bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiple Mutations Lead to MexXY-OprM-Dependent Aminoglycoside Resistance in Clinical Strains of Pseudomonas aeruginosa
Authors: Guénard Sophie , Muller Cédric , Monlezun Laura , Benas Philippe , Broutin Isabelle , Jeannot Katy , Plésiat Patrick 
Published: October 2013

ABSTRACT

Constitutive overproduction of the pump MexXY-OprM is recognized as a major cause of resistance to aminoglycosides, fluoroquinolones, and zwitterionic cephalosporins in
Pseudomonas aeruginosa
. In this study, 57 clonally unrelated strains recovered from non-cystic fibrosis patients were analyzed to characterize the mutations resulting in upregulation of the
mexXY
operon. Forty-four (77.2%) of the strains, classified as
agrZ
mutants were found to harbor mutations inactivating the local repressor gene (
mexZ
) of the
mexXY
operon (
n
= 33; 57.9%) or introducing amino acid substitutions in its product, MexZ (
n
= 11; 19.3%). These sequence variations, which mapped in the dimerization domain, the DNA binding domain, or the rest of the MexZ structure, mostly affected amino acid positions conserved in TetR-like regulators. The 13 remaining MexXY-OprM strains (22.8%) contained intact
mexZ
genes encoding wild-type MexZ proteins. Eight (14.0%) of these isolates, classified as
agrW1
mutants, overexpressed the gene PA5471, which codes for the MexZ antirepressor AmrZ, with 5 strains exhibiting growth defects at 37°C and 44°C, consistent with mutations impairing ribosome activity. Interestingly, one
agrW1
mutant appeared to harbor a 7-bp deletion in the coding sequence of the leader peptide, PA5471.1, involved in ribosome-dependent, translational attenuation of PA5471 expression. Finally, DNA sequencing and complementation experiments revealed that 5 (8.8%) strains, classified as
agrW2
mutants, harbored single amino acid variations in the sensor histidine kinase of ParRS, a two-component system known to positively control
mexXY
expression. Collectively, these results demonstrate that clinical strains of
P. aeruginosa
exploit different regulatory circuitries to mutationally overproduce the MexXY-OprM pump and become multidrug resistant, which accounts for the high prevalence of MexXY-OprM mutants in the clinical setting.
Curcumin Targets Cell Wall Integrity via Calcineurin-Mediated Signaling in Candida albicans
Authors: Kumar Awanish , Dhamgaye Sanjiveeni , Maurya Indresh Kumar , Singh Ashutosh , Sharma Monika , Prasad Rajendra 
Published: October 2013

ABSTRACT

Curcumin (CUR) shows antifungal activity against a range of pathogenic fungi, including
Candida albicans
. The reported mechanisms of action of CUR include reactive oxygen species (ROS) generation, defects in the ergosterol biosynthesis pathway, decrease in hyphal development, and modulation of multidrug efflux pumps. Reportedly, each of these pathways is independently linked to the cell wall machinery in
C. albicans
, but surprisingly, CUR has not been previously implicated in cell wall damage. In the present study, we performed transcriptional profiling to identify the yet-unidentified targets of CUR in
C. albicans
. We found that, among 348 CUR-affected genes, 51 were upregulated and 297 were downregulated. Interestingly, most of the cell wall integrity pathway genes were downregulated. The possibility of the cell wall playing a critical role in the mechanism of CUR required further validation; therefore, we performed specific experiments to establish if there was any link between the two. The fractional inhibitory concentration index values of 0.24 to 0.37 show that CUR interacts synergistically with cell wall-perturbing (CWP) agents (caspofungin, calcofluor white, Congo red, and SDS). Furthermore, we could observe cell wall damage and membrane permeabilization by CUR alone, as well as synergistically with CWP agents. We also found hypersusceptibility in calcineurin and mitogen-activated protein (MAP) kinase pathway mutants against CUR, which confirmed that CUR also targets cell wall biosynthesis in
C. albicans
. Together, these data provide strong evidence that CUR disrupts cell wall integrity in
C. albicans
. This new information on the mechanistic action of CUR could be employed in improving treatment strategies and in combinatorial drug therapy.
Deletion of the β-Acetoacetyl Synthase FabY in Pseudomonas aeruginosa Induces Hypoacylation of Lipopolysaccharide and Increases Antimicrobial Susceptibility
Authors: Six David A. , Yuan Yanqiu , Leeds Jennifer A. , Meredith Timothy C. 
Published: October 2013

ABSTRACT

The β-acetoacetyl-acyl carrier protein synthase FabY is a key enzyme in the initiation of fatty acid biosynthesis in
Pseudomonas aeruginosa
. Deletion of
fabY
results in an increased susceptibility of
P. aeruginosa
in vitro
to a number of antibiotics, including vancomycin and cephalosporins. Because antibiotic susceptibility can be influenced by changes in membrane lipid composition, we determined the total fatty acid profile of the Δ
fabY
mutant, which suggested alterations in the lipid A region of the lipopolysaccharide. The majority of lipid A species in the Δ
fabY
mutant lacked a single secondary lauroyl group, resulting in hypoacylated lipid A. Adding exogenous fatty acids to the growth media restored the wild-type antibiotic susceptibility profile and the wild-type lipid A fatty acid profile. We suggest that incorporation of hypoacylated lipid A species into the outer membrane contributes to the shift in the antibiotic susceptibility profile of the Δ
fabY
mutant.
Effect of Mature Blood-Stage Plasmodium Parasite Sequestration on Pathogen Biomass in Mathematical and
In Vivo
Models of Malaria
Authors: Khoury David S. , Cromer Deborah , Best Shannon E. , James Kylie R. , Kim Peter S. , Engwerda Christian R. , Haque Ashraful , Davenport Miles P. 
Published: October 2013

ABSTRACT

Parasite biomass and microvasculature obstruction are strongly associated with disease severity and death in
Plasmodium falciparum
-infected humans. This is related to sequestration of mature, blood-stage parasites (schizonts) in peripheral tissue. The prevailing view is that schizont sequestration leads to an increase in pathogen biomass, yet direct experimental data to support this are lacking. Here, we first studied parasite population dynamics in inbred wild-type (WT) mice infected with the rodent species of malaria,
Plasmodium berghei
ANKA. As is commonly reported, these mice became moribund due to large numbers of parasites in multiple tissues. We then studied infection dynamics in a genetically targeted line of mice, which displayed minimal tissue accumulation of parasites. We constructed a mathematical model of parasite biomass dynamics, incorporating schizont-specific host clearance, both with and without schizont sequestration. Combined use of mathematical and
in vivo
modeling indicated, first, that the slowing of parasite growth in the genetically targeted mice can be attributed to specific clearance of schizonts from the circulation and, second, that persistent parasite growth in WT mice can be explained solely as a result of schizont sequestration. Our work provides evidence that schizont sequestration could be a major biological process driving rapid, early increases in parasite biomass during blood-stage
Plasmodium
infection.
Geology and Mineral Deposits of the Superior Province of the Canadian Shield
Authors: Card K.D. , Poulsen K. Howard 
Published: October 2013

Abstract
It has been the custom of the Geological Survey of Canada (GSC) to periodically publish a summary account of the geology and economic mineral deposits of Canada. Such ‘Geology and Economic Minerals of Canada’ volumes were published in 1909, 1926, 1946, 1957, and 1970. During the 1980s, in lieu of a sixth edition, the GSC embarked on the production of a series of more comprehensive ‘Geology of Canada’ volumes as part of the Geological Society of America (GSA) Decade of North American Geology (DNAG) series. Much of the material for this review of the geology and economic minerals of Superior Province was prepared as part of the DNAG initiative but, due to revised operational requirements, the integration of the geological and metallogenic aspects arose much later. In this integrated review, we place particular emphasis on advances that have taken place in the 25 years since the last summaries of this kind (Stockwell et al., 1970; Lang et al., 1970; Goodwin, 1972).
The Archean Superior Craton forms the core of the North American continent (Fig. 2.1) and is surrounded and truncated on all sides by Proterozoic orogens, the collisional zones along which the elements of the Precambrian Canadian Shield were amalgamated (Hoffman, 1988, 1989). The Superior Province (Fig. 2.2) is the 2 × 106 km2 region of this craton which is free of significant post-Archean cover rocks and deformation. The rocks of Superior Province are of mainly Meso- and Neoarchean age and have been significantly affected by post-Archean deformation only along
Synopsis of Precambrian Fossil Occurrences in North America
Authors: Hofmann H.J. 
Published: October 2013

Abstract
The purpose of this paper is to provide a general, current overview of the Precambrian fossil occurrences in North America. This work, a sequel to earlier compilations for Canada (See Hofmann, 1971, 1972, 1981a), has been expanded to encompass the remainder of North America, for which similar compilations are not available (except for the western United States and northwestern Mexico: Horodyski, 1993a, b). On the other hand, several comprehensive monographs on the global Precambrian paleontological record (Schopf, 1983; Schopf and Klein, 1992; Bengtson, 1994) provide impressive detail with global coverage of all aspects of Precambrian paleobiology and evolution. Another topical volume that includes chapters on Precambrian stromatolite reef complexes is Geldsetzer et al. (1989). All the above references have extensive documentation and bibliographies. The present inventory is meant to complement this previous work by providing a synoptic view of North American occurrences in map form (Fig. 4.1, in pocket; Fig. 4.2–4.13), and some observations on the content of the database. This perspective allows a better continent-wide overview of geographic data than tabulated data dispersed in various publications; moreover, lateral relationships of areas where previous work has been concentrated, and those where data are not available, are more readily visualized. This continental overview should be helpful for those contemplating future paleontological work in the Precambrian sequences of North America.
Fossils and possible fossils have been reported from at least 383 formations in North America attributed to the Precambrian. These 383 occurrences, known up to mid-1996 from Canada, Greenland, U.S.A., and Mexico,
High-intensity interval training in patients with lifestyle-induced cardiometabolic disease: a systematic review and meta-analysis
Authors: Weston Kassia S , Wisløff Ulrik , Coombes Jeff S 
Published: October 2013

Background/AimCardiorespiratory fitness (CRF) is a strong determinant of morbidity and mortality. In athletes and the general population, it is established that high-intensity interval training (HIIT) is superior to moderate-intensity continuous training (MICT) in improving CRF. This is a systematic review and meta-analysis to quantify the efficacy and safety of HIIT compared to MICT in individuals with chronic cardiometabolic lifestyle diseases.MethodsThe included studies were required to have a population sample of chronic disease, where poor lifestyle is considered as a main contributor to the disease. The procedural quality of the studies was assessed by use of a modified Physiotherapy Evidence Base Database (PEDro) scale. A meta-analysis compared the mean difference (MD) of preintervention versus postintervention CRF (VO2peak) between HIIT and MICT.Results10 studies with 273 patients were included in the meta-analysis. Participants had coronary artery disease, heart failure, hypertension, metabolic syndrome and obesity. There was a significantly higher increase in the VO2peak after HIIT compared to MICT (MD 3.03 mL/kg/min, 95% CI 2.00 to 4.07), equivalent to 9.1%.ConclusionsHIIT significantly increases CRF by almost double that of MICT in patients with lifestyle-induced chronic diseases.
Sedentary behaviour and physical inactivity assessment in primary care: the Rapid Assessment Disuse Index (RADI) study
Authors: Shuval Kerem , Kohl Harold W , Bernstein Ira , Cheng Dunlei , Pettee Gabriel Kelley , Barlow Carolyn E , Yinghui Liu , DiPietro Loretta 
Published: October 2013

BackgroundThe emerging evidence of the effects of sedentary time on health outcomes suggests a need to better measure this exposure. Healthcare settings, however, are not equipped with a tool that can quickly assess the sedentary habits of their patient population. The purpose of this study was to validate a tool for rapidly quantifying and tracking the sedentary time and low levels of daily lifestyle physical activity among primary care patients.MethodsThe study examined the test–retest reliability and validity of the rapid assessment disuse index (RADI) among adult patients from a large primary care clinic. Patients completed RADI (comprised of 3 items: sitting, moving and stair climbing) twice, followed by accelerometer monitoring. Test–retest reliability was computed, and the correlation between survey responses and accelerometry was determined. A receiver operating characteristic curve was constructed and the area under the curve (AUC) was calculated.ResultsRADI was temporally stable (intraclass correlation coefficients 0.79), and a higher score was significantly correlated with greater sedentary time (ρ=0.40; p<0.01), fewer sedentary to active transitions (ρ=−0.42; p<0.01), and less light-intensity physical activity (ρ=−0.40; p<0.01). The ability of RADI to detect patients with high levels of sedentary time was fair (AUC=0.72).ConclusionsThis brief assessment tool, designed to quickly identify patients with high levels of sitting and low daily physical activity, exhibits good reliability and moderate validity. RADI can assist in providing recommendations at the point of care pertaining to modifying sedentary behaviour.
Clinical features, outcome and prognostic factors in dogs diagnosed with non‐cortisol‐secreting adrenal tumours without adrenalectomy: 20 cases (1994–2009)
Authors: Arenas C. , Pérez‐Alenza D. , Melián C. 
Published: October 2013

The aims of this study were to describe the clinical features, the outcome and the prognostic factors of dogs with non‐cortisol‐secreting adrenal masses without adrenalectomy, and also to provide clinical data that can be useful for making decisions when managing dogs with these types of neoplasms. Medical records from 1994 to 2009 were reviewed and 20 dogs were included in the study. The results showed that mean age at diagnosis for dogs with non‐cortisol‐secreting adrenal masses was 12 years with no sex predisposition. Most dogs were asymptomatic. The most frequent clinical signs, when present, were lethargy, weakness and hypertension. Radiological evidence of metastases at diagnosis was not frequent. The maximal dorso‐ventral thickness of the adrenal mass ranged from 10.0 to 45.0 mm. Right adrenal gland masses were more frequent than left‐sided. Hypertension was found to be related to tumour growth during follow‐up. The median survival time of dogs with non‐cortisol‐secreting tumours was 17.8 months. Body weight at diagnosis, tumour size and the presence of metastases at diagnosis were inversely related to survival. In conclusion, survival of dogs with non‐cortisol‐secreting adrenal tumours without adrenalectomy is relatively high and comparable with that of dogs treated with adrenalectomy. Dogs with metastasis and large adrenal tumours have a poorer prognosis. Hypertension is related to tumour growth, and might be used as an additional tool to assess the potential growing capacity of the tumour.
Power consumption estimation of CPU and peripheral components in virtual machines
Authors: Versick Daniel , Waßmann Ingolf , Tavangarian Djamshid 
Published: October 2013

Energy consumption of IT increased continuously during the last decades. Numerous works have been accomplished for improving energy efficiency of hardware whereas software energy efficiency has been ignored for a long time. This contribution presents a novel approach for estimating energy consumption of computer systems in dependency of software-caused workloads in different execution environments. The system is the basis for automatic optimization of software execution in an energy-efficient way by finding the best-suiting host computer (and best-suiting peripheral devices). Thus, it opens novel ways to further improve energy-efficiency of IT systems by migrating software-caused load to an energy-efficient target.
Exemplary, the approach is tested in a virtualized data center environment, where virtual machines are the applications. The presented approach is a vehicle for automatically computing an energy-efficient virtual machine placement. The paper presents a new algorithm for estimating virtual machine power consumption, which consists of CPU power consumption estimation as well as power usage estimation of peripheral components like hard disk drive and network interface controller. The accuracy of the presented approach is proved by means of measurements.
Antitumor Effects of Immunotoxins Are Enhanced by Lowering HCK or Treatment with Src Kinase Inhibitors
Authors: Liu Xiu-Fen , Xiang Laiman , FitzGerald David J. , Pastan Ira 
Published: October 2013

Abstract
Recombinant immunotoxins (RIT) are agents being developed for cancer treatment. They are composed of an Fv that binds to a cancer cell, fused to a 38-kDa fragment of Pseudomonas exotoxin A. SS1P is a RIT that targets mesothelin, a protein expressed on mesothelioma as well as pancreatic, ovarian, lung, and other cancers. Because the protein tyrosine kinase family regulates a variety of cellular processes and pathways, we hypothesized that tyrosine kinases might regulate susceptibility to immunotoxin killing. To investigate their role, we used siRNAs to lower the level of expression of the 88 known tyrosine kinases. We identified five tyrosine kinases, INSR, HCK, SRC, PDGFRβ, and BMX that enhance the activity of SS1P when their level of expression is lowered by siRNAs. We further investigated the Src family member HCK in this study. Knocking down of SRC slightly increased SS1P killing in A431/H9 cells, but knocking down HCK substantially enhanced killing by SS1P. We investigated the mechanism of enhancement and found that HCK knockdown enhanced SS1P cleavage by furin and lowered levels of Mcl-1 and raised Bax. We then found that Src inhibitors mimic the stimulatory effect of HCK knockdown; both SU6656 and SKI-606 (bosutinib) enhanced immunotoxin killing of mesothelin-expressing cells by SS1P and CD22-expressing cells by HA22 (moxetumomab pasudotox). SU6656 also enhanced the antitumor effects of SS1P and HA22 in mouse xenograft tumor models. Our data suggest that the combination of immunotoxin with tyrosine kinase inhibitors may be an effective way to treat some cancers. Mol Cancer Ther; 13(1); 82–89. ©2013 AACR.
Locally Delivered CD40 Agonist Antibody Accumulates in Secondary Lymphoid Organs and Eradicates Experimental Disseminated Bladder Cancer
Authors: Sandin Linda C. , Orlova Anna , Gustafsson Erika , Ellmark Peter , Tolmachev Vladimir , Tötterman Thomas H. , Mangsbo Sara M. 
Published: October 2013

Abstract
Immunotherapy with intratumoral injection of adenoviral vectors expressing CD40L has yielded positive results in experimental and clinical bladder cancer. We therefore hypothesized that anti-CD40 antibody would be effective in this setting. Agonistic CD40 antibodies were developed as vaccine adjuvants but have later been used as treatment of advanced solid tumors and hematologic cancers. Systemic anti-CD40 therapy has been associated with immune-related adverse events, such as cytokine release syndrome and liver toxicity, and local delivery is an attractive approach that could reduce toxicity. Herein, we compared local and systemic anti-CD40 antibody delivery to evaluate efficacy, toxicity, and biodistribution in the experimental MB49 bladder cancer model. Antitumor effects were confirmed in the B16 model. In terms of antitumor efficacy, local anti-CD40 antibody stimulation was superior to systemic therapy at an equivalent dose and CD8 T cells were crucial for tumor growth inhibition. Both administration routes were dependent on host CD40 expression for therapeutic efficacy. In vivo biodistribution studies revealed CD40-specific antibody accumulation in the tumor-draining lymph nodes and the spleen, most likely reflecting organs with frequent target antigen-expressing immune cells. Systemic administration led to higher antibody concentrations in the liver and blood compared with local delivery, and was associated with elevated levels of serum haptoglobin. Despite the lack of a slow-release system, local anti-CD40 therapy was dependent on tumor antigen at the injection site for clearance of distant tumors. To summarize, local low-dose administration of anti-CD40 antibody mediates antitumor effects in murine models with reduced toxicity and may represent an attractive treatment alternative in the clinic. Cancer Immunol Res; 2(1); 80–90. ©2013 AACR.
SCID patients with ARTEMIS vs RAG deficiencies following HCT: increased risk of late toxicity in ARTEMIS-deficient SCID
Authors: Schuetz Catharina , Neven Benedicte , Dvorak Christopher C. , Leroy Sandrine , Ege Markus J. , Pannicke Ulrich , Schwarz Klaus , Schulz Ansgar S. , Hoenig Manfred , Sparber-Sauer Monika , Gatz Susanne A. , Denzer Christian , Blanche Stephane , Moshous Despina , Picard Capucine , Horn Biljana N. , de Villartay Jean-Pierre , Cavazzana Marina , Debatin Klaus-Michael , Friedrich Wilhelm , Fischer Alain , Cowan Morton J. 
Published: October 2013

Abstract
A subgroup of severe combined immunodeficiencies (SCID) is characterized by lack of T and B cells and is caused by defects in genes required for T- and B-cell receptor gene rearrangement. Several of these genes are also involved in nonhomologous end joining of DNA double-strand break repair, the largest subgroup consisting of patients with T−B−NK+SCID due to DCLRE1C/ARTEMIS defects. We postulated that in patients with ARTEMIS deficiency, early and late complications following hematopoietic cell transplantation might be more prominent compared with patients with T−B−NK+SCID caused by recombination activating gene 1/2 (RAG1/2) deficiencies. We analyzed 69 patients with ARTEMIS and 76 patients with RAG1/2 deficiencies who received transplants from either HLA-identical donors without conditioning or from HLA-nonidentical donors without or with conditioning. There was no difference in survival or in the incidence or severity of acute graft-versus-host disease regardless of exposure to alkylating agents. Secondary malignancies were not observed. Immune reconstitution was comparable in both groups, however, ARTEMIS-deficient patients had a significantly higher occurrence of infections in long-term follow-up. There is a highly significant association between poor growth in ARTEMIS deficiency and use of alkylating agents. Furthermore, abnormalities in dental development and endocrine late effects were associated with alkylation therapy in ARTEMIS deficiency.