bluuebunny/crossref_metadata_2025_split huggingface dataset:
Concentration of Antifungal Agents within Host Cell Membranes: a New Paradigm Governing the Efficacy of Prophylaxis
Authors: Campoli P. , Al Abdallah Q. , Robitaille R. , Solis N. V. , Fielhaber J. A. , Kristof A. S. , Laverdiere M. , Filler S. G. , Sheppard D. C. 
Published: September 2011

ABSTRACT
Posaconazole prophylaxis has proven highly effective in preventing invasive fungal infections, despite relatively low serum concentrations. However, high tissue levels of this agent have been reported in treated patients. We therefore hypothesized that the intracellular levels of antifungal agents are an important factor in determining the success of fungal prophylaxis. To examine the effect of host cell-associated antifungals on the growth of medically important molds, we exposed cells to antifungal agents and removed the extracellular drug prior to infection. Epithelial cells loaded with posaconazole and its parent molecule itraconazole, but not other antifungals, were able to inhibit fungal growth for at least 48 h and were protected from damage caused by infection. Cell-associated posaconazole levels were 40- to 50-fold higher than extracellular levels, and the drug was predominantly detected in cellular membranes. Fungistatic levels of posaconazole persisted within epithelial cells for up to 48 h. Therefore, the concentration of posaconazole in mammalian host cell membranes mediates its efficacy in prophylactic regimens and likely explains the observed discrepancy between serum antifungal levels and efficacy.
Dose of Trimethoprim-Sulfamethoxazole To Treat Skin and Skin Structure Infections Caused by Methicillin-Resistant Staphylococcus aureus
Authors: Cadena Jose , Nair Shalini , Henao-Martinez Andres F. , Jorgensen James H. , Patterson Jan E. , Sreeramoju Pranavi V. 
Published: September 2011

ABSTRACT

We undertook this study to investigate whether treatment with a higher dose of trimethoprim-sulfamethoxazole (TMP/SMX) led to greater clinical resolution in patients with skin and soft tissue infections (SSTIs) caused by methicillin-resistant
Staphylococcus aureus
(MRSA). A prospective, observational cohort with nested case-control study was performed at a public tertiary health system. Among patients with MRSA SSTIs during the period from May 2008 to September 2008 who received oral monotherapy with TMP/SMX and whose clinical outcome was known, the clinical characteristics and outcomes were compared between patients treated with a high dose of TMP/SMX (320 mg/1,600 mg twice daily) for 7 to 15 days and patients treated with the standard dose of TMP/SMX (160 mg/800 mg twice daily) for 7 to 15 days. In patients with MRSA SSTIs, those treated with the high dose of TMP/SMX (
n
= 121) had clinical characteristics similar to those of patients treated with the standard dose of TMP/SMX (
n
= 170). The only exception was a higher proportion of patients with a history of trauma upon admission among the patients treated with the higher dose. The proportion of patients with clinical resolution of infection was not different in the two groups (88/121 [73%] versus 127/170 [75%];
P
= 0.79). The lack of significance remained in patients with abscess upon stratified analysis by whether surgical drainage was performed. The study found that patients with MRSA SSTIs treated with the higher dose of TMP/SMX (320/1,600 mg twice daily) for 7 to 15 days had a similar rate of clinical resolution as patients treated with the standard dose of TMP/SMX (160/800 mg twice daily) for 7 to 15 days.
Molecular Characteristics of KPC-Producing Enterobacteriaceae at the Early Stage of Their Dissemination in Poland, 2008–2009
Authors: Baraniak Anna , Grabowska Anna , Izdebski Radosław , Fiett Janusz , Herda Małgorzata , Bojarska Katarzyna , Żabicka Dorota , Kania-Pudło Marta , Młynarczyk Grażyna , Żak-Puławska Zofia , Hryniewicz Waleria , Gniadkowski Marek ,   the KPC-PL Study Group
Published: September 2011

ABSTRACT

After the first report in May 2008, the National Reference Center for Susceptibility Testing confirmed 113 cases of infection or colonization by KPC-producing members of the family
Enterobacteriaceae
in Poland by the end of 2009. The vast majority of patients were found in 18 hospitals; three patients were diagnosed at outpatient clinics. Most of the institutions were in the Warsaw area, including three hospitals with the highest numbers of cases. When available, the data on previous hospitalizations often indicated that these hospitals were the probable acquisition sites; one patient arrived from New York. The group of 119 unique isolates consisted of
Klebsiella pneumoniae
(
n
= 114), followed by
Klebsiella oxytoca
(
n
= 3), and
Escherichia coli
(
n
= 2). The
K. pneumoniae
isolates were dominated by the clone sequence type 258 (ST258) (
n
= 111); others were ST11 and ST23. The ST258 group was heterogeneous, with 28 pulsed-field gel electrophoresis (PFGE) subtypes, ∼25 plasmid profiles, and nine β-lactamase patterns differing by KPC variants (KPC-2 mainly), and SHV-12, CTX-M-3, and TEM-1-like enzymes. Plasmids carrying
bla
KPC
genes varied in size (∼48 to 250 kb), structure, and conjugation potential. Transferable IncFII
K
plasmids of ∼110 to 160 kb, probably pKpQIL or its derivatives, were observed in all
K. pneumoniae
clones and in
K. oxytoca
. Also prevalent were nontypeable pETKp50-like plasmids of ∼50 kb, found in
K. pneumoniae
ST258 and
E. coli
isolates (ST93 and ST224). Two
K. pneumoniae-E. coli
pairs from single patients might represent the
in vivo
transfer of such plasmids. The striking diversity of KPC producers at the early stage of dissemination could result from several introductions of these bacteria into the country, their multidirectional evolution during clonal spread, and transfer of the plasmids.
Identification and Characterization of the Anti-Methicillin-Resistant Staphylococcus aureus WAP-8294A2 Biosynthetic Gene Cluster from Lysobacter enzymogenes OH11
Authors: Zhang Wei , Li Yaoyao , Qian Guoliang , Wang Yan , Chen Haotong , Li Yue-Zhong , Liu Fengquan , Shen Yuemao , Du Liangcheng 
Published: September 2011

ABSTRACT

Lysobactor enzymogenes
strain OH11 is an emerging biological control agent of fungal and bacterial diseases. We recently completed its genome sequence and found it contains a large number of gene clusters putatively responsible for the biosynthesis of nonribosomal peptides and polyketides, including the previously identified antifungal dihydromaltophilin (HSAF). One of the gene clusters contains two huge open reading frames, together encoding 12 modules of nonribosomal peptide synthetases (NRPS). Gene disruption of one of the NRPS led to the disappearance of a metabolite produced in the wild type and the elimination of its antibacterial activity. The metabolite and antibacterial activity were also affected by the disruption of some of the flanking genes. We subsequently isolated this metabolite and subjected it to spectroscopic analysis. The mass spectrometry and nuclear magnetic resonance data showed that its chemical structure is identical to WAP-8294A2, a cyclic lipodepsipeptide with potent anti-methicillin-resistant
Staphylococcus aureus
(MRSA) activity and currently in phase I/II clinical trials. The WAP-8294A2 biosynthetic genes had not been described previously. So far, the Gram-positive
Streptomyces
have been the primary source of anti-infectives.
Lysobacter
are Gram-negative soil/water bacteria that are genetically amendable and have not been well exploited. The WAP-8294A2 synthetase represents one of the largest NRPS complexes, consisting of 45 functional domains. The identification of these genes sets the foundation for the study of the WAP-8294A2 biosynthetic mechanism and opens the door for producing new anti-MRSA antibiotics through biosynthetic engineering in this new source of
Lysobacter
.
Genotypic and Phenotypic Variation in Pseudomonas aeruginosa Reveals Signatures of Secondary Infection and Mutator Activity in Certain Cystic Fibrosis Patients with Chronic Lung Infections
Authors: Warren Ashley E. , Boulianne-Larsen Carla M. , Chandler Christine B. , Chiotti Kami , Kroll Evgueny , Miller Scott R. , Taddei Francois , Sermet-Gaudelus Isabelle , Ferroni Agnes , McInnerney Kathleen , Franklin Michael J. , Rosenzweig Frank 
Published: September 2011

ABSTRACTEvolutionary adaptation ofPseudomonas aeruginosato the cystic fibrosis lung is limited by genetic variation, which depends on rates of horizontal gene transfer and mutation supply. Because each may increase following secondary infection or mutator emergence, we sought to ascertain the incidence of secondary infection and genetic variability in populations containing or lacking mutators. Forty-nine strains collected over 3 years from 16 patients were phenotyped for antibiotic resistance and mutator status and were genotyped by repetitive-sequence PCR (rep-PCR), pulsed-field gel electrophoresis (PFGE), and multilocus sequence typing (MLST). Though phenotypic and genetic polymorphisms were widespread and clustered more strongly within than between longitudinal series, their distribution revealed instances of secondary infection. Sequence data, however, indicated that interlineage recombination predated initial strain isolation. Mutator series were more likely to be multiply antibiotic resistant, but not necessarily more variable in their nucleotide sequences, than nonmutators. One mutator and one nonmutator series were sequenced at mismatch repair loci and analyzed for gene content using DNA microarrays. Both were wild type with respect tomutL, but mutators carried an 8-bpmutSdeletion causing a frameshift mutation. Both series lacked 126 genes encoding pilins, siderophores, and virulence factors whose inactivation has been linked to adaptation during chronic infection. Mutators exhibited loss of severalfold more genes having functions related to mobile elements, motility, and attachment. A 105-kb, 86-gene deletion was observed in one nonmutator that resulted in loss of virulence factors related to pyoverdine synthesis and elements of the multidrug efflux regulon. Diminished DNA repair activity may facilitate but not be absolutely required for rapid evolutionary change.
Ehrlichia chaffeensis Induces Monocyte Inflammatory Responses through MyD88, ERK, and NF-κB but Not through TRIF, Interleukin-1 Receptor 1 (IL-1R1)/IL-18R1, or Toll-Like Receptors
Authors: Miura Koshiro , Matsuo Junji , Rahman M. Akhlakur , Kumagai Yumi , Li Xin , Rikihisa Yasuko 
Published: September 2011

ABSTRACTHuman monocytic ehrlichiosis, an influenza-like illness accompanied by signs of hepatitis, is caused by infection of monocytes/macrophages with a lipopolysaccharide-deficient bacterium,Ehrlichia chaffeensis. TheE. chaffeensisstrain Wakulla induces diffuse hepatitis with neutrophil infiltration in mice with severe combined immunodeficiency, which is accompanied by strong CXCL2 (mouse functional homolog of interleukin-8 [IL-8]) and tumor necrosis factor alpha (TNF-α) expression in the liver. In this study, we found that expression of IL-1β, CXCL2, and TNF-α was induced by strain Wakulla in mouse bone marrow-derived macrophages; this expression was dependent on MyD88, but not on TRIF, TLR2/4, IL-1R1/IL-18R1, or endosome acidification. When the human leukemia cell line THP-1 was exposed toE. chaffeensis, significant upregulation of IL-8, IL-1β, and TNF-α mRNA and extracellular regulated kinase 2 (ERK2) activation were detected. U0126 (inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 [MEK1/2] upstream of ERK), manumycin A (Ras inhibitor), BAY43-9006 (Raf-1 inhibitor), and NS-50 (inhibitor of NF-κB nuclear translocation) inhibited the cytokine gene expression. A luciferase reporter assay using HEK293 cells, which lack Toll-like receptors (TLRs), showed activation of both the IL-8 promoter and NF-κB byE. chaffeensis. Activation of the IL-8 promoter in transfected HEK293 cells was inhibited by manumycin A, BAY43-9006, U0126, and transfection with a dominant-negative Ras mutant. These results indicate that theE. chaffeensisWakulla strain can induce inflammatory responses through MyD88-dependent NF-κB and ERK pathways, without the involvement of TRIF and TLRs.
A randomised control trial of short term efficacy of in-shoe foot orthoses compared with a wait and see policy for anterior knee pain and the role of foot mobility
Authors: Mills Kathryn , Blanch Peter , Dev Priya , Martin Michael , Vicenzino Bill 
Published: September 2011

ObjectivesTo investigate the short-term clinical efficacy of in-shoe foot orthoses over a wait-and-see policy in the treatment of anterior knee pain (AKP) and evaluate the ability of foot posture measures to predict outcome.DesignSingle-blind, randomised control trial.ParticipantsForty participants (18–40 years) with clinically diagnosed AKP of greater than 6-week duration, who had not been treated with orthoses in the previous 5 years.InterventionPrefabricated orthoses perceived as most comfortable from a selection of 3 different hardness values compared with a wait-and-see control group.Outcome measuresParticipant-perceived global improvement, Kujala Patellofemoral Score, usual and worst pain severity over the previous week and the Patient Specific Functional Scale measures at 6 weeks.ResultsFoot orthoses produced a significant global improvement compared with the control group (p = 0.008, relative risk reduction = 8.47%, numbers needed to treat = 2). Significant differences also occurred in measures of function (standardised mean difference = 0.71). Within the intervention group, individuals who exhibited a change in midfoot width from weight bearing to non-weight bearing of >11.25 mm were more likely to report a successful outcome (correct classification 77.8%).ConclusionThis is the first study to show orthoses provide greater improvements in AKP than a wait-and-see approach. Individuals with greater midfoot mobility are more likely to experience success from treatment.Trial RegistrationACTRN12611000492954
Forest
Authors: Fisher Kathleen , Foster Nate , Walker David , Zhu Kenny Q. 
Published: September 2011

A
filestore
is a structured collection of data files housed in a conventional hierarchical file system. Many applications use filestores as a poor-man's database, and the correct execution of these applications requires that the collection of files, directories, and symbolic links stored on disk satisfy a variety of precise invariants. Moreover, all of these structures must have acceptable ownership, permission, and timestamp attributes. Unfortunately, current programming languages do not provide support for documenting assumptions about filestores, detecting errors in them, or safely loading from and storing to them.

This paper describes the design, implementation, and semantics of Forest, a new domain-specific language for describing filestores. The language uses a type-based metaphor to specify the expected structure, attributes, and invariants of filestores. Forest generates loading and storing functions that make it easy to connect data on disk to an isomorphic representation in memory that can be manipulated as if it were any other data structure. Forest also generates metadata that describes the degree to which the structures on the disk conform to the specification, making error detection easy. In a nutshell, Forest extends the rigorous discipline of typed programming languages to the untyped world of file systems.
We have implemented Forest as an embedded domain-specific language in Haskell. In addition to generating infrastructure for reading, writing and checking file systems, our implementation generates type class instances that make it easy to build generic tools that operate over arbitrary filestores. We illustrate the utility of this infrastructure by building a file system visualizer, a file access checker, a generic query interface, description-directed variants of several standard UNIX shell tools and (circularly) a simple Forest description inference engine. Finally, we formalize a core fragment of Forest in a semantics inspired by classical tree logics and prove round-tripping laws showing that the loading and storing functions behave sensibly.
Modular verification of preemptive OS kernels
Authors: Gotsman Alexey , Yang Hongseok 
Published: September 2011

Most major OS kernels today run on multiprocessor systems and are preemptive: it is possible for a process running in the kernel mode to get descheduled. Existing modular techniques for verifying concurrent code are not directly applicable in this setting: they rely on scheduling being implemented correctly, and in a preemptive kernel, the correctness of the scheduler is interdependent with the correctness of the code it schedules. This interdependency is even stronger in mainstream kernels, such as Linux, FreeBSD or XNU, where the scheduler and processes interact in complex ways.
We propose the first logic that is able to decompose the verification of preemptive multiprocessor kernel code into verifying the scheduler and the rest of the kernel separately, even in the presence of complex interdependencies between the two components. The logic hides the manipulation of control by the scheduler when reasoning about preemptable code and soundly inherits proof rules from concurrent separation logic to verify it thread-modularly. This is achieved by establishing a novel form of refinement between an operational semantics of the real machine and an axiomatic semantics of OS processes, where the latter assumes an abstract machine with each process executing on a separate virtual CPU. The refinement is local in the sense that the logic focuses only on the relevant state of the kernel while verifying the scheduler. We illustrate the power of our logic by verifying an example scheduler, modelled on the one from Linux 2.6.11.
Characteristic formulae for the verification of imperative programs
Authors: Charguéraud Arthur 
Published: September 2011

In previous work, we introduced an approach to program verification based on characteristic formulae. The approach consists of generating a higher-order logic formula from the source code of a program. This characteristic formula is constructed in such a way that it gives a sound and complete description of the semantics of that program. The formula can thus be exploited in an interactive proof assistant to formally verify that the program satisfies a particular specification.
This previous work was, however, only concerned with purely-functional programs. In the present paper, we describe the generalization of characteristic formulae to an imperative programming language. In this setting, characteristic formulae involve specifications expressed in the style of Separation Logic. They also integrate the frame rule, which enables local reasoning. We have implemented a tool based on characteristic formulae. This tool, called CFML, supports the verification of imperative Caml programs using the Coq proof assistant. Using CFML, we have formally verified nontrivial imperative algorithms, as well as CPS functions, higher-order iterators, and programs involving higher-order stores.
Load balancing and the power of preventive probing
Authors: Van Houdt B. 
Published: September 2011

Consider a randomized load balancing problem consisting of a large number n of server sites each equipped with K servers. Under the greedy policy, clients randomly probe a site to check whether there is still a server available. If not, d -- 1 other sites are probed and the task is assigned to the site with the fewest number of busy servers. If all the servers are also busy in each of these d -- 1 sites, the task is lost.
This short paper analyzes a set of policies, i.e., (L, d) policies, that will occasionally probe additional sites even when there is still a server available at the site that was probed first. Using mean field methods, we show that these policies, that preventively probe other sites, can achieve the same loss probability while requiring a lower overall probe rate.
The Histone Demethylase JMJD2B Plays an Essential Role in Human Carcinogenesis through Positive Regulation of Cyclin-Dependent Kinase 6
Authors: Toyokawa Gouji , Cho Hyun-Soo , Iwai Yukiko , Yoshimatsu Masanori , Takawa Masashi , Hayami Shinya , Maejima Kazuhiro , Shimizu Noriaki , Tanaka Hirotoshi , Tsunoda Tatsuhiko , Field Helen I. , Kelly John D. , Neal David E. , Ponder Bruce A.J. , Maehara Yoshihiko , Nakamura Yusuke , Hamamoto Ryuji 
Published: September 2011

Abstract
Histone methyltransferases and demethylases are known to regulate transcription by altering the epigenetic marks on histones, but the pathologic roles of their dysfunction in human diseases, such as cancer, still remain to be elucidated. Herein, we show that the histone demethylase JMJD2B is involved in human carcinogenesis. Quantitative real-time PCR showed notably elevated levels of JMJD2B expression in bladder cancers, compared with corresponding nonneoplastic tissues (P &lt; 0.0001), and elevated protein expression was confirmed by immunohistochemistry. In addition, cDNA microarray analysis revealed transactivation of JMJD2B in lung cancer, and immunohistochemical analysis showed protein overexpression in lung cancer. siRNA-mediated reduction of expression of JMJD2B in bladder and lung cancer cell lines significantly suppressed the proliferation of cancer cells, and suppressing JMJD2B expression lead to a decreased population of cancer cells in S phase, with a concomitant increase of cells in G1 phase. Furthermore, a clonogenicity assay showed that the demethylase activity of JMJD2B possesses an oncogenic activity. Microarray analysis after knockdown of JMJD2B revealed that JMJD2B could regulate multiple pathways which contribute to carcinogenesis, including the cell-cycle pathway. Of the downstream genes, chromatin immunoprecipitation showed that CDK6 (cyclin-dependent kinase 6), essential in G1–S transition, was directly regulated by JMJD2B, via demethylation of histone H3-K9 in its promoter region. Expression levels of JMJD2B and CDK6 were significantly correlated in various types of cell lines. Deregulation of histone demethylation resulting in perturbation of the cell cycle, represents a novel mechanism for human carcinogenesis and JMJD2B is a feasible molecular target for anticancer therapy. Cancer Prev Res; 4(12); 2051–61. ©2011 AACR.
Urbanization Effect on the Diurnal Temperature Range: Different Roles under Solar Dimming and Brightening*
Authors: Wang Kai , Ye Hong , Chen Feng , Xiong Yongzhu , Wang Cuiping 
Published: September 2011

Abstract
Based on the 1960–2009 meteorological data from 559 stations across China, the urbanization effect on the diurnal temperature range (DTR) was evaluated in this study. Different roles of urbanization were specially detected under solar dimming and solar brightening. During the solar dimming time, both urban and rural stations showed decreasing trends in maximum temperature (Tmax) because of decreased radiation, suggesting that the dimming effects are not only evident in urban areas but also in rural areas. However, minimum temperature (Tmin) increased more substantially in urban areas than in rural areas during the dimming period, resulting in a greater decrease in the DTR in the urban areas. When the radiation reversed from dimming to brightening, the change in the DTR became different. The Tmax increased faster in rural areas, suggesting that the brightening could be much stronger in rural areas than in urban areas. Similar trends of Tmin between urban and rural areas appeared during the brightening period. The urban DTR continued to show a decreasing trend because of the urbanization effect, while the rural DTR presented an increasing trend. The remarkable DTR difference in the urban and rural areas showed a significant urbanization effect in the solar brightening time.