable for different age groups. We study the rules of all four variants in the family, and design principles describing what makes a good puzzle. We identify general principles that apply across the different variants, as well as specific implementations of those principles in the different variants. We make these mathematically precise in the form of criteria a puzzle should satisfy.
Furthermore, we investigate methods for the automatic generation of puzzles from a plane graph that describes the input drawing. We show that the problem of generating a good puzzle --one satisfying the mentioned criteria-- is computationally hard, and present several heuristic algorithms.
Using our implementation for generating puzzles, we evaluate the quality of the resulting puzzles with respect to two parameters: one for similarity to the original line drawing, and one for ambiguity; i.e. what is the visual accuracy needed to solve the puzzle.
Natural Allelic Variations in Glutathione Peroxidase-1 Affect Its Subcellular Localization and Function
Authors: Bera Soumen , Weinberg Frank , Ekoue Dede N. , Ansenberger-Fricano Kristine , Mao Mao , Bonini Marcelo G. , Diamond Alan M. 
Published: July 2014

Abstract
Glutathione peroxidase 1 (GPx-1) has been implicated in the etiology of several common diseases due to the association between specific allelic variations and cancer risk. The most common among these variations are the codon 198 polymorphism that results in either a leucine or proline and the number of alanine repeat codons in the coding sequence. The molecular and biologic consequences of these variations remain to be characterized. Toward achieving this goal, we have examined the cellular location of GPx-1 encoded by allelic variants by ectopically expressing these genes in MCF-7 human breast carcinoma cells that produce undetectable levels of GPx-1, thus achieving exclusive expression in the same cellular environment. A differential distribution between the cytoplasm and mitochondria was observed, with the allele expressing the leucine-198 polymorphism and 7 alanine repeats being more cytoplasmically located than the other alleles examined. To assess whether the distribution of GPx-1 between the cytoplasm and mitochondria had a biologic consequence, we engineered derivative GPx-1 proteins that were targeted to the mitochondria by the addition of a mitochondria targeting sequence and expressed these proteins in MCF-7 cells. These cells were examined for their response to oxidative stress, energy metabolism, and impact on cancer-associated signaling molecules. The results obtained indicated that both primary GPx-1 sequence and cellular location have a profound impact on cellular biology and offer feasible hypotheses about how expression of distinct GPx-1 alleles can affect cancer risk. Cancer Res; 74(18); 5118–26. ©2014 AACR.
TLR9 Is Critical for Glioma Stem Cell Maintenance and Targeting
Authors: Herrmann Andreas , Cherryholmes Gregory , Schroeder Anne , Phallen Jillian , Alizadeh Darya , Xin Hong , Wang Tianyi , Lee Heehyoung , Lahtz Christoph , Swiderski Piotr , Armstrong Brian , Kowolik Claudia , Gallia Gary L. , Lim Michael , Brown Christine , Badie Behnam , Forman Stephen , Kortylewski Marcin , Jove Richard , Yu Hua 
Published: July 2014

Abstract
Understanding supports for cancer stem–like cells in malignant glioma may suggest therapeutic strategies for their elimination. Here, we show that the Toll-like receptor TLR9 is elevated in glioma stem–like cells (GSC) in which it contributes to glioma growth. TLR9 overexpression is regulated by STAT3, which is required for GSC maintenance. Stimulation of TLR9 with a CpG ligand (CpG ODN) promoted GSC growth, whereas silencing TLR9 expression abrogated GSC development. CpG-ODN treatment induced Frizzled4-dependent activation of JAK2, thereby activating STAT3. Targeted delivery of siRNA into GSC was achieved via TLR9 using CpG–siRNA conjugates. Through local or systemic treatment, administration of CpG-Stat3 siRNA to silence STAT3 in vivo reduced GSC along with glioma growth. Our findings identify TLR9 as a functional marker for GSC and a target for the delivery of efficacious therapeutics for glioma treatment. Cancer Res; 74(18); 5218–28. ©2014 AACR.
Breast Cancer Risk in Young Women in the National Breast Screening Programme: Implications for Applying NICE Guidelines for Additional Screening and Chemoprevention
Authors: Evans D. Gareth , Brentnall Adam R. , Harvie Michelle , Dawe Sarah , Sergeant Jamie C. , Stavrinos Paula , Astley Susan , Wilson Mary , Ainsworth John , Cuzick Jack , Buchan Iain , Donnelly Louise S. , Howell Anthony 
Published: July 2014

Abstract
In the United Kingdom, women at moderate and high risk of breast cancer between the ages of 40 and 49 years are eligible for annual mammographic screening and preventive therapy with tamoxifen. Here, we estimate the numbers of women in a population eligible for this service and the proportion of breast cancers detected in this group compared with the whole population. Women &lt;50 attending for mammographic screening in the National Health Service Breast Screening Programme (NHSBSP) completed a risk questionnaire. The proportion at moderate and high risk according to National Institute of Health Care Excellence (NICE) guidelines was estimated. An estimate was also made using a different model of risk estimation (Tyrer–Cuzick). The numbers of cancers detected in the moderate/high risk groups were compared with numbers detected in the whole population. Completed questionnaires were available for 4,360 women between ages 46 and 49 years. Thirty women [0.7%; 95% confidence interval (CI), 0.5–1.0%] were at high risk and 130 (3.0%, 2.5–3.5%) were at moderate risk according to NICE guidelines. Thirty-seven cancers were detected by mammography in the whole group. Five of these were found in the moderate-/high-risk group giving a 3.2-fold increase in detection compared with the standard risk group. More women were assigned to the moderate- or high-risk group using the Tyrer–Cuzick model (N = 384), but the numbers of cancers in this group were not appreciably increased (N = 8). Systematic assessment of family history in primary care or through population-based screening will identify appreciable numbers of women in their forties, eligible for additional surveillance and chemoprevention Cancer Prev Res; 7(10); 993–1001. ©2014 AACR.
G Protein–Coupled Receptor Kinase 5 Gene Polymorphisms Are Associated With Postoperative Atrial Fibrillation After Coronary Artery Bypass Grafting in Patients Receiving β-Blockers
Authors: Kertai Miklos D. , Li Yen-Wei , Li Yi-Ju , Shah Svati H. , Kraus William E. , Fontes Manuel L. , Stafford-Smith Mark , Newman Mark F. , Podgoreanu Mihai V. , Mathew Joseph P. 
Published: July 2014

Background—
We hypothesized that genetic variations in the adrenergic signaling pathway and cytochrome P450 2D6 enzyme are associated with new-onset atrial fibrillation (AF) in patients who underwent coronary artery bypass grafting and were treated with perioperative β-blockers (BBs).

Methods and Results—

Two cohorts of patients who underwent coronary artery bypass grafting and received perioperative BBs at Duke University Medical Center were studied. In a discovery cohort of 563 individuals from the Perioperative Genetics and Safety Outcomes Study (PEGASUS), using a covariate-adjusted logistic regression analysis, we tested 492 single-nucleotide polymorphisms (SNPs) in 10 candidate genes of the adrenergic signaling pathway and cytochrome P450 2D6 for association with postoperative AF despite perioperative BB therapy. SNPs meeting a false discovery rate ≤0.20 (
P
<0.002) were then tested in the replication cohort of 245 individuals from the Catheterization Genetics biorepository. Of the 492 SNPs examined, 4 intronic SNPs of the G protein–coupled kinase 5 (
GRK5
) gene were significantly associated with postoperative AF despite perioperative BB therapy in the discovery cohort with additive odds ratios between 1.72 and 2.75 (
P
=4.78×10
−5
to 0.0015). Three of these SNPs met nominal significance levels in the replication cohort with odds ratios between 2.07 and 2.60 (
P
=0.007 to 0.016). However, meta-analysis of the 2 data sets cohorts suggested strong association with postoperative AF despite perioperative BB therapy in all 4 SNPs (meta-
P
values from 1.66×10
–6
to 3.39×10
–5
).

Conclusions—

In patients undergoing coronary artery bypass grafting, genetic variation in
GRK5
is associated with postoperative AF despite perioperative BB therapy.
Pulmonary Hypertension Is Related to Peripheral Endothelial Dysfunction in Heart Failure With Preserved Ejection Fraction
Authors: Farrero Marta , Blanco Isabel , Batlle Montserrat , Santiago Evelyn , Cardona Montserrat , Vidal Barbara , Castel M. Angeles , Sitges Marta , Barbera Joan Albert , Perez-Villa Felix 
Published: July 2014

Background—
Pulmonary hypertension (PH) and collagen metabolism abnormalities are prevalent in patients with heart failure with preserved ejection fraction (HFpEF). Peripheral endothelial dysfunction (PED) has been described in HF and in pulmonary arterial hypertension. Our aim is to determine whether PH is associated with PED and impaired collagen metabolism in patients with HFpEF.;

Methods and Results—

Flow-mediated dilation of the brachial artery, matrix metalloproteinase-2 and matrix metalloproteinase-9, tissue metalloproteinase inhibitor 1, and C-terminal propeptide of type I procollagen were determined in 28 patients with HFpEF and 42 hypertensive controls. Patients with systolic pulmonary artery pressure >35 mm Hg on echocardiogram underwent a right heart catheterization. Patients with HFpEF had more severe PED than controls: flow-mediated dilation 1.95% (−0.81 to 4.92) versus 5.02% (3.90 to 10.12),
P
=0.002. Twenty patients with PH underwent right heart catheterization: mean pulmonary artery pressure 38 (27–52) mm Hg, wedge capillary pressure 18 (16–22) mm Hg, pulmonary vascular resistance 362 (235–603) dyn s cm
-5
. There was a significant inverse correlation between flow-mediated dilation and pulmonary vascular resistance in patients with HFpEF and PH (
r
=−0.679;
P
=0.002). Patients with HFpEF showed higher matrix metalloproteinase-2 and C-terminal propeptide of type I procollagen values than hypertensive controls. Patients with HFpEF and higher C-terminal propeptide of type I procollagen values also had higher mean pulmonary artery pressure (
r
=0.553;
P
=0.014), transpulmonary gradient (
r
=0.560;
P
=0.013), and pulmonary vascular resistance (
r
=0.626;
P
=0.004).

Conclusions—
In patients with HFpEF, there is a significant correlation between PED and pulmonary vascular resistance. Collagen metabolism was more impaired in patients with HFpEF and PH. PED and collagen metabolism assessment could be useful tools to identify patients with HFpEF at risk of developing PH.