bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome-Wide Saturation Mutagenesis of Burkholderia pseudomallei K96243 Predicts Essential Genes and Novel Targets for Antimicrobial Development
Authors: Moule Madeleine G. , Hemsley Claudia M. , Seet Qihui , Guerra-Assunção José Afonso , Lim Jiali , Sarkar-Tyson Mitali , Clark Taane G. , Tan Patrick B. O. , Titball Richard W. , Cuccui Jon , Wren Brendan W. 
Published: February 2014

ABSTRACT

Burkholderia pseudomallei
is the causative agent of melioidosis, an often fatal infectious disease for which there is no vaccine.
B. pseudomallei
is listed as a tier 1 select agent, and as current therapeutic options are limited due to its natural resistance to most antibiotics, the development of new antimicrobial therapies is imperative. To identify drug targets and better understand the complex
B. pseudomallei
genome, we sought a genome-wide approach to identify lethal gene targets. As
B. pseudomallei
has an unusually large genome spread over two chromosomes, an extensive screen was required to achieve a comprehensive analysis. Here we describe transposon-directed insertion site sequencing (TraDIS) of a library of over 10
6
transposon insertion mutants, which provides the level of genome saturation required to identify essential genes. Using this technique, we have identified a set of 505 genes that are predicted to be essential in
B. pseudomallei
K96243. To validate our screen, three genes predicted to be essential,
pyrH
,
accA
, and
sodB
, and a gene predicted to be nonessential,
bpss0370
, were independently investigated through the generation of conditional mutants. The conditional mutants confirmed the TraDIS predictions, showing that we have generated a list of genes predicted to be essential and demonstrating that this technique can be used to analyze complex genomes and thus be more widely applied.

IMPORTANCE
Burkholderia pseudomallei
is a lethal human pathogen that is considered a potential bioterrorism threat and has limited treatment options due to an unusually high natural resistance to most antibiotics. We have identified a set of genes that are required for bacterial growth and thus are excellent candidates against which to develop potential novel antibiotics. To validate our approach, we constructed four mutants in which gene expression can be turned on and off conditionally to confirm that these genes are required for the bacteria to survive.
Two Lipid Signals Guide Fruiting Body Development of Myxococcus xanthus
Authors: Bhat Swapna , Ahrendt Tilman , Dauth Christina , Bode Helge B. , Shimkets Lawrence J. 
Published: February 2014

ABSTRACT

Myxococcus xanthus
produces several extracellular signals that guide fruiting body morphogenesis and spore differentiation. Mutants defective in producing a signal may be rescued by codevelopment with wild-type cells or cell fractions containing the signal. In this paper, we identify two molecules that rescue development of the E signal-deficient mutant LS1191 at physiological concentrations,
iso
15:0 branched-chain fatty acid (FA) and 1-
iso
15:0-alkyl-2,3-di-
iso
15:0-acyl glycerol (TG1), a development-specific monoalkyl-diacylglycerol. The physiological concentrations of the bioactive lipids were determined by mass spectrometry from developing wild-type cells using chemically synthesized standards. Synthetic TG1 restored fruiting body morphogenesis and sporulation and activated the expression of the developmentally regulated gene with locus tag
MXAN_2146
at physiological concentrations, unlike its nearly identical tri-
iso
15:0 triacylglycerol (TAG) counterpart, which has an ester linkage instead of an ether linkage.
iso
15:0 FA restored development at physiological concentrations, unlike palmitic acid, a straight-chain fatty acid. The addition of either lipid stimulates cell shortening, with an 87% decline in membrane surface area, concomitantly with the production of lipid bodies at each cell pole and in the center of the cell. We suggest that cells produce triacylglycerol from membrane phospholipids. Bioactive lipids may be released by
p
rogrammed
c
ell
d
eath (PCD), which claims up to 80% of developing cells, since cells undergoing PCD produce lipid bodies before lysing.

IMPORTANCE
Like mammalian adipose tissue, many of the
M. xanthus
lipid body lipids are triacylglycerols (TAGs), containing ester-linked fatty acids. In both systems, ester-linked fatty acids are retrieved from TAGs with lipases and consumed by the fatty acid degradation cycle. Both mammals and
M. xanthus
also produce lipids containing ether-linked fatty alcohols with alkyl or vinyl linkages, such as plasmalogens. Alkyl and vinyl linkages are not hydrolyzed by lipases, and no clear role has emerged for lipids bearing them. For example, plasmalogen deficiency in mice has detrimental consequences to spermatocyte development, myelination, axonal survival, eye development, and long-term survival, though the precise reasons remain elusive. Lipids containing alkyl- and vinyl-linked fatty alcohols are development-specific products in
M. xanthus
. Here, we show that one of them rescues the development of E signal-producing mutants at physiological concentrations.
Treatments for macular oedema following central retinal vein occlusion: systematic review
Authors: Ford John A , Clar Christine , Lois Noemi , Barton Samantha , Thomas Sian , Court Rachel , Shyangdan Deepson , Waugh Norman 
Published: February 2014

ObjectivesTo review systematically the randomised controlled trial (RCT) evidence for treatment of macular oedema due to central retinal vein occlusion (CRVO).Data sourcesMEDLINE, EMBASE, CDSR, DARE, HTA, NHSEED, CENTRAL and meeting abstracts (January 2005 to March 2013).Study eligibility criteria, participants and interventionsRCTs with at least 12 months of follow-up assessing pharmacological treatments for CRVO were included with no language restrictions.Study appraisal and synthesis methods2 authors screened titles and abstracts and conducted data extracted and Cochrane risk of bias assessment. Meta-analysis was not possible due to lack of comparable studies.Results8 studies (35 articles, 1714 eyes) were included, assessing aflibercept (n=2), triamcinolone (n=2), bevacizumab (n=1), pegaptanib (n=1), dexamethasone (n=1) and ranibizumab (n=1). In general, bevacizumab, ranibizumab, aflibercept and triamcinolone resulted in clinically significant increases in the proportion of participants with an improvement in visual acuity of ≥15 letters, with 40–60% gaining ≥15 letters on active drugs, compared to 12–28% with sham. Results for pegaptanib and dexamethasone were mixed. Steroids were associated with cataract formation and increased intraocular pressure. No overall increase in adverse events was found with bevacizumab, ranibizumab, aflibercept or pegaptanib compared with control. Quality of life was poorly reported. All studies had a low or unclear risk of bias.LimitationsAll studies evaluated a relatively short primary follow-up (1 year or less). Most had an unmasked extension phase. There was no head-to-head evidence. The majority of participants included had non-ischaemic CRVO.Conclusions and implications of key findingsBevacizumab, ranibizumab, aflibercept and triamcinolone appear to be effective in treating macular oedema secondary to CRVO. Long-term data on effectiveness and safety are needed. Head-to-head trials and research to identify ‘responders’ is needed to help clinicians make the right choices for their patients. Research aimed to improve sight in people with ischaemic CRVO is required.
Facial self-mutilation: an analysis of published cases
Authors: Ciorba Irina , Farcus Oana , Giger Roland , Nisa Lluís 
Published: February 2014

AbstractObjectivesFacial self-mutilation is rare. It is usually discussed from the psychiatric or psychoanalytic perspectives but has little prominence in general medical literature. Our objective was to describe facial self-mutilation in terms of its comorbidities, and to outline the different types of facial mutilation, as well as the basic approach to the patients with facial self-mutilation.MethodsWe undertook a review of all published cases of facial self-mutilation (1960–2011).ResultsWe identified 200 published cases in 123 relevant papers. Four major groups of comorbidities emerged: psychiatric, neurological and hereditary disorders, and a group of patients without identified comorbidities. There were three general patterns of facial self-mutilation: (1) major and definitive mutilation, with the ocular globe as primary target—seen in patients with psychotic disorders; (2) stereotypical mutilation involving the oral cavity and of variable degree of severity, most often seen in patients with hereditary neuropathy or encephalopathy; (3) mild chronic self-mutilation, seen in patients with non-psychotic psychiatric disorders, acquired neurological disorders, and patients without comorbidities. About 20% of patients that mutilated their face also mutilated extra-facial structures.Patients with psychiatric conditions, especially those with psychotic disorders, had significantly higher (p&lt;0.05) rates of permanent facial self-mutilation than others. Most treatment plans were very individually based, but some principles, such as prevention of irreversible loss of function and structure, or development of infection are applicable to all patients with facial self-mutilation.ConclusionsFacial self-mutilation is a potentially severe manifestation of diverse conditions. Several aspects of facial self-mutilation remain to be fully characterised from a clinical perspective.
Indemics
Authors: Bisset Keith R. , Chen Jiangzhuo , Deodhar Suruchi , Feng Xizhou , Ma Yifei , Marathe Madhav V. 
Published: February 2014

We describe the design and prototype implementation of Indemics(_Interactive; Epi_demic; _Simulation;)—a modeling environment utilizing high-performance computing technologies for supporting complex epidemic simulations. Indemicscan support policy analysts and epidemiologists interested in planning and control of pandemics. Indemicsgoes beyond traditional epidemic simulations by providing a simple and powerful way to represent and analyze policy-based as well as individual-basedadaptive interventions. Users can also stop the simulation at any point, assess the state of the simulated system, and add additional interventions. Indemicsis available to end-users via a web-based interface.Detailed performance analysis shows that Indemicsgreatly enhances the capability and productivity of simulating complex intervention strategies with a marginal decrease in performance. We also demonstrate how Indemicswas applied in some real case studies where complex interventions were implemented.
A review of the October 1968 Microprogramming Workshop held at Mitre
Authors: Sullivan Joseph E. 
Published: February 2014

The Workshop on Microprograiming, sponsored by the ACM with the cooperation of MITRE, took place at MITRE on October 7-8, 1968, The purposes of the workship were to:
- Identify the work currently being done in the field
- Promote conmunication between microprogramming practitioners
- Identify promising new directions for investigation
Ninety-one individuals attended the Workshops fifty-seven from industry, twenty-three from the academic world or university-associated laboratories and eleven from non-profits or government. Eighty-nine were from the United States, with one each from Italy and Great Britain.
Light In and Sound Out: Emerging Translational Strategies for Photoacoustic Imaging
Authors: Zackrisson S. , van de Ven S.M.W.Y. , Gambhir S.S. 
Published: February 2014

AbstractPhotoacoustic imaging (PAI) has the potential for real-time molecular imaging at high resolution and deep inside the tissue, using nonionizing radiation and not necessarily depending on exogenous imaging agents, making this technique very promising for a range of clinical applications. The fact that PAI systems can be made portable and compatible with existing imaging technologies favors clinical translation even more. The breadth of clinical applications in which photoacoustics could play a valuable role include: noninvasive imaging of the breast, sentinel lymph nodes, skin, thyroid, eye, prostate (transrectal), and ovaries (transvaginal); minimally invasive endoscopic imaging of gastrointestinal tract, bladder, and circulating tumor cells (in vivo flow cytometry); and intraoperative imaging for assessment of tumor margins and (lymph node) metastases. In this review, we describe the basics of PAI and its recent advances in biomedical research, followed by a discussion of strategies for clinical translation of the technique. Cancer Res; 74(4); 979–1004. ©2014 AACR.
Recurrent Prostate Cancer Genomic Alterations Predict Response to Brachytherapy Treatment
Authors: Fontugne Jacqueline , Lee Daniel , Cantaloni Chiara , Barbieri Christopher E. , Caffo Orazio , Hanspeter Esther , Mazzoleni Guido , Palma Paolo Dalla , Rubin Mark A. , Fellin Giovanni , Mosquera Juan Miguel , Barbareschi Mattia , Demichelis Francesca 
Published: February 2014

Abstract
Background: This study aimed to evaluate the association of recurrent molecular alterations in prostate cancer, such as ERG rearrangements and phosphatase and tensin homolog gene (PTEN) deletions, with oncologic outcomes in patients with prostate cancer treated with brachytherapy.
Methods: Ninety-two men underwent I-125 brachytherapy with a 145 Gy delivered dose between 2000 and 2008. Pretreatment prostate biopsies were analyzed by immunohistochemistry (IHC) and FISH for ERG rearrangement and overexpression, PTEN deletion, and expression loss. Univariable and multivariable Cox-regression analyses evaluated association of ERG and PTEN status with biochemical recurrence (BCR).
Results: Within a median follow-up of 73 months, 11% of patients experienced BCR. Of 80 samples with both IHC and FISH performed for ERG, 46 (57.8%) demonstrated rearrangement by FISH and 45 (56.3%) by IHC. Of 77 samples with both IHC and FISH for PTEN, 14 (18.2%) had PTEN deletion by FISH and 22 (28.6%) by IHC. No significant associations were found between ERG, PTEN status, and clinicopathologic features. Patients with concurrent ERG rearrangement and PTEN deletion demonstrated significantly worse relapse-free survival rates compared with those with ERG or PTEN wild type (P &lt; 0.01). In multivariable Cox regression analysis adjusted for the effects of standard clinicopathologic features, combined ERG rearranged and PTEN deletion was independently associated with BCR (HR = 2.6; P = 0.02).
Conclusions: Concurrent ERG rearrangement and PTEN loss was independently associated with time to BCR in patients undergoing brachytherapy. Future studies are needed to validate prostate cancer molecular subtyping for risk stratification.
Impact: Identifying patients in the ERG-rearranged/PTEN-deleted molecular subclass may improve treatment personalization. Cancer Epidemiol Biomarkers Prev; 23(4); 594–600. ©2014 AACR.
Reduced Expression of miRNA-27a Modulates Cisplatin Resistance in Bladder Cancer by Targeting the Cystine/Glutamate Exchanger SLC7A11
Authors: Drayton Ross M. , Dudziec Ewa , Peter Stefan , Bertz Simone , Hartmann Arndt , Bryant Helen E. , Catto James WF. 
Published: February 2014

Abstract
Purpose: Resistance to cisplatin-based chemotherapy is a major obstacle to bladder cancer treatment. We aimed to identify microRNAs (miRNA) that are dysregulated in cisplatin-resistant disease, ascertain how these contribute to a drug-resistant phenotype, and how this resistance might be overcome.
Experimental Design: miRNA expression in paired cisplatin-resistant and -sensitive cell lines was measured. Dysregulated miRNAs were further studied for their ability to mediate resistance. The nature of the cisplatin-resistant phenotype was established by measurement of cisplatin/DNA adducts and intracellular glutathione (GSH). Candidate miRNAs were examined for their ability to (i) mediate resistance and (ii) alter the expression of a candidate target protein (SLC7A11); direct regulation of SLC7A11 was confirmed using a luciferase assay. SLC7A11 protein and mRNA, and miRNA-27a were quantified in patient tumor material.
Results: A panel of miRNAs were found to be dysregulated in cisplatin-resistant cells. miRNA-27a was found to target the cystine/glutamate exchanger SLC7A11 and to contribute to cisplatin resistance through modulation of GSH biosynthesis. In patients, SLC7A11 expression was inversely related to miRNA-27a expression, and those tumors with high mRNA expression or high membrane staining for SLC7A11 experienced poorer clinical outcomes. Resistant cell lines were resensitized by restoring miRNA-27a expression or reducing SLC7A11 activity with siRNA or with sulfasalazine.
Conclusion: Our findings indicate that miRNA-27a negatively regulates SLC7A11 in cisplatin-resistant bladder cancer, and shows promise as a marker for patients likely to benefit from cisplatin-based chemotherapy. SLC7A11 inhibition with sulfasalazine may be a promising therapeutic approach to the treatment of cisplatin-resistant disease. Clin Cancer Res; 20(7); 1990–2000. ©2014 AACR.
The Orphan Nuclear Receptor NR4A1 (Nur77) Regulates Oxidative and Endoplasmic Reticulum Stress in Pancreatic Cancer Cells
Authors: Lee Syng-Ook , Jin Un-Ho , Kang Jeong Han , Kim Sang Bae , Guthrie Aaron S. , Sreevalsan Sandeep , Lee Ju-Seog , Safe Stephen 
Published: February 2014

Abstract
NR4A1 (Nur77, TR3) is an orphan nuclear receptor that is overexpressed in pancreatic cancer and exhibits pro-oncogenic activity. RNA interference of NR4A1 expression in Panc-1 cells induced apoptosis and subsequent proteomic analysis revealed the induction of several markers of endoplasmic reticulum stress, including glucose-related protein 78 (GRP78), CCAAT/enhancer-binding protein-homologous protein (CHOP), and activating transcription factor-4 (ATF-4). Treatment of pancreatic cancer cells with the NR4A1 antagonist 1,1-bis(3′-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) gave similar results. Moreover, both NR4A1 knockdown and DIM-C-pPhOH induced reactive oxygen species (ROS), and induction of ROS and endoplasmic reticulum stress by these agents was attenuated after cotreatment with antioxidants. Manipulation of NR4A1 expression coupled with gene expression profiling identified a number of ROS metabolism transcripts regulated by NR4A1. Knockdown of one of these transcripts, thioredoxin domain containing 5 (TXNDC5), recapitulated the elevated ROS and endoplasmic reticulum stress; thus, demonstrating that NR4A1 regulates levels of endoplasmic reticulum stress and ROS in pancreatic cancer cells to facilitate cell proliferation and survival. Finally, inactivation of NR4A1 by knockdown or DIM-C-pPhOH decreased TXNDC5, resulting in activation of the ROS/endoplasmic reticulum stress and proapoptotic pathways.
Implications: The NR4A1 receptor is pro-oncogenic, regulates the ROS/endoplasmic reticulum stress pathways, and inactivation of the receptor represents a novel pathway for inducing cell death in pancreatic cancer. Mol Cancer Res; 12(4); 527–38. ©2014 AACR.
An Articulatory and Acoustic Study of the Fricative Clusters /sʃ/ and /ʃs/ in Catalan
Authors: Recasens Daniel , Mira Meritxell 
Published: February 2014

Abstract
Elect ropalatographic and acoustic data for the fricative clusters /sʃ/ and /ʃs/ and the single fricatives /s/ and /ʃ/ in Eastern Catalan reveal that, while /sʃ/ undergoes regressive assimilation, /ʃs/ blends into an intermediate fricative or exhibits a twotarget realization. On the other hand, acoustic data for /ʃs/ in Western Catalan show that /s/ may assimilate to preceding /ʃ/ or undergo blending or a two-target realization depending on speaker and prosodic condition (no data are available for /sʃ/ in this dialect). Duration values for the two fricative clusters suggest that the assimilated outcome of /sʃ/ shortens down to the length of /ʃ/. A production-based account of the two sequences /sʃ/ and /ʃs/ in Catalan and other languages is proposed.
Semantic Features of ‘Stepped' versus ‘Continuous' Contours in German Intonation
Authors: Dombrowski Ernst 
Published: February 2014

Abstract
This study analyses the meaning spaces of German pitch contours using two modes of melodic movement: continuous or in steps of sustained pitch. Both the continuous and stepped movements are represented by a set of five basic patterns, the latter being derived from the former. Thirty-six German native speakers judged the pattern sets on a 12-scale semantic differential. The semantic profiles confirm that stepped contours can be conceived of as stylized intonation, in a formal as well as in a functional sense. On the one hand, continuous (non-stylized) and stepped (stylized) contours are assigned different overall meanings (especially on the scales astonished - commonplace and interested - not interested). On the other hand, listeners organize the two contour sets in a similar fashion, which speaks in favour of parallel pattern inventories of continuous and stepped movement, respectively. However, the meaning space of the stylized patterns is affected by formal restrictions, for instance in the step transformation of continuous rises.
Different Prognostic Value of Functional Right Ventricular Parameters in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
Authors: Saguner Ardan M. , Vecchiati Alessandra , Baldinger Samuel H. , Rüeger Sina , Medeiros-Domingo Argelia , Mueller-Burri Andreas S. , Haegeli Laurent M. , Biaggi Patric , Manka Robert , Lüscher Thomas F. , Fontaine Guy , Delacrétaz Etienne , Jenni Rolf , Held Leonhard , Brunckhorst Corinna , Duru Firat , Tanner Felix C. 
Published: February 2014

Background—
The value of standard 2-dimensional transthoracic echocardiographic parameters for risk stratification in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is controversial.

Methods and Results—

We investigated the impact of RV fractional area change (FAC) and tricuspid annulus plane systolic excursion (TAPSE) for the prediction of major adverse cardiovascular events (MACE) defined as the occurrence of cardiac death, heart transplantation, survived sudden cardiac death, ventricular fibrillation, sustained ventricular tachycardia, or arrhythmogenic syncope. Among 70 patients who fulfilled the 2010 ARVC/D Revised Task Force Criteria and underwent baseline transthoracic echocardiography, 37 (53%) patients experienced MACE during a median follow-up period of 5.3 (interquartile range, 1.8–9.8) years. Average values for FAC, TAPSE, and TAPSE indexed to body surface area (BSA) decreased over time (
P
=0.03 for FAC,
P
=0.03 for TAPSE, and
P
=0.01 for TAPSE/BSA, each versus baseline). In contrast, median RV end-diastolic area increased (
P
=0.001 versus baseline). Based on the results of Kaplan–Meier estimates, the time between baseline transthoracic echocardiography and experiencing MACE was significantly shorter for patients with FAC <23% (
P
<0.001), TAPSE <17 mm (
P
=0.02), or right atrial short axis/BSA ≥25 mm/m
2
(
P
=0.04) at baseline. A reduced FAC constituted the strongest predictor of MACE (hazard ratio, 1.08 per 1% decrease; 95% confidence interval, 1.04–1.12;
P
<0.001) on bivariable analysis.

Conclusions—
This long-term observational study indicates that TAPSE and dilation of right-sided cardiac chambers are associated with an increased risk for MACE in patients with ARVC/D with advanced disease and a high risk for adverse events. However, FAC is the strongest echocardiographic predictor of adverse outcome in these patients. Our data advocate a role for transthoracic echocardiography in risk stratification in patients with ARVC/D, although our results may not be generalizable to lower-risk ARVC/D cohorts.