bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anti-
Pseudomonas
Activity of Frog Skin Antimicrobial Peptides in a
Caenorhabditis elegans
Infection Model: a Plausible Mode of Action
In Vitro
and
In Vivo
Authors: Uccelletti Daniela , Zanni Elena , Marcellini Ludovica , Palleschi Claudio , Barra Donatella , Mangoni Maria Luisa 
Published: July 2010

ABSTRACT

The emergence of multidrug-resistant (MDR) microorganisms makes it increasingly difficult to treat infections. These infections include those associated with
Pseudomonas aeruginosa
, which are hard to eradicate, especially in patients with a compromised immune system. Naturally occurring membrane-active cationic antimicrobial peptides (CAMPs) serve as attractive candidates for the development of new therapeutic agents. Amphibian skin is one of the richest sources for such peptides, but only a few studies on their
in vivo
activities and modes of action have been reported. We investigated (i) the activity and mechanism underlying the killing of short CAMPs from frog skin (e.g., temporins and esculentin fragments) on an MDR clinical isolate of
P. aeruginosa
and (ii) their
in vivo
antibacterial activities and modes of action, using the minihost model of
Caenorhabditis elegans
. Our data revealed that
in vivo
, both temporin-1Tb and esculentin(1-18) were highly active in promoting the survival of
Pseudomonas
-infected nematodes, although temporin-1Tb did not show significant activity
in vitro
under the experimental conditions used. Importantly, esculentin(1-18) permeated the membrane of
Pseudomonas
cells within the infected nematode. To the best of our knowledge, this is the first report showing the ability of a CAMP to permeate the microbial membrane within a living organism. Besides shedding light on a plausible mode of action of frog skin CAMPs
in vivo
, our data suggest that temporins and esculentins would be attractive molecules as templates for the development of new therapeutics against life-threatening infections.
Inhibition of Antibiotic-Resistant
Staphylococcus aureus
by the Broad-Spectrum Dihydrofolate Reductase Inhibitor RAB1
Authors: Bourne C. R. , Barrow E. W. , Bunce R. A. , Bourne P. C. , Berlin K. D. , Barrow W. W. 
Published: July 2010

ABSTRACT

The bacterial burden on human health is quickly outweighing available therapeutics. Our long-term goal is the development of antimicrobials with the potential for broad-spectrum activity. We previously reported phthalazine-based inhibitors of dihydrofolate reductase (DHFR) with potent activity against
Bacillus anthracis
, a major component of Project BioShield. The most active molecule, named RAB1, performs well
in vitro
and, in a cocrystal structure, was found deep within the active site of
B. anthracis
DHFR. We have now examined the activity of RAB1 against a panel of bacteria relevant to human health and found broad-spectrum applicability, particularly with regard to Gram-positive organisms. RAB1 was most effective against
Staphylococcus aureus
, including methicillin- and vancomycin-resistant (MRSA/VRSA) strains. We have determined the cocrystal structure of the wild-type and trimethoprim-resistant (Phe 98 Tyr) DHFR enzyme from
S. aureus
with RAB1, and we found that rotational freedom of the acryloyl linker region allows the phthalazine moiety to occupy two conformations. This freedom in placement also allows either enantiomer of RAB1 to bind to
S. aureus
, in contrast to the specificity of
B. anthracis
for the
S
-enantiomer. Additionally, one of the conformations of RAB1 defines a unique surface cavity that increases the strength of interaction with
S. aureus
. These observations provide insights into the binding capacity of
S. aureus
DHFR and highlight atypical features critical for future exploitation in drug development.
Liposomal Amphotericin B and Echinocandins as Monotherapy or Sequential or Concomitant Therapy in Murine Disseminated and Pulmonary
Aspergillus fumigatus
Infections
Authors: Olson Jon A. , George Ancy , Constable David , Smith Peter , Proffitt Richard T. , Adler-Moore Jill P. 
Published: July 2010

ABSTRACT

Monotherapy and combination therapy were compared using optimal doses of liposomal amphotericin B, micafungin, or caspofungin in
Aspergillus fumigatus
pulmonary and disseminated infections. Mice were challenged intravenously (2.8 × 10
4
to 5.7 × 10
4
conidia) or intranasally (5.8 × 10
7
conidia) with
A. fumigatus
. Drugs (5, 10, or 15 mg/kg of body weight) were given for 3 or 6 days as single, concomitant, or sequential therapy (i.e., days 1 to 3 and then days 4 to 6). Mice were monitored for survival, and tissues were assayed for fungal burden and drug concentrations. Treatments starting 24 h postchallenge significantly prolonged survival in disseminated aspergillosis (
P
< 0.002), but only liposomal amphotericin B treatments or treatments beginning with liposomal amphotericin B increased survival to 100% in the pulmonary aspergillosis model. Fungi in kidneys and spleens (disseminated) and lungs (pulmonary) were significantly decreased (
P
≤ 0.04) by liposomal amphotericin B, liposomal amphotericin B plus echinocandin, or liposomal amphotericin B prior to echinocandin. In the disseminated infection, liposomal amphotericin B and micafungin (10 or 15 mg/kg) had similar kidney drug levels, while in the spleen, 5 and 15 mg/kg liposomal amphotericin B gave higher drug levels than micafungin (
P
< 0.02). In the pulmonary infection, drug levels in lungs and spleen with 5-mg/kg dosing were significantly higher with liposomal amphotericin B than with caspofungin (
P
≤ 0.002). In summary, treatment of
A. fumigatus
infections with liposomal amphotericin B plus echinocandin or liposomal amphotericin B prior to echinocandin was as effective as liposomal amphotericin B alone, and a greater decrease in the fungal burden with liposomal amphotericin B supports using liposomal amphotericin B prior to echinocandin.
The BceABRS Four-Component System Regulates the Bacitracin-Induced Cell Envelope Stress Response in
Streptococcus mutans
Authors: Ouyang Jing , Tian Xiao-Lin , Versey Jennifer , Wishart Alexander , Li Yung-Hua 
Published: July 2010

ABSTRACT

Streptococcus mutans
is known to be resistant to bacitracin, a cyclic polypeptide antibiotic produced by certain species of the genus
Bacillus
. This property is often exploited in the isolation of
S. mutans
strains from highly heterogeneous oral microflora. A genetic locus consisting of a four-gene operon,
bceABRS
(formerly
mbrABCD
), the component genes of which are homologous to
Bacillus subtilis bceRS-bceAB
(encoding a two-component system and an ABC transporter), is required for bacitracin resistance in
S. mutans
. Here we describe the identification of a DNA binding site for the BceR response regulator and its transcriptional control of the
bceABRS
operon in response to the presence of bacitracin. We provide evidence indicating that phosphorylated BceR binds directly to a conserved invert repeat located between bp −120 and −78 of the
bceABRS
promoter region and positively regulates expression of the
bceABRS
operon. We also demonstrate that sensing of bacitracin by the BceS histidine kinase requires the presence of an intact BceAB transporter, since deletion of either
bceA
or
bceB
abolishes BceRS-mediated bacitracin sensing. The results suggest that the BceAB transporter acts as a cosensor, together with the BceRS two-component system, for bacitracin perception in
S. mutans
. By searching the
S. mutans
genome databases, we have identified three additional genes that share the consensus BceR binding motif at their promoter regions. Our initial work has confirmed that expression of these genes is directly controlled by BceRS, indicating that the
bceABRS
operon, along with the three additional genes, forms the BceRS regulon in
S. mutans
. Taking these findings together, we conclude that BceABRS comprises a four-component system that plays an important role in stimulus sensing, signal transduction, the gene regulatory network, and substrate transport for the cell envelope stress response in
S. mutans
.
Medical and Legal Implications of Testing for Sexually Transmitted Infections in Children
Authors: Hammerschlag Margaret R. , Guillén Christina D. 
Published: July 2010

SUMMARY

Testing for sexually transmitted infections (STIs) in children presents a number of problems for the practitioner that are not usually faced when testing adults for the same infections. The identification of an STI in a child can have, in addition to medical implications, serious legal implications. The presence of an STI is often used to support the presence or allegations of sexual abuse, and conversely, the identification of an STI in a child will prompt an investigation of possible abuse. The purpose of this paper is to review the epidemiology of child sexual abuse, including the epidemiology of major STIs including
N
eisseria gonorrhoeae
,
C
hlamydia trachomatis
, syphilis, herpes simplex virus (HSV),
Trichomonas vaginalis
, and human papillomavirus, and the current recommendations for diagnostic testing in this population.
Validation of Laboratory-Developed Molecular Assays for Infectious Diseases
Authors: Burd Eileen M. 
Published: July 2010

SUMMARY
Molecular technology has changed the way that clinical laboratories diagnose and manage many infectious diseases. Excellent sensitivity, specificity, and speed have made molecular assays an attractive alternative to culture or enzyme immunoassay methods. Many molecular assays are commercially available and FDA approved. Others, especially those that test for less common analytes, are often laboratory developed. Laboratories also often modify FDA-approved assays to include different extraction systems or additional specimen types. The Clinical Laboratory Improvement Amendments (CLIA) federal regulatory standards require clinical laboratories to establish and document their own performance specifications for laboratory-developed tests to ensure accurate and precise results prior to implementation of the test. The performance characteristics that must be established include accuracy, precision, reportable range, reference interval, analytical sensitivity, and analytical specificity. Clinical laboratories are challenged to understand the requirements and determine the types of experiments and analyses necessary to meet the requirements. A variety of protocols and guidelines are available in various texts and documents. Many of the guidelines are general and more appropriate for assays in chemistry sections of the laboratory but are applied in principle to molecular assays. This review presents information that laboratories may consider in their efforts to meet regulatory requirements.
Causes of Outbreaks Associated with Drinking Water in the United States from 1971 to 2006
Authors: Craun Gunther F. , Brunkard Joan M. , Yoder Jonathan S. , Roberts Virginia A. , Carpenter Joe , Wade Tim , Calderon Rebecca L. , Roberts Jacquelin M. , Beach Michael J. , Roy Sharon L. 
Published: July 2010

SUMMARY

Since 1971, the CDC, EPA, and Council of State and Territorial Epidemiologists (CSTE) have maintained the collaborative national Waterborne Disease and Outbreak Surveillance System (WBDOSS) to document waterborne disease outbreaks (WBDOs) reported by local, state, and territorial health departments. WBDOs were recently reclassified to better characterize water system deficiencies and risk factors; data were analyzed for trends in outbreak occurrence, etiologies, and deficiencies during 1971 to 2006. A total of 833 WBDOs, 577,991 cases of illness, and 106 deaths were reported during 1971 to 2006. Trends of public health significance include (i) a decrease in the number of reported outbreaks over time and in the annual proportion of outbreaks reported in public water systems, (ii) an increase in the annual proportion of outbreaks reported in individual water systems and in the proportion of outbreaks associated with premise plumbing deficiencies in public water systems, (iii) no change in the annual proportion of outbreaks associated with distribution system deficiencies or the use of untreated and improperly treated groundwater in public water systems, and (iv) the increasing importance of
Legionella
since its inclusion in WBDOSS in 2001. Data from WBDOSS have helped inform public health and regulatory responses. Additional resources for waterborne disease surveillance and outbreak detection are essential to improve our ability to monitor, detect, and prevent waterborne disease in the United States.
Mechanisms of Action and Clinical Application of Macrolides as Immunomodulatory Medications
Authors: Kanoh Soichiro , Rubin Bruce K. 
Published: July 2010

SUMMARYMacrolides have diverse biological activities and an ability to modulate inflammation and immunity in eukaryotes without affecting homeostatic immunity. These properties have led to their long-term use in treating neutrophil-dominated inflammation in diffuse panbronchiolitis, bronchiectasis, rhinosinusitis, and cystic fibrosis. These immunomodulatory activities appear to be polymodal, but evidence suggests that many of these effects are due to inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and nuclear factor kappa B (NF-κB) activation. Macrolides accumulate within cells, suggesting that they may associate with receptors or carriers responsible for the regulation of cell cycle and immunity. A concern is that long-term use of macrolides increases the emergence of antimicrobial resistance. Nonantimicrobial macrolides are now in development as potential immunomodulatory therapies.
The Changing Epidemiology of
Clostridium difficile
Infections
Authors: Freeman J. , Bauer M. P. , Baines S. D. , Corver J. , Fawley W. N. , Goorhuis B. , Kuijper E. J. , Wilcox M. H. 
Published: July 2010

SUMMARY

The epidemiology of
Clostridium difficile
infection (CDI) has changed dramatically during this millennium. Infection rates have increased markedly in most countries with detailed surveillance data. There have been clear changes in the clinical presentation, response to treatment, and outcome of CDI. These changes have been driven to a major degree by the emergence and epidemic spread of a novel strain, known as PCR ribotype 027 (sometimes referred to as BI/NAP1/027). We review the evidence for the changing epidemiology, clinical virulence and outcome of treatment of CDI, and the similarities and differences between data from various countries and continents. Community-acquired CDI has also emerged, although the evidence for this as a distinct new entity is less clear. There are new data on the etiology of and potential risk factors for CDI; controversial issues include specific antimicrobial agents, gastric acid suppressants, potential animal and food sources of
C. difficile
, and the effect of the use of alcohol-based hand hygiene agents.
Acanthamoeba culbertsoni
Elicits Soluble Factors That Exert Anti-Microglial Cell Activity
Authors: Harrison Jenica L. , Ferreira Gabriela A. , Raborn Erinn S. , Lafrenaye Audrey D. , Marciano-Cabral Francine , Cabral Guy A. 
Published: July 2010

ABSTRACT

Acanthamoeba culbertsoni
is an opportunistic pathogen that causes granulomatous amoebic encephalitis (GAE), a chronic and often fatal disease of the central nervous system (CNS). A hallmark of GAE is the formation of granulomas around the amoebae. These cellular aggregates consist of microglia, macrophages, lymphocytes, and neutrophils, which produce a myriad of proinflammatory soluble factors. In the present study, it is demonstrated that
A. culbertsoni
secretes serine peptidases that degrade chemokines and cytokines produced by a mouse microglial cell line (BV-2 cells). Furthermore, soluble factors present in cocultures of
A. culbertsoni
and BV-2 cells, as well as in cocultures of
A. culbertsoni
and primary neonatal rat cerebral cortex microglia, induced apoptosis of these macrophage-like cells. Collectively, the results indicate that
A. culbertsoni
can apply a multiplicity of cell contact-independent modes to target macrophage-like cells that exert antiamoeba activities in the CNS.
Accumulation ofPlasmodium berghei-Infected Red Blood Cells in the Brain Is Crucial for the Development of Cerebral Malaria in Mice
Authors: Baptista Fernanda G. , Pamplona Ana , Pena Ana C. , Mota Maria M. , Pied Sylviane , Vigário Ana M. 
Published: July 2010

ABSTRACTCerebral malaria is the most severe complication of human infection withPlasmodium falciparum. It was shown thatPlasmodium bergheiANKA-induced cerebral malaria was prevented in 100% of mice depleted of CD8+T cells 1 day prior to the development of neurological signs. However, the importance of parasites in the brains of these mice was never clearly investigated. Moreover, the relevance of this model to human cerebral malaria has been questioned many times, especially concerning the relative importance of leukocytes versus parasitized erythrocytes sequestered in the brain. Here, we show that mice protected from cerebral malaria by CD8+T-cell depletion have significantly fewer parasites in the brain. Treatment of infected mice with an antimalarial drug 15 to 20 h prior to the estimated time of death also protected mice from cerebral malaria without altering the number of CD8+T cells in the brain. These mice subsequently developed cerebral malaria with parasitized red blood cells in the brain. Our results clearly demonstrated that sequestration of CD8+T cells in the brain is not sufficient for the development of cerebral malaria in C57BL/6 mice but that the concomitant presence of parasitized red blood cells is crucial for the onset of pathology. Importantly, these results also demonstrated that the experimental cerebral malaria model shares many features with human pathology and might be a relevant model to study its pathogenesis.
Conidia but Not Yeast Cells of the Fungal PathogenHistoplasma capsulatumTrigger a Type I Interferon Innate Immune Response in Murine Macrophages
Authors: Inglis Diane O. , Berkes Charlotte A. , Hocking Murray Davina R. , Sil Anita 
Published: July 2010

ABSTRACTHistoplasma capsulatumis the most common cause of fungal respiratory infections and can lead to progressive disseminated infections, particularly in immunocompromised patients. Infection occurs upon inhalation of the aerosolized spores, known as conidia. Once inside the host, conidia are phagocytosed by alveolar macrophages. The conidia subsequently germinate and produce a budding yeast-like form that colonizes host macrophages and can disseminate throughout host organs and tissues. Even though conidia are the predominant infectious particle forH. capsulatumand are the first cell type encountered by the host during infection, very little is known at a molecular level about conidia or about their interaction with cells of the host immune system. We examined the interaction between conidia and host cells in a murine bone-marrow-derived macrophage model of infection. We used whole-genome expression profiling and quantitative reverse transcription-PCR (qRT-PCR) to monitor the macrophage signaling pathways that are modulated during infection with conidia. Our analysis revealed that type I interferon (IFN)-responsive genes and the beta type I IFN (IFN-β) were induced in macrophages during infection withH. capsulatumconidia but notH. capsulatumyeast cells. Further analysis revealed that the type I IFN signature induced in macrophages in response to conidia is independent of Toll-like receptor (TLR) signaling and the cytosolic RNA sensor MAVS but is dependent on the transcription factor interferon regulatory factor 3 (IRF3). Interestingly,H. capsulatumgrowth was restricted in mice lacking the type I IFN receptor, indicating that an intact host type I IFN response is required for full virulence ofH. capsulatumin mice.
Delineation and Analysis of Chromosomal Regions Specifying
Yersinia pestis
Authors: Derbise Anne , Chenal-Francisque Viviane , Huon Christèle , Fayolle Corinne , Demeure Christian E. , Chane-Woon-Ming Béatrice , Médigue Claudine , Hinnebusch B. Joseph , Carniel Elisabeth 
Published: July 2010

ABSTRACT

Yersinia pestis
, the causative agent of plague, has recently diverged from the less virulent enteropathogen
Yersinia pseudotuberculosis
. Its emergence has been characterized by massive genetic loss and inactivation and limited gene acquisition. The acquired genes include two plasmids, a filamentous phage, and a few chromosomal loci. The aim of this study was to characterize the chromosomal regions acquired by
Y. pestis
. Following
in silico
comparative analysis and PCR screening of 98 strains of
Y. pseudotuberculosis
and
Y. pestis
, we found that eight chromosomal loci (six regions [R1
pe
to R6
pe
] and two coding sequences [CDS1
pe
and CDS2
pe
]) specified
Y. pestis
. Signatures of integration by site specific or homologous recombination were identified for most of them. These acquisitions and the loss of ancestral DNA sequences were concentrated in a chromosomal region opposite to the origin of replication. The specific regions were acquired very early during
Y. pestis
evolution and were retained during its microevolution, suggesting that they might bring some selective advantages. Only one region (R3
pe
), predicted to carry a lambdoid prophage, is most likely no longer functional because of mutations. With the exception of R1
pe
and R2
pe
, which have the potential to encode a restriction/modification and a sugar transport system, respectively, no functions could be predicted for the other
Y. pestis
-specific loci. To determine the role of the eight chromosomal loci in the physiology and pathogenicity of the plague bacillus, each of them was individually deleted from the bacterial chromosome. None of the deletants exhibited defects during growth
in vitro
. Using the
Xenopsylla cheopis
flea model, all deletants retained the capacity to produce a stable and persistent infection and to block fleas. Similarly, none of the deletants caused any acute flea toxicity. In the mouse model of infection, all deletants were fully virulent upon subcutaneous or aerosol infections. Therefore, our results suggest that acquisition of new chromosomal materials has not been of major importance in the dramatic change of life cycle that has accompanied the emergence of
Y. pestis
.
Comparative Proteomic Analysis of Extracellular Proteins of
Clostridium perfringens
Type A and Type C Strains
Authors: Sengupta Nabonita , Alam Syed Imteyaz , Kumar Bhoj , Kumar Ravi Bhushan , Gautam Vandana , Kumar Subodh , Singh Lokendra 
Published: July 2010

ABSTRACT

Clostridium perfringens
is a medically important clostridial pathogen and an etiological agent causing several diseases in humans and animals.
C. perfringens
and its toxins have been listed as potential biological and toxin warfare (BTW) agents; thus, efforts to develop strategies for detection and protection are warranted. Forty-eight extracellular proteins of
C. perfringens
type A and type C strains have been identified here using a 2-dimensional gel electrophoresis-mass spectrometry (2-DE-MS) technique. The SagA protein, the DnaK-type molecular chaperone hsp70, endo-beta-
N
-acetylglucosaminidase, and hypothetical protein CPF_0656 were among the most abundant proteins secreted by
C. perfringens
ATCC 13124. The antigenic component of the exoproteome of this strain has also been identified. Most of the extracellular proteins were predicted to be involved in carbohydrate transport and metabolism (16%) or cell envelope biogenesis or to be outer surface protein constituents (13%). More than 50% of the proteins were predictably secreted by either classical or nonclassical pathways. LipoP and TMHMM indicated that nine proteins were extracytoplasmic but cell associated. Immunization with recombinant ornithine carbamoyltransferase (cOTC) clearly resulted in protection against a direct challenge with
C. perfringens
organisms. A significant rise in IgG titers in response to recombinant cOTC was observed in mice, and IgG2a titers predominated over IgG1 titers (IgG2a/IgG1 ratio, 2). The proliferation of spleen lymphocytes in cOTC-immunized animals suggested a cellular immune response. There were significant increases in the levels of gamma interferon (IFN-γ) and interleukin 2 (IL-2), suggesting a Th1 type immune response.