bluuebunny/crossref_metadata_2025_split huggingface dataset:
MtvR Is a Global Small Noncoding Regulatory RNA in Burkholderia cenocepacia
Authors: Ramos Christian G. , Grilo André M. , da Costa Paulo J. P. , Feliciano Joana R. , Leitão Jorge H. 
Published: June 2013

ABSTRACT

Burkholderia cenocepacia
J2315 is a highly epidemic and transmissible clinical isolate of the
Burkholderia cepacia
complex (Bcc), a group of bacteria causing life-threatening respiratory infections among cystic fibrosis patients. This work describes the functional analysis of the 136-nucleotide (nt)-long MtvR small noncoding RNA (sRNA) from the Bcc member
B. cenocepacia
J2315, with homologues restricted to the genus
Burkholderia
. Bioinformatic target predictions revealed a total of 309 mRNAs to be putative MtvR targets. The mRNA levels corresponding to 17 of 19 selected genes were found to be affected when MtvR was either overexpressed or silenced. Analysis of the interaction between MtvR and the
hfq
mRNA, one of its targets, showed that the sRNA binds exclusively to the 5′ untranslated region (UTR) of the
hfq
mRNA. This interaction resulted in decreased protein synthesis, suggesting a negative regulatory effect of MtvR on the RNA chaperone Hfq. Bacterial strains with MtvR silenced or overexpressed exhibited pleiotropic phenotypes related to growth and survival after several stresses, swimming and swarming motilities, biofilm formation, resistance to antibiotics, and ability to colonize and kill the nematode
Caenorhabditis elegans
. Together, the results indicate that the MtvR sRNA is a major posttranscriptional regulator in
B. cenocepacia
.
Allelic Variation in a Simple Sequence Repeat Element of Neisserial
pglB2
and Its Consequences for Protein Expression and Protein Glycosylation
Authors: Viburiene Raimonda , Vik Åshild , Koomey Michael , Børud Bente 
Published: June 2013

ABSTRACT

Neisseria
species express an
O
-linked glycosylation system in which functionally distinct proteins are elaborated with variable glycans. A major source of glycan diversity in
N. meningitidis
results from two distinct
pglB
alleles responsible for the synthesis of either
N
,
N
′-diacetylbacillosamine or glyceramido-acetamido trideoxyhexose that occupy the reducing end of the oligosaccharides. Alternative modifications at C-4 of the precursor UDP-4-amino are attributable to distinct C-terminal domains that dictate either acetyltransferase or glyceramidotransferase activity, encoded by
pglB
and
pglB2
, respectively. Naturally occurring alleles of
pglB2
have homopolymeric tracts of either 7 or 8 adenosines (As) bridging the C-terminal open reading frame (ORF) and the ORF encompassing the conserved N-terminal domain associated with phosphoglycosyltransferase activity. In the work presented here, we explored the consequences of such
pglB2
allele variation and found that, although both alleles are functional vis-à-vis glycosylation, the 7A form results in the expression of a single, multidomain protein, while the 8A variant elicits two single-domain proteins. We also found that the glyceramidotransferase activity-encoding domain is essential to protein glycosylation, showing the critical role of the C-4 modification of the precursor UDP-4-amino in the pathway. These findings were further extended and confirmed by examining the phenotypic consequences of extended poly(A) tract length variation. Although ORFs related to those of
pglB2
are broadly distributed in eubacteria, they are primarily found as two distinct, juxtaposed ORFs. Thus, the neisserial
pglB2
system provides novel insights into the potential influence of hypermutability on modular evolution of proteins by providing a unique snapshot of the progression of ongoing gene fusion.
Brucella BioR Regulator Defines a Complex Regulatory Mechanism for Bacterial Biotin Metabolism
Authors: Feng Youjun , Xu Jie , Zhang Huimin , Chen Zeliang , Srinivas Swaminath 
Published: June 2013

ABSTRACT

The enzyme cofactor biotin (vitamin H or B7) is an energetically expensive molecule whose
de novo
biosynthesis requires 20 ATP equivalents. It seems quite likely that diverse mechanisms have evolved to tightly regulate its biosynthesis. Unlike the model regulator BirA, a bifunctional biotin protein ligase with the capability of repressing the biotin biosynthetic pathway, BioR has been recently reported by us as an alternative machinery and a new type of GntR family transcriptional factor that can repress the expression of the
bioBFDAZ
operon in the plant pathogen
Agrobacterium tumefaciens
. However, quite unusually, a closely related human pathogen,
Brucella melitensis
, has four putative BioR-binding sites (both
bioR
and
bioY
possess one site in the promoter region, whereas the
bioBFDAZ
[
bio
] operon contains two tandem BioR boxes). This raised the question of whether BioR mediates the complex regulatory network of biotin metabolism. Here, we report that this is the case. The
B. melitensis
BioR ortholog was overexpressed and purified to homogeneity, and its solution structure was found to be dimeric. Functional complementation in a
bioR
isogenic mutant of
A. tumefaciens
elucidated that
Brucella
BioR is a functional repressor. Electrophoretic mobility shift assays demonstrated that the four predicted BioR sites of
Brucella
plus the BioR site of
A. tumefaciens
can all interact with the
Brucella
BioR protein. In a reporter strain that we developed on the basis of a double mutant of
A. tumefaciens
(the Δ
bioR
Δ
bioBFDA
mutant), the β-galactosidase (β-Gal) activity of three plasmid-borne transcriptional fusions (
bioB
bme
-lacZ
,
bioY
bme
-lacZ
, and
bioR
bme
-lacZ
) was dramatically decreased upon overexpression of
Brucella bioR
. Real-time quantitative PCR analyses showed that the expression of
bioBFDA
and
bioY
is significantly elevated upon removal of
bioR
from
B. melitensis
. Together, we conclude that
Brucella
BioR is not only a negative autoregulator but also a repressor of expression of
bioY
and
bio
operons that separately function in biotin transport and the biosynthesis pathway.
Implication of the VirD4 Coupling Protein of the Lvh Type 4 Secretion System in Virulence Phenotypes of Legionella pneumophila
Authors: Bandyopadhyay Purnima , Lang Elza A. S. , Rasaputra Komal S. , Steinman Howard M. 
Published: June 2013

ABSTRACTThe genome of the Philadelphia-1 strain ofLegionella pneumophila, the causative organism of Legionnaires' disease, encodes two virulence-associated type 4 secretion systems (T4SSs), the Dot/Icm type 4B (T4BSS) and the Lvh type 4A (T4ASS). Broth stationary-phase cultures of mostdot/icmmutants are defective in entry and evasion of phagosome acidification. However, those virulence defects can be reversed by incubating broth cultures ofdot/icmmutants in water, termed water stress (WS). WS reversal requires thelvhT4ASS locus, suggesting an interaction between the two T4SSs in producingLegionellavirulence phenotypes. In the current work, the loss of WS reversal in adotAΔlvhmutant of strain JR32 was shown to be attributable to loss of thelvh virD4gene, encoding the putative coupling protein of the T4ASS. Transformation of adotAΔlvhmutant withvirD4also reversed entry and phagosome acidification defects in broth cultures. In addition, broth cultures of Δlvhand ΔvirD4mutants, which weredot/icm+, showed 5-fold and >6-fold increases in translocation of the Dot/Icm translocation substrates, proteins RalF and SidD, respectively. These data demonstrate that the Lvh T4ASS functions in both broth stationary-phase cultures conventionally used for infection and cultures exposed to WS treatment. Our studies in adotAΔlvhmutant and in adot/icm+background establish that VirD4 and the Lvh T4ASS contribute to virulence phenotypes and are consistent with independent functioning of Dot/Icm and Lvh T4SSs or functional substitution of the Lvh VirD4 protein for a component(s) of the Dot/Icm T4BSS.
Key Amino Acid Residues Involved in the Transitions of L- to R-Type Protofilaments of the Salmonella Flagellar Filament
Authors: Hayashi Fumio , Tomaru Hidetoshi , Furukawa Eiji , Ikeda Kanae , Fukano Hiroko , Oosawa Kenji 
Published: June 2013

ABSTRACT

The flagellar filament enables bacteria to swim by functioning as a helical propeller. The filament is a supercoiled assembly of a single protein, flagellin, and is formed by 11 protofilaments arranged in a circle. Bacterial swimming and tumbling correlate with changes of the various helical structures, called polymorphic transformation, that are determined by the ratios of two distinct forms of protofilaments, the L and R types. The polymorphic transformation is caused by transition of the protofilament between L and R types. Elucidation of this transition mechanism has been addressed by comparing the atomic structures of L- and R-type straight filaments or using massive molecular dynamic simulation. Here, we found amino acid residues required for the transition of the protofilament using
fliC
-intragenic suppressor analysis. We isolated a number of revertants producing supercoiled filaments from mutants with straight filaments and identified the second-site mutations in all of the revertants. The results suggest that Asp107, Gly426, and Ser448 and Ser106, Ala416, Ala427, and Arg431 are the key residues involved in inducing supercoiled filaments from the R- and the L-type straight filaments, respectively. Considering the structures of the R- and L-type protofilaments and the relationship between the rotation of the flagellar motor and the polymorphic transformation, we propose that Gly426, Ala427, and Arg431 contribute to the first stage of the transition and that Ser106, Asp107, and Ala416 play a role in propagating the transitions along the flagellar filament.
Occupational homicide of law enforcement officers in the US, 1996–2010
Authors: Swedler David I , Kercher Cassandra , Simmons Molly M , Pollack Keshia M 
Published: June 2013

ObjectiveTo understand the circumstances surrounding the occupational homicides of law enforcement officers (LEOs) in the USA.MethodsNarrative text analysis of Federal Bureau of InvestigationLaw Enforcement Officers Killed and Assaultedreports.ResultsA total of 796 officers were killed in the line of duty between 1996 and 2010. The occupational homicide rate during the time peaked in 2001 at 3.76/100 000 (excluding those killed during the September 11 2001 terrorist attacks), and was lowest in 2008 at 1.92/100 000. Most LEOs (67%) were killed by short-barrel firearms; 10% were killed with their own service weapon. The most frequent encounter with a suspect prior to a homicide was responding to a disturbance call.ConclusionsThese results should inform officer training and the policies, as well as procedures used when interacting with suspects, especially when firearms are involved.
Inhibition of GSK3B Bypass Drug Resistance of p53-Null Colon Carcinomas by Enabling Necroptosis in Response to Chemotherapy
Authors: Grassilli Emanuela , Narloch Robert , Federzoni Elena , Ianzano Leonarda , Pisano Fabio , Giovannoni Roberto , Romano Gabriele , Masiero Laura , Leone Biagio Eugenio , Bonin Serena , Donada Marisa , Stanta Giorgio , Helin Kristian , Lavitrano Marialuisa 
Published: June 2013

Abstract
Purpose: Evasion from chemotherapy-induced apoptosis due to p53 loss strongly contributes to drug resistance. Identification of specific targets for the treatment of drug-resistant p53-null tumors would therefore increase the effectiveness of cancer therapy.
Experimental Design: By using a kinase-directed short hairpin RNA library and HCT116p53KO drug-resistant colon carcinoma cells, glycogen synthase kinase 3 beta (GSK3B) was identified as a target whose silencing bypasses drug resistance due to loss of p53. p53-null colon cancer cell lines with different sets of mutations were used to validate the role of GSK3B in sustaining resistance and to characterize cell death mechanisms triggered by chemotherapy when GSK3B is silenced. In vivo xenograft studies were conducted to confirm resensitization of drug-resistant cells to chemotherapy upon GSK3 inhibition. Colon cancer samples from a cohort of 50 chemotherapy-treated stage II patients were analyzed for active GSK3B expression.
Results: Downregulation of GSK3B in various drug-resistant p53-null colon cancer cell lines abolished cell viability and colony growth after drug addition without affecting cell proliferation or cell cycle in untreated cells. Cell death of 5-fluorouracil (5FU)–treated p53-null GSK3B-silenced colon carcinoma cells occurred via PARP1-dependent and AIF-mediated but RIP1-independent necroptosis. In vivo studies showed that drug-resistant xenograft tumor mass was significantly reduced only when 5FU was given after GSK3B inhibition. Tissue microarray analysis of colon carcinoma samples from 5FU-treated patients revealed that GSK3B is significantly more activated in drug-resistant versus responsive patients.
Conclusions: Targeting GSK3B, in combination with chemotherapy, may represent a novel strategy for the treatment of chemotherapy-resistant tumors. Clin Cancer Res; 19(14); 3820–31. ©2013 AACR.
Spinophilin Loss Correlates with Poor Patient Prognosis in Advanced Stages of Colon Carcinoma
Authors: Estevez-Garcia Purificacion , Lopez-Calderero Iker , Molina-Pinelo Sonia , Muñoz-Galvan Sandra , Salinas Ana , Gomez-Izquierdo Lourdes , Lucena-Cacace Antonio , Felipe-Abrio Blanca , Paz-Ares Luis , Garcia-Carbonero Rocio , Carnero Amancio 
Published: June 2013

Abstract
Purpose: The genomic region 17q21 is frequently associated with microsatellite instability and LOH in cancer, including gastric and colorectal carcinomas. This region contains several putative tumor suppressor genes, including Brca1, NM23, prohibitin, and spinophilin (Spn, PPP1R9B, neurabin II). The scaffold protein Spn is one of the regulatory subunits of phosphatase-1 (PP1) that targets PP1 to distinct subcellular locations and couples PP1 to its target. Thus, Spn may alter cell-cycle progression via the regulation of the phosphorylation status of the retinoblastoma protein, a direct target of PP1. Therefore, we analyzed whether Spn levels were reduced in colorectal carcinomas and whether Spn levels correlated with prognosis or response to therapy.
Experimental Design: By means of immunohistochemistry or quantitative PCR, we studied the levels of Spn in stages II, III, and IV colorectal carcinoma tumors and correlated to other clinicopathologic features as well as prognosis or response to therapy.
Results: Spn was lost in a percentage of human gastric, small intestine, and colorectal carcinomas. In patients with colorectal carcinoma, tumoral Spn downregulation correlated with a more aggressive histologic phenotype (poorer tumor differentiation and higher proliferative Ki67 index). Consistent with this observation, lower Spn protein expression levels were associated with faster relapse and poorer survival in patients with stage III colorectal carcinoma, particularly among those receiving adjuvant fluoropyrimidine therapy. We validated this result in an independent cohort of patients with metastatic colorectal carcinoma treated with standard chemotherapy. Although patients that achieved an objective tumor response exhibited Spn levels similar to nontumoral tissue, nonresponding patients showed a significant reduction in Spn mRNA levels.
Conclusions: Our data suggest that Spn downregulation contributes to a more aggressive biologic behavior, induces chemoresistance, and is associated with a poorer survival in patients with advanced stages of colorectal carcinoma. Clin Cancer Res; 19(14); 3925–35. ©2013 AACR.
Endoplasmic Reticulum Stress and the Unfolded Protein Response: Targeting the Achilles Heel of Multiple Myeloma
Authors: Vincenz Lisa , Jäger Richard , O'Dwyer Michael , Samali Afshin 
Published: June 2013

AbstractMultiple myeloma is characterized by the malignant proliferating antibody-producing plasma cells in the bone marrow. Despite recent advances in therapy that improve the survival of patients, multiple myeloma remains incurable and therapy resistance is the major factor causing lethality. Clearly, more effective treatments are necessary. In recent years it has become apparent that, as highly secretory antibody-producing cells, multiple myeloma cells require an increased capacity to cope with unfolded proteins and are particularly sensitive to compounds targeting proteostasis such as proteasome inhibitors, which represent one of the most prominent new therapeutic strategies. Because of the increased requirement for dealing with secretory proteins within the endoplasmic reticulum, multiple myeloma cells are heavily reliant for survival on a set of signaling pathways, known as the unfolded protein response (UPR). Thus, directly targeting the UPR emerges as a new promising therapeutic strategy. Here, we provide an overview of the current understanding of the UPR signaling in cancer, and outline its important role in myeloma pathogenesis and treatment. We discuss new therapeutic approaches based on targeting the protein quality control machinery and particularly the IRE1α/XBP1 axis of the UPR. Mol Cancer Ther; 12(6); 831–43. ©2013 AACR.
Therapeutic Potential of the Poly(ADP-ribose) Polymerase Inhibitor Rucaparib for the Treatment of Sporadic Human Ovarian Cancer
Authors: Ihnen Maike , zu Eulenburg Christine , Kolarova Teodora , Qi Jing Wei , Manivong Kanthinh , Chalukya Meenal , Dering Judy , Anderson Lee , Ginther Charles , Meuter Alexandra , Winterhoff Boris , Jones Siân , Velculescu Victor E. , Venkatesan Natarajan , Rong Hong-Mei , Dandekar Sugandha , Udar Nitin , Jänicke Fritz , Los Gerrit , Slamon Dennis J. , Konecny Gottfried E. 
Published: June 2013

Abstract
Here, we investigate the potential role of the PARP inhibitor rucaparib (CO-338, formerly known as AG014699 and PF-01367338) for the treatment of sporadic ovarian cancer. We studied the growth inhibitory effects of rucaparib in a panel of 39 ovarian cancer cell lines that were each characterized for mutation and methylation status of BRCA1/2, baseline gene expression signatures, copy number variations of selected genes, PTEN status, and sensitivity to platinum-based chemotherapy. To study interactions with chemotherapy, we used multiple drug effect analyses and assessed apoptosis, DNA fragmentation, and γH2AX formation. Concentration-dependent antiproliferative effects of rucaparib were seen in 26 of 39 (67%) cell lines and were not restricted to cell lines with BRCA1/2 mutations. Low expression of other genes involved in homologous repair (e.g., BCCIP, BRCC3, ATM, RAD51L1), amplification of AURKA or EMSY, and response to platinum-based chemotherapy was associated with sensitivity to rucaparib. Drug interactions with rucaparib were synergistic for topotecan, synergistic, or additive for carboplatin, doxorubicin or paclitaxel, and additive for gemcitabine. Synergy was most pronounced when rucaparib was combined with topotecan, which resulted in enhanced apoptosis, DNA fragmentation, and γH2AX formation. Importantly, rucaparib potentiated chemotherapy independent of its activity as a single agent. PARP inhibition may be a useful therapeutic strategy for a wider range of ovarian cancers bearing deficiencies in the homologous recombination pathway other than just BRCA1/2 mutations. These results support further clinical evaluation of rucaparib either as a single agent or as an adjunct to chemotherapy for the treatment of sporadic ovarian cancer. Mol Cancer Ther; 12(6); 1002–15. ©2013 AACR.
Cyclooxygenase-2, Epidermal Growth Factor Receptor, and Aromatase Signaling in Inflammation and Mesothelioma
Authors: Nuvoli Barbara , Galati Rossella 
Published: June 2013

Abstract
Malignant mesothelioma or mesothelioma is a rare form of cancer that develops from transformed cells originating in the mesothelium, the protective lining that covers many of the internal organs of the body. It is directly linked to asbestos exposure, which acts as a carcinogen by initiating the carcinogenic process. Because of their shape, asbestos fibers can cross the membrane barriers inside the body and cause inflammatory and fibrotic reactions. Such reactions are believed to be the mechanism by which asbestos fibers may trigger malignant mesothelioma in the pleural membrane around the lungs. Carcinogens are known to modulate the transcription factors, antiapoptotic proteins, proapoptotic proteins, protein kinases, cell-cycle proteins, cell adhesion molecules, COX-2, and growth factor signaling pathways. This article reviews recent studies regarding some malignant mesothelioma molecular targets not only for cancer prevention but also for cancer therapy. Mol Cancer Ther; 12(6); 844–52. ©2013 AACR.
Left Cardiac Sympathetic Denervation in Long QT Syndrome
Authors: Bos J. Martijn , Bos Katy M. , Johnson Jonathan N. , Moir Christopher , Ackerman Michael J. 
Published: June 2013

Background—
Long QT syndrome (LQTS) is a potentially lethal but highly treatable cardiac channelopathy. Treatment options include pharmacotherapy, device therapy, and left cardiac sympathetic denervation (LCSD). Here, we sought to determine the characteristics of LQTS patients who have had ≥1 LQTS-related breakthrough cardiac event (BCE) after LCSD.

Methods and Results—

We performed retrospective chart review for 52 consecutive patients (24 males; mean age at diagnosis, 10.0±10 years; mean QTc, 528±74 ms) with LQTS who underwent LCSD between 2005 and 2010 (mean age at LCSD, 14.1±10 years) and have been followed up for 3.6±1.3 years. A BCE was defined as either (1) an appropriate ventricular fibrillation-terminating implantable cardioverter defibrillator shock or (2) arrhythmogenic syncope, seizures, or aborted cardiac arrest after LCSD. Thirty-three patients (61%) had LCSD as primary prevention because of either high-risk assessment or β-blocker intolerance. So far, 12 of 52 (23%) patients (7 males) have experienced ≥1 BCE post LCSD. The clinical phenotype of patients with BCEs was significantly more severe than patients without a BCE. No BCEs were seen in patients undergoing LCSD for β-blocker intolerance (0/12 versus 17/40;
P
<0.001).

Conclusions—
Although a marked reduction in number of cardiac events is usually seen after LCSD, ≈50% of high-risk LQTS patients have experienced ≥1 post-LCSD breakthrough. Therefore, LCSD must not be viewed as curative or as an alternative in implantable cardioverter defibrillator for high-risk patients. Prophylactic LCSD may provide another option to counter a suboptimal quality of life resulting from medication-related side effects.