bluuebunny/crossref_metadata_2025_split huggingface dataset:
Piperaquine Resistance Is Associated with a Copy Number Variation on Chromosome 5 in Drug-Pressured
Plasmodium falciparum
Parasites
Authors: Eastman Richard T. , Dharia Neekesh V. , Winzeler Elizabeth A. , Fidock David A. 
Published: May 2011

ABSTRACT

The combination of piperaquine and dihydroartemisinin has recently become the official first-line therapy in several Southeast Asian countries. The pharmacokinetic mismatching of these drugs, whose plasma half-lives are ∼20 days and ∼1 h, respectively, implies that recrudescent or new infections emerging shortly after treatment cessation will encounter piperaquine as a monotherapy agent. This creates substantial selection pressure for the emergence of resistance. To elucidate potential resistance determinants, we subjected cloned
Plasmodium falciparum
Dd2 parasites to continuous piperaquine pressure
in vitro
(47 nM; ∼2-fold higher than the Dd2 50% inhibitory concentration [IC
50
]). The phenotype of outgrowth parasites was assayed in two clones, revealing an IC
50
against piperaquine of 2.1 μM and 1.7 μM, over 100-fold greater than that of the parent. To identify the genetic determinant of resistance, we employed comparative whole-genome hybridization analysis. Compared to the Dd2 parent, this analysis found (in both resistant clones) a novel single-nucleotide polymorphism in
P. falciparum crt
(
pfcrt
), deamplification of an 82-kb region of chromosome 5 (that includes
pfmdr1
), and amplification of an adjacent 63-kb region of chromosome 5. Continued propagation without piperaquine selection pressure resulted in “revertant” piperaquine-sensitive parasites. These retained the
pfcrt
polymorphism and further deamplified the chromosome 5 segment that encompasses
pfmdr1
; however, these two independently generated revertants both lost the neighboring 63-kb amplification. These results suggest that a copy number variation event on chromosome 5 (825600 to 888300) is associated with piperaquine resistance. Transgene expression studies are underway with individual genes in this segment to evaluate their contribution to piperaquine resistance.
Interleukin-10 and Immunity against Prokaryotic and Eukaryotic Intracellular Pathogens
Authors: Cyktor Joshua C. , Turner Joanne 
Published: May 2011

ABSTRACTThe generation of an effective immune response against an infection while also limiting tissue damage requires a delicate balance between pro- and anti-inflammatory responses. Interleukin-10 (IL-10) has potent immunosuppressive effects and is essential for regulation of immune responses. However, the immunosuppressive properties of IL-10 can also be exploited by pathogens to facilitate their own survival. In this minireview, we discuss the role of IL-10 in modulating intracellular bacterial, fungal, and parasitic infections. Using information from several different infection models, we bring together and highlight some common pathways for IL-10 regulation and function that cannot be fully appreciated by studies of a single pathogen.
Innate Immune Responses to Systemic Acinetobacter baumannii Infection in Mice: Neutrophils, but Not Interleukin-17, Mediate Host Resistance
Authors: Breslow Jessica M. , Meissler Joseph J. , Hartzell Rebecca R. , Spence Phillip B. , Truant Allan , Gaughan John , Eisenstein Toby K. 
Published: May 2011

ABSTRACT

Acinetobacter baumannii
is a nosocomial pathogen with a high prevalence of multiple-drug-resistant strains, causing pneumonia and sepsis. The current studies further develop a systemic mouse model of this infection and characterize selected innate immune responses to the organism. Five clinical isolates, with various degrees of antibiotic resistance, were assessed for virulence in two mouse strains, and between male and female mice, using intraperitoneal infection. A nearly 1,000-fold difference in virulence was found between bacterial strains, but no significant differences between sexes or mouse strains were observed. It was found that microbes disseminated rapidly from the peritoneal cavity to the lung and spleen, where they replicated. A persistent septic state was observed. The infection progressed rapidly, with mortality between 36 and 48 h. Depletion of neutrophils with antibody to Ly-6G decreased mean time to death and increased mortality. Interleukin-17 (IL-17) promotes the response of neutrophils by inducing production of the chemokine keratinocyte-derived chemoattractant (KC/CXCL1), the mouse homolog of human IL-8.
Acinetobacter
infection resulted in biphasic increases in both IL-17 and KC/CXCL1. Depletion of neither IL-17 nor KC/CXCL1, using specific antibodies, resulted in a difference in bacterial burdens in organs of infected mice at 10 h postinfection. Comparison of bacterial burdens between IL-17
a
−/−
and wild-type mice confirmed that the absence of this cytokine did not sensitize mice to
Acinetobacter
infection. These studies definitely demonstrate the importance of neutrophils in resistance to systemic
Acinetobacter
infection. However, neither IL-17 nor KC/CXCL1 alone is required for effective host defense to systemic infection with this organism.
Rapid Immune Responses to a Botulinum Neurotoxin Hc Subunit Vaccine through
In Vivo
Targeting to Antigen-Presenting Cells
Authors: White David M. , Pellett Sabine , Jensen Mark A. , Tepp William H. , Johnson Eric A. , Arnason Barry G. W. 
Published: May 2011

ABSTRACT

The clostridial botulinum neurotoxins (BoNTs) are the most potent protein toxins known. The carboxyl-terminal fragment of the toxin heavy chain (Hc) has been intensively investigated as a BoNT vaccine immunogen. We sought to determine whether targeting Hc to antigen-presenting cells (APCs) could accelerate the immune responses to vaccination with BoNT serotype A (BoNT/A) Hc. To test this hypothesis, we targeted Hc to the Fc receptors for IgG (FcγRs) expressed by dendritic cells (DCs) and other APCs. Hc was expressed as a fusion protein with a recombinant ligand for human FcγRs (R4) to produce HcR4 or a similar ligand for murine FcγRs to produce HcmR4. HcR4, HcmR4, and Hc were produced as secreted proteins using baculovirus-mediated expression in SF9 insect cells.
In vitro
receptor binding assays showed that HcR4 effectively targets Hc to all classes of FcγRs. APCs loaded with HcR4 or HcmR4 are substantially more effective at stimulating Hc-reactive T cells than APCs loaded with nontargeted Hc. Mice immunized with a single dose of HcmR4 or HcR4 had earlier and markedly higher Hc-reactive antibody titers than mice immunized with nontargeted Hc. These results extend to BoNT neutralizing antibody titers, which are substantially higher in mice immunized with HcmR4 than in mice immunized with Hc. Our results demonstrate that targeting Hc to FcγRs augments the pace and magnitude of immune responses to Hc.
Functional Characterization of the Type III Secretion Substrate Specificity Switch Protein HpaC from Xanthomonas campestris pv. vesicatoria
Authors: Schulz Steve , Büttner Daniela 
Published: May 2011

ABSTRACT

Pathogenicity of
Xanthomonas campestris
pv.
vesicatoria
depends on a type III secretion (T3S) system which translocates effector proteins into eukaryotic cells and is associated with an extracellular pilus and a translocon in the host plasma membrane. T3S substrate specificity is controlled by the cytoplasmic switch protein HpaC, which interacts with the C-terminal domain of the inner membrane protein HrcU (HrcU
C
). HpaC promotes the secretion of translocon and effector proteins but prevents the efficient secretion of the early T3S substrate HrpB2, which is required for pilus assembly. In this study, complementation assays with serial 10-amino-acid HpaC deletion derivatives revealed that the T3S substrate specificity switch depends on N- and C-terminal regions of HpaC, whereas amino acids 42 to 101 appear to be dispensable for the contribution of HpaC to the secretion of late substrates. However, deletions in the central region of HpaC affect the secretion of HrpB2, suggesting that the mechanisms underlying HpaC-dependent control of early and late substrates can be uncoupled. The results of interaction and expression studies with HpaC deletion derivatives showed that amino acids 112 to 212 of HpaC provide the binding site for HrcU
C
and severely reduce T3S when expressed ectopically in the wild-type strain. We identified a conserved phenylalanine residue at position 175 of HpaC that is required for both protein function and the binding of HpaC to HrcU
C
. Taking these findings together, we concluded that the interaction between HpaC and HrcU
C
is essential but not sufficient for T3S substrate specificity switching.
In VivoUltrastructural Analysis of the Intimate Relationship between Polymorphonuclear Leukocytes and the Chlamydial Developmental Cycle
Authors: Rank Roger G. , Whittimore Judy , Bowlin Anne K. , Wyrick Priscilla B. 
Published: May 2011

ABSTRACTWe utilized a recently developed model of intracervical infection withChlamydia muridarumin the mouse to elicit a relatively synchronous infection during the initial developmental cycle in order to examine at the ultrastructural level the development of both the chlamydial inclusion and the onset of the inflammatory response. At 18 h after infection, only a few elementary bodies attached to cells were visible, as were an occasional intracellular intermediate body and reticulate body. By 24 h, inclusions had 2 to 5 reticulate bodies and were beginning to fuse. A few polymorphonuclear leukocytes (PMNs) were already present in the epithelium in the vicinity of and directly adjacent to infected cells. By 30 h, the inclusions were larger and consisted solely of reticulate bodies, but by 36 to 42 h, they contained intermediate bodies and elementary bodies as well. Many PMNs were adjacent to or actually inside infected cells. Chlamydiae appeared to exit the cell either (i) through disintegration of the inclusion membrane and rupture of the cell, (ii) by dislodgement of the cell from the epithelium by PMNs, or (iii) by direct invasion of the infected cell by the PMNs. When PMNs were depleted, the number of released elementary bodies was significantly greater as determined both visually and by culture. Interestingly, depletion of PMNs revealed the presence of inclusions containing aberrant reticulate bodies, reminiscent of effects seenin vitrowhen chlamydiae are incubated with gamma interferon.In vivoevidence for the contact-dependent development hypothesis, a potential mechanism for triggering the conversion of reticulate bodies to elementary bodies, and for translocation of lipid droplets into the inclusion is also presented.
Mouse Relapse Model of Clostridium difficile Infection
Authors: Sun Xingmin , Wang Haiying , Zhang Yongrong , Chen Kevin , Davis Barbara , Feng Hanping 
Published: May 2011

ABSTRACT

Clostridium difficile
is the causative agent of primary and recurrent antibiotic-associated diarrhea and colitis in hospitalized patients. The disease is caused mainly by two exotoxins, TcdA and TcdB, produced by the bacteria. Recurrent
C. difficile
infection (CDI) constitutes one of the most significant clinical issues of this disease, occurs in more than 20% of patients after the first episode, and may be increasing in frequency. However, there is no well-established animal model of CDI relapse currently available for studying disease pathogenesis, prevention, and therapy. Here we report the establishment of a conventional mouse model of recurrence/relapse CDI. We found that the primary episode of CDI induced little or no protective antibody response against
C. difficile
toxins and mice continued shedding
C. difficile
spores. Antibiotic treatment of surviving mice induced a second episode of diarrhea, while a simultaneous reexposure of animals to
C. difficile
bacteria or spores elicited a full spectrum of CDI similar to that of the primary infection. Moreover, mice treated with immunosuppressive agents were prone to more severe and fulminant recurrent disease. Finally, utilizing this model, we demonstrated that vancomycin only delayed disease recurrence, whereas neutralizing polysera against both TcdA and TcdB completely protected mice against CDI relapse. In conclusion, we have established a mouse relapse CDI model that allows for future investigations of the role of the host immune response in the disease's pathogenesis and permits critical testing of new therapeutics targeting recurrent disease.
Haemophilus ducreyi Lipooligosaccharides Induce Expression of the Immunosuppressive Enzyme Indoleamine 2,3-Dioxygenase via Type I Interferons and Tumor Necrosis Factor Alpha in Human Dendritic Cells
Authors: Li Wei , Katz Barry P. , Spinola Stanley M. 
Published: May 2011

ABSTRACTHaemophilus ducreyicauses chancroid, a genital ulcer disease. In human inoculation experiments, most volunteers fail to clear the bacteria despite the infiltration of innate and adaptive immune cells to the infected sites. The immunosuppressive protein indoleamine 2,3-dioxygenase (IDO) is a rate-limiting enzyme in thel-tryptophan-kynurenine metabolic pathway. Tryptophan depletion and tryptophan metabolites contribute to pathogen persistence by inhibiting T cell proliferation, inducing T cell apoptosis, and promoting the expansion of FOXP3+regulatory T (Treg) cells. We previously found that FOXP3+Treg cells are enriched in experimental lesions and thatH. ducreyiinduced IDO transcription in dendritic cells (DC) derived from blood of infected volunteers who developed pustules. Here, we showed that enzymatically active IDO was induced in DC byH. ducreyi. Neutralizing antibodies against interferon alpha/beta receptor 2 chain (IFNAR2) and tumor necrosis factor alpha (TNF-α) inhibited IDO induction. Inhibitors of the mitogen-activated protein kinase (MAPK) p38 and nuclear factor-κB (NF-κB) also inhibited IDO expression. Neither bacterial contact with nor uptake by DC was required for IDO activation.H. ducreyiculture supernatant andH. ducreyilipooligosaccharides (LOS) induced IDO expression, which required type I interferons, TNF-α, and the three MAPK (p38, c-Jun N-terminal kinase, and extracellular signal regulated kinase) and NF-κB pathways. In addition, LOS-induced IFN-β activated the JAK-STAT pathway. Blocking the LOS/Toll-like receptor 4 (TLR4) signaling pathway greatly reducedH. ducreyi-induced IDO production. These findings indicate thatH. ducreyi-induced IDO expression in DC is largely mediated by LOS via type I interferon- and TNF-α-dependent mechanisms and the MAPK, NF-κB, and JAK-STAT pathways.
Complete Genome Sequence of the Marine Fish Pathogen Vibrio anguillarum Harboring the pJM1 Virulence Plasmid and Genomic Comparison with Other Virulent Strains of V. anguillarum and V. ordalii
Authors: Naka Hiroaki , Dias Graciela M. , Thompson Cristiane C. , Dubay Christopher , Thompson Fabiano L. , Crosa Jorge H. 
Published: May 2011

ABSTRACTWe dissected the complete genome sequence of the O1 serotype strainVibrio anguillarum775(pJM1) and determined the draft genomic sequences of plasmidless strains of serotype O1 (strain 96F) and O2β (strain RV22) andV. ordalii. All strains harbor two chromosomes, but 775 also harbors the virulence plasmid pJM1, which carries the anguibactin-producing and cognate transport genes, one of the main virulence factors ofV. anguillarum. Genomic analysis identified eight genomic islands in chromosome 1 ofV. anguillarum775(pJM1) and two in chromosome 2. Some of them carried potential virulence genes for the biosynthesis of O antigens, hemolysins, and exonucleases as well as others for sugar transport and metabolism. The majority of genes for essential cell functions and pathogenicity are located on chromosome 1. In contrast, chromosome 2 contains a larger fraction (59%) of hypothetical genes than does chromosome 1 (42%). Chromosome 2 also harbors a superintegron, as well as host “addiction” genes that are typically found on plasmids. Unique distinctive properties include homologues of type III secretion system genes in 96F, homologues ofV. choleraezotandacetoxin genes in RV22, and the biofilm formationsypgenes inV. ordalii.Mobile genetic elements, some of them possibly originated in the pJM1 plasmid, were very abundant in 775, resulting in the silencing of specific genes, with only few insertions in the 96F and RV22 chromosomes.
Chemical bond and hardness of M-,W-type hexagonal barium ferrites
Authors: Li Zhiping , Gao Faming 
Published: May 2011

Using the chemical bond theory of dielectric description, the chemical bond parameters of the M-, W-type hexagonal barium ferrites were calculated. The hardness of BaFe12O19 and BaFe18O27 were calculated. The calculated hardness of BaFe12O19 is 5.9 GPa, which is in agreement with the experimental values. The calculated hardness of planes parallel to the c axis of BaFe18O27 is 5.5 GPa, which is smaller than that of BaFe12O19..
1st international requirements engineering efficiency workshop
Authors: Fricker Samuel , Seyff Norbert 
Published: May 2011

Requirements engineering research has for a long time focused on specification quality, leading to recommendations of how to engineer "perfect" requirements specifications. Practitioners, however, do not have the time, resources, and interests for overdoing requirements engineering. Rather, many situations call for shortcuts that allow investing effort in those concerns that are critical for success, while reducing effort in other areas where risk is comparably smaller. The social context, smart collaboration processes, and novel ways of looking at the interface between stakeholders and the supplier can be a basis to increase the yield of requirements engineering, while reducing required effort.
The International Requirements Engineering Efficiency Workshop (REEW 2011) aimed at initiating, facilitating, and nurturing the discussion on efficient approaches to engineer just goodenough requirements. Requirements engineering was seen as a means that can be simplified, automated, or combined with other practices to achieve successful systems in an economically efficient manner. REEW 2011 provided a platform for the community of practitioners and research experts that are interested in productivity-enhancing approaches to requirements engineering. This report describes the workshop results including tactics, practice, and trade-offs for achieving requirements engineering efficiency.
Planning an accessible conference
Authors: Trewin Shari 
Published: May 2011

This document contains information for organizers of academic conferences who wish to make their events as accessible as possible, so that people with disabilities can participate fully. It is not intended as an accessibility checklist or requirements document, but offers general ideas and information that conference planners may wish to consider.
These ideas are based on experiences in running the ACM SIGACCESS Conference on Computers and Accessibility (ASSETS). ASSETS is a conference of around 130 people, consisting of technical paper presentations, posters and demonstrations. The conference proceedings are published in the ACM digital library. Most attendees are non-local, and stay in the conference hotel. ASSETS is often attended by people with disabilities. In a typical year, there might be attendees who are blind, have low vision, are deaf or hard of hearing, use a power wheelchair or an electric scooter, have limited dexterity, and limited mobility. ASSETS strives to create an environment in which all attendees can participate and socialize together.
Immune Recruitment and Therapeutic Synergy: Keys to Optimizing Oncolytic Viral Therapy?
Authors: Naik Jay D. , Twelves Christopher J. , Selby Peter J. , Vile Richard G. , Chester John D. 
Published: May 2011

Abstract
Oncolytic viruses consist of a diverse range of DNA and RNA viruses traditionally thought to mediate their effects by exploiting aberrations in tumor pathways, allowing preferential viral replication in, and killing of, tumor cells. Clinical development has progressed to late-phase trials, potentially heralding their introduction into clinical practice. However, despite this promise, the activity of oncolytic viruses has yet to achieve the potential suggested in preclinical models. To address this disparity, we need to recognize the complex interaction among oncolytic viruses, tumor, chemotherapy, and host immune system, and appreciate that direct oncolysis may not be the only factor to play an important role in oncolytic virus-mediated antitumor efficacy. Although key in inactivating viruses, the host immune system can also act as an ally against tumors, interacting with oncolytic viruses under the right conditions to generate useful and long-lasting antitumor immunity. Preclinical data also suggest that oncolytic viruses show synergy with standard therapies, which may offer improved clinical response rates. Here, we explore clinical and preclinical data on clinically relevant oncolytic viruses, highlighting areas of progress, uncertainty, and translational opportunity, with respect to immune recruitment and therapeutic synergy. Clin Cancer Res; 17(13); 4214–24. ©2011 AACR.
Selective PGE2 Suppression Inhibits Colon Carcinogenesis and Modifies Local Mucosal Immunity
Authors: Nakanishi Masako , Menoret Antoine , Tanaka Takuji , Miyamoto Shingo , Montrose David C. , Vella Anthony T. , Rosenberg Daniel W. 
Published: May 2011

AbstractProstaglandin E2 (PGE2) is a bioactive lipid that mediates a wide range of physiologic effects and plays a central role in inflammation and cancer. PGE2 is generated from arachidonic acid by the sequential actions of the COX and terminal synthases (PGES). Increased levels of COX-2, with a concomitant elevation of PGE2, are often found in colorectal cancers (CRC), providing the rationale for the use of COX-2 inhibitors for chemoprevention. Despite their proven efficacy in cancer prevention, however, COX-2 inhibitors exhibit dose-dependent toxicities that are mediated in part by their nonspecific reduction of essential prostanoids, thus limiting their chemopreventive benefit. To achieve enhanced specificity, recent efforts have been directed toward targeting the inducible terminal synthase in the production of PGE2, microsomal PGES (mPGES-1). In the present study, we show that genetic deletion of mPGES-1 affords significant protection against carcinogen-induced colon cancer. mPGES-1 gene deletion results in an about 80% decrease in tumor multiplicity and up to a 90% reduction in tumor load in the distal colon of azoxymethane (AOM)-treated mice. Associated with the striking cancer suppression, we have identified a critical role for PGE2 in the control of immunoregulatory cell expansion (FoxP3-positive regulatory T cells) within the colon-draining mesenteric lymph nodes, providing a potential mechanism by which suppression of PGE2 may protect against CRC. These results provide new insights into how PGE2 controls antitumor immunity. Cancer Prev Res; 4(8); 1198–208. ©2011 AACR.