bluuebunny/crossref_metadata_2025_split huggingface dataset:
A
Francisella tularensis
Live Vaccine Strain (LVS) Mutant with a Deletion in
capB
, Encoding a Putative Capsular Biosynthesis Protein, Is Significantly More Attenuated than LVS yet Induces Potent Protective Immunity in Mice against
F. tularensis
Challenge
Authors: Jia Qingmei , Lee Bai-Yu , Bowen Richard , Dillon Barbara Jane , Som Susan M. , Horwitz Marcus A. 
Published: July 2010

ABSTRACT

Francisella tularensis
, the causative agent of tularemia, is in the top category (category A) of potential agents of bioterrorism. The
F. tularensis
live vaccine strain (LVS) is the only vaccine currently available to protect against tularemia; however, this unlicensed vaccine is relatively toxic and provides incomplete protection against aerosolized
F. tularensis
, the most dangerous mode of transmission. Hence, a safer and more potent vaccine is needed. As a first step toward addressing this need, we have constructed and characterized an attenuated version of LVS, LVS Δ
capB
, both as a safer vaccine and as a vector for the expression of recombinant
F. tularensis
proteins. LVS Δ
capB
, with a targeted deletion in a putative capsule synthesis gene (
capB
), is antibiotic resistance marker free. LVS Δ
capB
retains the immunoprotective O antigen, is serum resistant, and is outgrown by parental LVS in human macrophage-like THP-1 cells in a competition assay. LVS Δ
capB
is significantly attenuated in mice; the 50% lethal dose (LD
50
) intranasally (i.n.) is >10,000-fold that of LVS. Providing CapB in
trans
to LVS Δ
capB
partially restores its virulence in mice. Mice immunized with LVS Δ
capB
i.n. or intradermally (i.d.) developed humoral and cellular immune responses comparable to those of mice immunized with LVS, and when challenged 4 or 8 weeks later with a lethal dose of LVS i.n., they were 100% protected from illness and death and had significantly lower levels (3 to 5 logs) of LVS in the lung, liver, and spleen than sham-immunized mice. Most importantly, mice immunized with LVS Δ
capB
i.n. or i.d. and then challenged 6 weeks later by aerosol with 10× the LD
50
of the highly virulent type A
F. tularensis
strain SchuS4 were significantly protected (100% survival after i.n. immunization). These results show that LVS Δ
capB
is significantly safer than LVS and yet provides potent protective immunity against virulent
F. tularensis
SchuS4 challenge.
A Decade of
Burkholderia cenocepacia
Virulence Determinant Research
Authors: Loutet Slade A. , Valvano Miguel A. 
Published: July 2010

ABSTRACT

The
Burkholderia cepacia
complex (Bcc) is a group of genetically related environmental bacteria that can cause chronic opportunistic infections in patients with cystic fibrosis (CF) and other underlying diseases. These infections are difficult to treat due to the inherent resistance of the bacteria to antibiotics. Bacteria can spread between CF patients through social contact and sometimes cause cepacia syndrome, a fatal pneumonia accompanied by septicemia.
Burkholderia cenocepacia
has been the focus of attention because initially it was the most common Bcc species isolated from patients with CF in North America and Europe. Today,
B. cenocepacia
, along with
Burkholderia multivorans
, is the most prevalent Bcc species in patients with CF. Given the progress that has been made in our understanding of
B. cenocepacia
over the past decade, we thought that it was an appropriate time to review our knowledge of the pathogenesis of
B. cenocepacia
, paying particular attention to the characterization of virulence determinants and the new tools that have been developed to study them. A common theme emerging from these studies is that
B. cenocepacia
establishes chronic infections in immunocompromised patients, which depend more on determinants mediating host niche adaptation than those involved directly in host cells and tissue damage.
The K1 Capsular Polysaccharide of
Acinetobacter baumannii
Strain 307-0294 Is a Major Virulence Factor
Authors: Russo Thomas A. , Luke Nicole R. , Beanan Janet M. , Olson Ruth , Sauberan Shauna L. , MacDonald Ulrike , Schultz L. Wayne , Umland Timothy C. , Campagnari Anthony A. 
Published: July 2010

ABSTRACT

Acinetobacter baumannii
is a pathogen of increasing medical importance with a propensity to be multidrug resistant, thereby making treatment challenging. Little is known of virulence traits in
A. baumannii
. To identify virulence factors and potential drug targets, random transposon (Tn) mutants derived from the
A. baumannii
strain AB307-0294 were screened to identify genes essential for growth in human ascites fluid
in vitro
, an inflammatory exudative fluid. These studies led to the identification of two genes that were predicted to be required for capsule polymerization and assembly. The first,
ptk
, encodes a putative protein tyrosine kinase (PTK), and the second,
epsA
, encodes a putative polysaccharide export outer membrane protein (EpsA). Monoclonal antibodies used in flow cytometric and Western analyses confirmed that these genes are required for a capsule-positive phenotype. A capsule-positive phenotype significantly optimized growth in human ascites fluid, survival in human serum, and survival in a rat soft tissue infection model. Importantly, the clearance of the capsule-minus mutants AB307.30 (
ptk
mutant, capsule minus) and AB307.45 (
epsA
mutant, capsule minus) was complete and durable. These data demonstrated that the K1 capsule from AB307-0294 was an important protectin. Further, these data suggested that conserved proteins, which contribute to the capsule-positive phenotype, are potential antivirulence drug targets. Therefore, the results from this study have important biologic and translational implications and, to the best of our knowledge, are the first to address the role of capsule in the pathogenesis of
A. baumannii
infection.
Modulation of the Local Neutrophil Response by a Novel Hyaluronic Acid-Binding Peptide Reduces Bacterial Burden during Staphylococcal Wound Infection
Authors: Lee Jerry C. , Greenwich Jennifer L. , Zhanel George G. , Han Xiaobing , Cumming Andrew , Saward Laura , McLoughlin Rachel M. 
Published: July 2010

ABSTRACTNovel approaches targeting the host's immune response to treatStaphylococcus aureusinfections have significant potential to improve clinical outcomes, in particular during infection with antibiotic-resistant strains. The hyaluronic acid-binding peptide (HABP) PEP35 was assessed for its ability to treatS. aureusinfections using a clinically relevant murine model of surgical wound infection. PEP35 demonstrated no direct antimicrobial activity against a range of antibiotic-susceptible and antibiotic-resistant clinical isolates ofStaphylococcus aureus. However, when this peptide was administered at the onset of infection and up to 4 h postchallenge with a methicillin-susceptible (MSSA) or a methicillin-resistant (MRSA) strain ofS. aureus, it significantly reduced the bacterial burden at the wound infection site. PEP35 reduced the tissue bacterial burden by exclusively modulating the local neutrophil response. PEP35 administration resulted in a significant early increase in local CXCL1 and CXCL2 production, which resulted in a more rapid influx of neutrophils to the infection site. Importantly, neutrophil influx was not sustained after treatment with PEP35, and administration of PEP35 alone did not induce a local inflammatory response. The immunomodulatory effects of PEP35 on CXC chemokine production were TLR2 and NF-κB dependent. We propose a novel role for a HABP as an innate immunomodulator in the treatment of MSSA and MRSA surgical wound infection through enhancement of the local CXC chemokine-driven neutrophil response.
Mutagenesis of Conserved Amino Acids ofHelicobacter pyloriFur Reveals Residues Important for Function
Authors: Carpenter Beth M. , Gancz Hanan , Benoit Stéphane L. , Evans Sarah , Olsen Cara H. , Michel Sarah L. J. , Maier Robert J. , Merrell D. Scott 
Published: July 2010

ABSTRACTThe ferric uptake regulator (Fur) of the medically important pathogenHelicobacter pyloriis unique in that it has been shown to function as a repressor both in the presence of an Fe2+cofactor and in itsapo(non-Fe2+-bound) form. However, virtually nothing is known concerning the amino acid residues that are important for Fur functioning. Therefore, mutations in six conserved amino acid residues ofH. pyloriFur were constructed and analyzed for their impact on both iron-bound andaporepression. In addition, accumulation of the mutant proteins, protein secondary structure, DNA binding ability, iron binding capacity, and the ability to form higher-order structures were also examined for each mutant protein. While none of the mutated residues completely abrogated the function of Fur, we were able to identify residues that were critical for both iron-bound andapo-Fur repression. One mutation, V64A, did not alter regulation of any target genes. However, each of the five remaining mutations showed an effect on either iron-bound oraporegulation. Of these, H96A, E110A, and E117A mutations altered iron-bound Fur regulation and were all shown to influence iron binding to different extents. Additionally, the H96A mutation was shown to alter Fur oligomerization, and the E110A mutation was shown to impact oligomerization and DNA binding. Conversely, the H134A mutant exhibited changes inapo-Fur regulation that were the result of alterations in DNA binding. Although the E90A mutant exhibited alterations inapo-Fur regulation, this mutation did not affect any of the assessed protein functions. This study is the first forH. pylorito analyze the roles of specific amino acid residues of Fur in function and continues to highlight the complexity of Fur regulation in this organism.
Discontinuity and Limited Linkage in the Homologous Recombination System of a Hyperthermophilic Archaeon
Authors: Grogan Dennis W. , Rockwood Jananie 
Published: July 2010

ABSTRACT

Genetic transformation of
Sulfolobus acidocaldarius
by a multiply marked
pyrE
gene provided a high-resolution assay of homologous recombination in a hyperthermophilic archaeon. Analysis of 100 Pyr
+
transformants revealed that this recombination system could transfer each of 23 nonselected base pair substitutions to the recipient chromosome along with the selected marker. In 30% of the recombinants, donor markers were transferred as multiple blocks. In at least 40% of the recombinants, donor markers separated by 5 or 6 bp segregated from each other, whereas similar markers separated by 2 bp did not segregate. Among intermarker intervals, the frequency of recombination tract endpoints varied 40-fold, but in contrast to other recombination systems, it did not correlate with the length of the interval. The average length of donor tracts (161 bp) and the frequent generation of multiple tracts seemed generally consistent with the genetic properties observed previously in
S. acidocaldarius
conjugation. The efficiency with which short intervals of diverged
pyrE
sequence were incorporated into the genome raises questions about the threat of ectopic recombination in
Sulfolobus
spp. mediated by this apparently efficient yet permissive system.
Matched cohort analysis in traffic injury epidemiology: including adults when estimating exposure risks for children
Authors: Elliott Michael R 
Published: July 2010

BackgroundMatched cohort analyses and their extension to conditional logistic and Poisson regression are powerful tools for assessing risk and protective factors in automobile crashes. However, these analyses rely on assumptions about latent (unobserved) ‘crash severity’ risk measures for subjects in the vehicle being common for all such subjects if confounding with crash severity is present. The assumptions may be questionable if adults are being matched to children.MethodsSimulations were conducted to evaluate conditional Poisson regression in settings where different types of subjects may have different underlying baseline summary risk measures in a given crash—for example, adults and children. Situations were considered where baseline summary risk measures and protective factors are confounded with each other and where the adult and child baseline risk measures are either highly correlated or weakly correlated.ResultsWhen the risk or protective factor is confounded with crash severity, baseline summary risk measures due to crash severity must be perfectly correlated for all subjects in the crash for the factor to be consistently estimated. Relative bias estimates ranged from 5% to 50% depending on the degree of correlation of the risk measure and the number of matched subjects in a crash.ConclusionsMatched cohort analysis and its regression extensions are useful tools in the injury epidemiology toolkit, but require assumptions about high correlation of baseline summary risk measures among adults and children to accurately account for confounding between risk or protective factors of interest by crash severity. Conservative coverage intervals can preserve correct nominal coverage as long as the adult–child risk factors are highly correlated.
Modelling the population-level impact of tai-chi on falls and fall-related injury among community-dwelling older people
Authors: Day Lesley , Finch Caroline F , Harrison James E , Hoareau Effie , Segal Leonie , Ullah Shahid 
Published: July 2010

ObjectiveTo model the population level impact of tai-chi on future rates of falls and fall-related injury in older people as a tool for policy development.DesignAn epidemiological and economic model for estimating population-level effectiveness of tai-chi.SettingAustralia, 2009.Patients or subjectsAustralian community-dwelling population aged 70+ years, ambulatory and without debilitating conditions or profound visual defects.InterventionGroup-based tai-chi, for 1 h twice weekly for 26 weeks, assuming no sustained effect beyond the intervention period.Main outcome measureTotal falls and fall-related hospitalisation prevented in 2009.ResultsPopulation-wide tai-chi delivery would prevent an estimated 5440 falls and 109 fall-related hospitalisations, resulting in a 0.18% reduction in the fall-related hospital admission rate for community-dwelling older people. The gross costs per fall and per fall-related hospital admission prevented were $A4414 (€3013) and $A220 712 (€150 684), respectively. A total investment of $A24.01 million (€16.39 million), equivalent to 4.2% of the cost of fall-related episodes of hospital care in 2003/4, would be required to provide tai-chi for 31 998 people and achieve this effect.ConclusionsSubstantial investment in, and high population uptake of, tai-chi would be required to have a large effect on falls and fall-related hospitalisation rates. Although not accounted for in this study, investment in tai-chi is likely to be associated with additional significant health benefits beyond falls prevention. This approach could be applied to other interventions to assist selection of the most cost-effective falls-prevention portfolio for Australia and other countries.
Diagnostic significance of CK19, RET, galectin-3 and HBME-1 expression for papillary thyroid carcinoma
Authors: Zhu Xiaoli , Sun Tuanqi , Lu Hongfen , Zhou Xiaoyan , Lu Yongming , Cai Xu , Zhu Xiongzeng 
Published: July 2010

AimsTo evaluate CK19, RET, galectin-3 and HBME-1 expression in papillary thyroid carcinoma (PTC) and to evaluate their diagnostic significance.Methods155 PTC specimens and 83 other diseased-thyroid specimens were collected. Immunohistochemistry for CK19, RET, galectin-3 and HBME-1 was performed.ResultsThe 155 PTC cases were classified into eight variants according to the WHO classification, including 74 cases of classic PTC, 40 cases of papillary microcarcinoma, and rare variants. CK19, RET, galectin-3 and HBME-1 expression was 87.1% (135/155), 71.0% (110/155), 91.6% (142/155), and 95.5% (148/155), respectively, for the PTC group; expression of all these markers was much higher than that in the control group (p<0.05). However, the expression of these markers did not differ among the variants (p>0.05). The expression of these markers, particularly CK19 and RET, was diffuse and strong in the papillary structure of PTC, but weak and focal in the papilla of tissue with benign disease. The expression of CK19 in follicular PTC was significantly higher than in follicular thyroid carcinoma (FTC) (p<0.05).ConclusionsCK19, RET, galectin-3 and HBME-1 expression in PTC was higher than that in benign disease cases, but these were not specific markers for PTC. In summary, combining markers can increase the reliability and differential diagnosis of PTC. It is also worth noting that CK19 was very useful not only for the differentiation of benign and malignant papillary structure but also for the differential diagnosis of follicular PTC and FTC.
Exploring XML web collections with DescribeX
Authors: Consens Mariano P. , Miller Renée J. , Rizzolo Flavio , Vaisman Alejandro A. 
Published: July 2010

As Web applications mature and evolve, the nature of the semistructured data that drives these applications also changes. An important trend is the need for increased flexibility in the structure of Web documents. Hence, applications cannot rely solely on schemas to provide the complex knowledge needed to visualize, use, query and manage documents. Even when XML Web documents are valid with regard to a schema, the actual structure of such documents may exhibit significant variations across collections for several reasons: the schema may be very lax (e.g., RSS feeds), the schema may be large and different subsets of it may be used in different documents (e.g., industry standards like UBL), or open content models may allow arbitrary schemas to be mixed (e.g., RSS extensions like those used for podcasting). For these reasons, many applications that incorporate XPath queries to process a large Web document collection require an understanding of the actual structure present in the collection, and not just the schema.
To support modern Web applications, we introduce DescribeX, a powerful framework that is capable of describing complex XML summaries of Web collections. DescribeX supports the construction of heterogenous summaries that can be declaratively defined and refined by means of axis path regular expression (AxPREs). AxPREs provide the flexibility necessary for declaratively defining complex mappings between instance nodes (in the documents) and summary nodes. These mappings are capable of expressing order and cardinality, among other properties, which can significantly help in the understanding of the structure of large collections of XML documents and enhance the performance of Web applications over these collections. DescribeX captures most summary proposals in the literature by providing (for the first time) a common declarative definition for them. Experimental results demonstrate the scalability of DescribeX summary operations (summary creation, as well as refinement and stabilization, two key enablers for tailoring summaries) on multi-gigabyte Web collections.
Lung Squamous Cell Carcinoma mRNA Expression Subtypes Are Reproducible, Clinically Important, and Correspond to Normal Cell Types
Authors: Wilkerson Matthew D. , Yin Xiaoying , Hoadley Katherine A. , Liu Yufeng , Hayward Michele C. , Cabanski Christopher R. , Muldrew Kenneth , Miller C. Ryan , Randell Scott H. , Socinski Mark A. , Parsons Alden M. , Funkhouser William K. , Lee Carrie B. , Roberts Patrick J. , Thorne Leigh , Bernard Philip S. , Perou Charles M. , Hayes D. Neil 
Published: July 2010

Abstract
Purpose: Lung squamous cell carcinoma (SCC) is clinically and genetically heterogeneous, and current diagnostic practices do not adequately substratify this heterogeneity. A robust, biologically based SCC subclassification may describe this variability and lead to more precise patient prognosis and management. We sought to determine if SCC mRNA expression subtypes exist, are reproducible across multiple patient cohorts, and are clinically relevant.
Experimental Design: Subtypes were detected by unsupervised consensus clustering in five published discovery cohorts of mRNA microarrays, totaling 382 SCC patients. An independent validation cohort of 56 SCC patients was collected and assayed by microarrays. A nearest-centroid subtype predictor was built using discovery cohorts. Validation cohort subtypes were predicted and evaluated for confirmation. Subtype survival outcome, clinical covariates, and biological processes were compared by statistical and bioinformatic methods.
Results: Four lung SCC mRNA expression subtypes, named primitive, classical, secretory, and basal, were detected and independently validated (P &lt; 0.001). The primitive subtype had the worst survival outcome (P &lt; 0.05) and is an independent predictor of survival (P &lt; 0.05). Tumor differentiation and patient sex were associated with subtype. The expression profiles of the subtypes contained distinct biological processes (primitive: proliferation; classical: xenobiotic metabolism; secretory: immune response; basal: cell adhesion) and suggested distinct pharmacologic interventions. Comparison with lung model systems revealed distinct subtype to cell type correspondence.
Conclusions: Lung SCC consists of four mRNA expression subtypes that have different survival outcomes, patient populations, and biological processes. The subtypes stratify patients for more precise prognosis and targeted research. Clin Cancer Res; 16(19); 4864–75. ©2010 AACR.
The Novel Hsp90 Inhibitor NXD30001 Induces Tumor Regression in a Genetically Engineered Mouse Model of Glioblastoma Multiforme
Authors: Zhu Haihao , Woolfenden Steve , Bronson Roderick T. , Jaffer Zahara M. , Barluenga Sofia , Winssinger Nicolas , Rubenstein Allan E. , Chen Ruihong , Charest Al 
Published: July 2010

Abstract
Glioblastoma multiforme (GBM) has an abysmal prognosis. We now know that the epidermal growth factor receptor (EGFR) signaling pathway and the loss of function of the tumor suppressor genes p16Ink4a/p19ARF and PTEN play a crucial role in GBM pathogenesis: initiating the early stages of tumor development, sustaining tumor growth, promoting infiltration, and mediating resistance to therapy. We have recently shown that this genetic combination is sufficient to promote the development of GBM in adult mice. Therapeutic agents raised against single targets of the EGFR signaling pathway have proven rather inefficient in GBM therapy, showing the need for combinatorial therapeutic approaches. An effective strategy for concurrent disruption of multiple signaling pathways is via the inhibition of the molecular chaperone heat shock protein 90 (Hsp90). Hsp90 inhibition leads to the degradation of so-called client proteins, many of which are key effectors of GBM pathogenesis. NXD30001 is a novel second generation Hsp90 inhibitor that shows improved pharmacokinetic parameters. Here we show that NXD30001 is a potent inhibitor of GBM cell growth in vitro consistent with its capacity to inhibit several key targets and regulators of GBM biology. We also show the efficacy of NXD30001 in vivo in an EGFR-driven genetically engineered mouse model of GBM. Our findings establish that the Hsp90 inhibitor NXD30001 is a therapeutically multivalent molecule, whose actions strike GBM at the core of its drivers of tumorigenesis and represent a compelling rationale for its use in GBM treatment. Mol Cancer Ther; 9(9); 2618–26. ©2010 AACR.