bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bactericidal Effects and Mechanism of Action of Olanexidine Gluconate, a New Antiseptic
Authors: Hagi Akifumi , Iwata Koushi , Nii Takuya , Nakata Hikaru , Tsubotani Yoshie , Inoue Yasuhide 
Published: May 2015

ABSTRACT

Olanexidine gluconate [1-(3,4-dichlorobenzyl)-5-octylbiguanide gluconate] (development code OPB-2045G) is a new monobiguanide compound with bactericidal activity. In this study, we assessed its spectrum of bactericidal activity and mechanism of action. The minimal bactericidal concentrations of the compound for 30-, 60-, and 180-s exposures were determined with the microdilution method using a neutralizer against 320 bacterial strains from culture collections and clinical isolates. Based on the results, the estimated bactericidal olanexidine concentrations with 180-s exposures were 869 μg/ml for Gram-positive cocci (155 strains), 109 μg/ml for Gram-positive bacilli (29 strains), and 434 μg/ml for Gram-negative bacteria (136 strains). Olanexidine was active against a wide range of bacteria, especially Gram-positive cocci, including methicillin-resistant
Staphylococcus aureus
and vancomycin-resistant enterococci, and had a spectrum of bactericidal activity comparable to that of commercial antiseptics, such as chlorhexidine and povidone-iodine.
In vitro
experiments exploring its mechanism of action indicated that olanexidine (i) interacts with the bacterial surface molecules, such as lipopolysaccharide and lipoteichoic acid, (ii) disrupts the cell membranes of liposomes, which are artificial bacterial membrane models, (iii) enhances the membrane permeability of
Escherichia coli
, (iv) disrupts the membrane integrity of
S. aureus
, and (v) denatures proteins at relatively high concentrations (≥160 μg/ml). These results indicate that olanexidine probably binds to the cell membrane, disrupts membrane integrity, and its bacteriostatic and bactericidal effects are caused by irreversible leakage of intracellular components. At relatively high concentrations, olanexidine aggregates cells by denaturing proteins. This mechanism differs slightly from that of a similar biguanide compound, chlorhexidine.
First Staphylococcal Cassette Chromosome
mec
Containing a
mecB
-Carrying Gene Complex Independent of Transposon Tn
6045
in a Macrococcus caseolyticus Isolate from a Canine Infection
Authors: Gómez-Sanz Elena , Schwendener Sybille , Thomann Andreas , Gobeli Brawand Stefanie , Perreten Vincent 
Published: May 2015

ABSTRACT

A methicillin-resistant
mecB
-positive
Macrococcus caseolyticus
(strain KM45013) was isolated from the nares of a dog with rhinitis. It contained a novel 39-kb transposon-defective complete
mecB
-carrying staphylococcal cassette chromosome
mec
element (SCC
mec
KM45013
). SCC
mec
KM45013
contained 49 coding sequences (CDSs), was integrated at the 3′ end of the chromosomal
orfX
gene, and was delimited at both ends by imperfect direct repeats functioning as integration site sequences (ISSs). SCC
mec
KM45013
presented two discontinuous regions of homology (SCC
mec
coverage of 35%) to the chromosomal and transposon Tn
6045
-associated SCC
mec
-like element of
M. caseolyticus
JCSC7096: (i) the
mec
gene complex (98.8% identity) and (ii) the
ccr
-carrying segment (91.8% identity). The
mec
gene complex, located at the right junction of the cassette, also carried the β-lactamase gene
blaZm
(
mecRm-mecIm-mecB-blaZm
). SCC
mec
KM45013
contained two cassette chromosome recombinase genes,
ccrAm2
and
ccrBm2
, which shared 94.3% and 96.6% DNA identity with those of the SCC
mec
-like element of JCSC7096 but shared less than 52% DNA identity with the staphylococcal
ccrAB
and
ccrC
genes. Three distinct extrachromosomal circularized elements (the entire SCC
mec
KM45013
, ΨSCC
mec
KM45013
lacking the
ccr
genes, and SCC
KM45013
lacking
mecB
) flanked by one ISS copy, as well as the chromosomal regions remaining after excision, were detected. An unconventional circularized structure carrying the
mecB
gene complex was associated with two extensive direct repeat regions, which enclosed two open reading frames (ORFs) (ORF46 and ORF51) flanking the chromosomal
mecB
-carrying gene complex. This study revealed
M. caseolyticus
as a potential disease-associated bacterium in dogs and also unveiled an SCC
mec
element carrying
mecB
not associated with Tn
6045
in the genus
Macrococcus
.
Causes and Implications of the Disappearance of Rifampin Resistance in a Rat Model of Methicillin-Resistant Staphylococcus aureus Foreign Body Osteomyelitis
Authors: Brinkman Cassandra L. , Tyner Harmony L. , Schmidt-Malan Suzannah M. , Mandrekar Jayawant N. , Patel Robin 
Published: May 2015

ABSTRACT

Orthopedic foreign body-associated infections are often treated with rifampin-based combination antimicrobial therapy. We previously observed that rifampin-resistant and methicillin-resistant
Staphylococcus aureus
(MRSA) isolates were present 2 days after cessation of rifampin therapy in experimental foreign body osteomyelitis. Unexpectedly, only rifampin-susceptible isolates were detected 14 days after the completion of treatment. We studied two rifampin-resistant isolates recovered 2 days after treatment and one rifampin-susceptible isolate recovered 14 days after treatment. Growing these isolates alone
in vitro
or
in vivo
demonstrated no fitness defects; however, in mixed culture, rifampin-susceptible bacteria outcompeted rifampin-resistant bacteria.
In vivo
, two courses of rifampin treatment (25 mg/kg of body weight every 12 h for 21 days) yielded a greater decrease in bacterial quantity in the bones of treated animals 14 days following treatment than that in animals receiving a single course of treatment (
P
= 0.0398). In infections established with equal numbers of rifampin-resistant and rifampin-susceptible bacteria, one course of rifampin treatment did not affect bacterial quantities. Rifampin-resistant and rifampin-susceptible isolates were recovered both 2 days and 14 days following treatment completion; however, the proportion of animals with rifampin-resistant isolates was lower at 14 days than that at 2 days following treatment completion (
P
= 0.024). In untreated animals infected with equal numbers of rifampin-resistant and rifampin-susceptible bacteria for 4 weeks, rifampin-susceptible isolates were exclusively recovered, indicating the outcompetition of rifampin-resistant by rifampin-susceptible isolates. The data presented imply that although there is no apparent fitness defect in rifampin-resistant bacteria when grown alone, they are outcompeted by rifampin-susceptible bacteria when the two are present together. The findings also suggest that selected rifampin resistance may not persist in initially rifampin-susceptible infections following the discontinuation of rifampin.
A Derivative of the Thiopeptide GE2270A Highly Selective against Propionibacterium acnes
Authors: Fabbretti Attilio , He Cheng-Guang , Gaspari Eleonora , Maffioli Sonia , Brandi Letizia , Spurio Roberto , Sosio Margherita , Jabes Daniela , Donadio Stefano 
Published: May 2015

ABSTRACT

A chemical derivative of the thiopeptide GE2270A, designated NAI003, was found to possess a substantially reduced antibacterial spectrum in comparison to the parent compound, being active against just a few Gram-positive bacteria. In particular, NAI003 retained low MICs against all tested isolates of
Propionibacterium acnes
and, to a lesser extent, against
Enterococcus faecalis
. Furthermore, NAI003 showed a time- and dose-dependent killing of both a clindamycin-resistant and a clindamycin-sensitive
P. acnes
isolate. Gel shift experiments indicated that, like the parent compound, NAI003 retained the ability to bind to elongation factors Tu (EF-Tus) derived from
Escherichia coli
,
E. faecalis
, or
P. acnes
, albeit with reduced efficiency. In contrast, EF-Tus derived from the NAI003-insensitive
Staphylococcus aureus
or
Streptococcus pyogenes
did not bind this compound. These results were confirmed by
in vitro
studies using a hybrid translation system, which indicated that NAI003 can inhibit most efficiently protein synthesis driven by the
P. acnes
EF-Tu.
P. acnes
mutants resistant to NAI003 were isolated by direct plating. With one exception, all analyzed strains carried mutations in the
tuf
gene, encoding EF-Tu. Because of its selective effect on
P. acnes
in comparison to resident skin flora, NAI003 represents a promising candidate for the topical treatment of acne, which has already completed a phase 1 clinical study.
Identifying Francisella tularensis Genes Required for Growth in Host Cells
Authors: Brunton J. , Steele S. , Miller C. , Lovullo E. , Taft-Benz S. , Kawula T. 
Published: May 2015

ABSTRACT

Francisella tularensis
is a highly virulent Gram-negative intracellular pathogen capable of infecting a vast diversity of hosts, ranging from amoebae to humans. A hallmark of
F. tularensis
virulence is its ability to quickly grow to high densities within a diverse set of host cells, including, but not limited to, macrophages and epithelial cells. We developed a luminescence reporter system to facilitate a large-scale transposon mutagenesis screen to identify genes required for growth in macrophage and epithelial cell lines. We screened 7,454 individual mutants, 269 of which exhibited reduced intracellular growth. Transposon insertions in the 269 growth-defective strains mapped to 68 different genes.
FTT_0924
, a gene of unknown function but highly conserved among
Francisella
species, was identified in this screen to be defective for intracellular growth within both macrophage and epithelial cell lines.
FTT_0924
was required for full Schu S4 virulence in a murine pulmonary infection model. The Δ
FTT_0924
mutant bacterial membrane is permeable when replicating in hypotonic solution and within macrophages, resulting in strongly reduced viability. The permeability and reduced viability were rescued when the mutant was grown in a hypertonic solution, indicating that
FTT_0924
is required for resisting osmotic stress. The Δ
FTT_0924
mutant was also significantly more sensitive to β-lactam antibiotics than Schu S4. Taken together, the data strongly suggest that
FTT_0924
is required for maintaining peptidoglycan integrity and virulence.
Colonization of Epidermal Tissue by Staphylococcus aureus Produces Localized Hypoxia and Stimulates Secretion of Antioxidant and Caspase-14 Proteins
Authors: Lone Abdul G. , Atci Erhan , Renslow Ryan , Beyenal Haluk , Noh Susan , Fransson Boel , Abu-Lail Nehal , Park Jeong-Jin , Gang David R. , Call Douglas R. 
Published: May 2015

ABSTRACT

A partial-thickness epidermal explant model was colonized with green fluorescent protein (GFP)-expressing
Staphylococcus aureus
, and the pattern of
S. aureus
biofilm growth was characterized using electron and confocal laser scanning microscopy. The oxygen concentration in explants was quantified using microelectrodes. The relative effective diffusivity and porosity of the epidermis were determined using magnetic resonance imaging, while hydrogen peroxide (H
2
O
2
) concentration in explant media was measured by using microelectrodes. Secreted proteins were identified and quantified using elevated-energy mass spectrometry (MS
E
).
S. aureus
biofilm grows predominantly in lipid-rich areas around hair follicles and associated skin folds. Dissolved oxygen was selectively depleted (2- to 3-fold) in these locations, but the relative effective diffusivity and porosity did not change between colonized and control epidermis. Histological analysis revealed keratinocyte damage across all the layers of colonized epidermis after 4 days of culture. The colonized explants released significantly (
P
< 0.01) more antioxidant proteins of both epidermal and
S. aureus
origin, consistent with elevated H
2
O
2
concentrations found in the media from the colonized explants (
P
< 0.001). Caspase-14 was also elevated significantly in the media from the colonized explants. While H
2
O
2
induces primary keratinocyte differentiation, caspase-14 is required for terminal keratinocyte differentiation and desquamation. These results are consistent with a localized biological impact from
S. aureus
in response to colonization of the skin surface.
Pathogenic Leptospira interrogans Exoproteins Are Primarily Involved in Heterotrophic Processes
Authors: Eshghi Azad , Pappalardo Elisa , Hester Svenja , Thomas Benjamin , Pretre Gabriela , Picardeau Mathieu 
Published: May 2015

ABSTRACTLeptospirosis is a life-threatening and emerging zoonotic disease with a worldwide annual occurrence of more than 1 million cases. Leptospirosis is caused by spirochetes belonging to the genusLeptospira. The mechanisms of disease manifestation in the host remain elusive, and the roles of leptospiral exoproteins in these processes have yet to be determined. Our aim in this study was to assess the composition and quantity of exoproteins of pathogenicLeptospira interrogansand to construe how these proteins contribute to disease pathogenesis. Label-free quantitative mass spectrometry of proteins obtained fromLeptospiraspirochetes culturedin vitrounder conditions mimicking infection identified 325 exoproteins. The majority of these proteins are conserved in the nonpathogenic speciesLeptospira biflexa, and proteins involved in metabolism and energy-generating functions were overrepresented and displayed the highest relative abundance in culture supernatants. Conversely, proteins of unknown function, which represent the majority of pathogen-specific proteins (presumably involved in virulence mechanisms), were underrepresented. Characterization of variousL. interrogansexoprotein mutants in the animal infection model revealed host mortality rates similar to those of hosts infected with wild-typeL. interrogans. Collectively, these results indicate that pathogenicLeptospiraexoproteins primarily function in heterotrophic processes (the processes by which organisms utilize organic substances as nutrient sources) to maintain the saprophytic lifestyle rather than the virulence of the bacteria. The underrepresentation of proteins homologous to known virulence factors, such as toxins and effectors in the exoproteome, also suggests that disease manifesting fromLeptospirainfection is likely caused by a combination of the primary and potentially moonlight functioning of exoproteins.
Tim-3 Induces Th2-Biased Immunity and Alternative Macrophage Activation during Schistosoma japonicum Infection
Authors: Hou Nan , Piao Xianyu , Liu Shuai , Wu Chuang , Chen Qijun 
Published: May 2015

ABSTRACTT cell immunoglobulin- and mucin-domain-containing molecule 3 (Tim-3) has been regarded as an important regulatory factor in both adaptive and innate immunity. Recently, Tim-3 was reported to be involved in Th2-biased immune responses in mice infected withSchistosoma japonicum, but the exact mechanism behind the involvement of Tim-3 remains unknown. The present study aims to understand the role of Tim-3 in the immune response againstS. japonicuminfection. Tim-3 expression was determined by flow cytometry, and increased Tim-3 expression was observed on CD4+and CD8+T cells, NK1.1+cells, and CD11b+cells from the livers ofS. japonicum-infected mice. However, the increased level of Tim-3 was lower in the spleen than in the liver, and no increase in Tim-3 expression was observed on splenic CD8+T cells or CD11b+cells. The schistosome-induced upregulation of Tim-3 on natural killer (NK) cells was accompanied by reduced NK cell numbersin vitroandin vivo. Tim-3 antibody blockade led to upregulation of inducible nitric oxide synthase and interleukin-12 (IL-12) mRNA in CD11b+cells cocultured with soluble egg antigen and downregulation of Arg1 and IL-10, which are markers of M2 macrophages. In summary, we observed schistosome-induced expression of Tim-3 on critical immune cell populations, which may be involved in the Th2-biased immune response and alternative activation of macrophages during infection.
Immunoprofiling of the Tryptophan-Rich Antigen Family in Plasmodium vivax
Authors: Wang Bo , Lu Feng , Cheng Yang , Chen Jun-Hu , Jeon Hye-Yoon , Ha Kwon-Soo , Cao Jun , Nyunt Myat Htut , Han Jin-Hee , Lee Seong-Kyun , Kyaw Myat Phone , Sattabongkot Jetsumon , Takashima Eizo , Tsuboi Takafumi , Han Eun-Taek 
Published: May 2015

ABSTRACTTryptophan-rich antigens (TRAgs) are an antigen family that has been identified in human and rodent malaria parasites. TRAgs have been proposed as candidate antigens for potential vaccines. ThePlasmodium vivaxTRAg (PvTRAg) family includes 36 members. Each PvTRAg contains a tryptophan-rich (TR) domain in the C-terminal region. In this study, we recombinantly expressed all 36 PvTRAgs using a cell-free expression system, and, for the first time, profiled the IgG antibody responses against all PvTRAgs in the sera from 96 vivax malaria patients and 40 healthy individuals using protein microarray technology. The mean seropositive rate for all PvTRAgs was 60.3%. Among them, nine PvTRAgs were newly identified in this study and showed a seropositive rate of >50%. Five of them, PvTRAg_13, PvTRAg_15, PvTRAg_16, PvTRAg_26, and PvTRAg_29, produced higher levels of IgG antibody, even in low-endemicity countries. In addition, the results of an immunofluorescence analysis suggest that PvTRAgs are, at least in part, associated with caveola-vesicle complexes, a unique structure ofP. vivax-infected erythrocytes. The mechanism of formation and the function of these abundant membrane structures are not known. Further investigation aimed at determining the functions of these proteins would lead to a better understanding of the blood-stage biology ofP. vivax.
The Protein Interactome of Mycobacteriophage Giles Predicts Functions for Unknown Proteins
Authors: Mehla Jitender , Dedrick Rebekah M. , Caufield J. Harry , Siefring Rachel , Mair Megan , Johnson Allison , Hatfull Graham F. , Uetz Peter 
Published: May 2015

ABSTRACT

Mycobacteriophages are viruses that infect mycobacterial hosts and are prevalent in the environment. Nearly 700 mycobacteriophage genomes have been completely sequenced, revealing considerable diversity and genetic novelty. Here, we have determined the protein complement of mycobacteriophage Giles by mass spectrometry and mapped its genome-wide protein interactome to help elucidate the roles of its 77 predicted proteins, 50% of which have no known function. About 22,000 individual yeast two-hybrid (Y2H) tests with four different Y2H vectors, followed by filtering and retest screens, resulted in 324 reproducible protein-protein interactions, including 171 (136 nonredundant) high-confidence interactions. The complete set of high-confidence interactions among Giles proteins reveals new mechanistic details and predicts functions for unknown proteins. The Giles interactome is the first for any mycobacteriophage and one of just five known phage interactomes so far. Our results will help in understanding mycobacteriophage biology and aid in development of new genetic and therapeutic tools to understand
Mycobacterium tuberculosis
.

IMPORTANCE
Mycobacterium tuberculosis
causes over 9 million new cases of tuberculosis each year. Mycobacteriophages, viruses of mycobacterial hosts, hold considerable potential to understand phage diversity, evolution, and mycobacterial biology, aiding in the development of therapeutic tools to control mycobacterial infections. The mycobacteriophage Giles protein-protein interaction network allows us to predict functions for unknown proteins and shed light on major biological processes in phage biology. For example, Giles gp76, a protein of unknown function, is found to associate with phage packaging and maturation. The functions of mycobacteriophage-derived proteins may suggest novel therapeutic approaches for tuberculosis. Our ORFeome clone set of Giles proteins and the interactome data will be useful resources for phage interactomics.
The Effectiveness of Acupuncture versus Clonazepam in Patients with Burning Mouth Syndrome
Authors: Jurisic Kvesic A , Zavoreo I , Basic Kes V , Vucicevic Boras V , Ciliga D , Gabric D , Vrdoljak D V 
Published: May 2015

Objective Burning mouth syndrome (BMS) is a chronic oral condition, characterised by burning symptoms, which mainly affects perimenopausal and postmenopausal women. Neuropathy might be the underlying cause of the condition. There are still insufficient data regarding successful therapy. The aim of this study was to compare the effectiveness of acupuncture and clonazepam. Methods Forty-two patients with BMS (38 women, 4 men) aged 66.7±12.0 years were randomly divided into two groups. Acupuncture was performed on 20 participants over 4 weeks, 3 times per week, on points ST8, GB2, TE21, SI19, SI18 and LI4 bilaterally as well as GV20 in the midline, each session lasting half an hour. Twenty-two patients took clonazepam once a day (0.5 mg in the morning) for 2 weeks and, after 2 weeks, two tablets (0.5 mg in the morning and in the evening) were taken for the next 2 weeks. Prior to and 1 month after either therapy, participants completed questionnaires: visual analogue scale, Beck Depression Inventory, Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) pain scale, 36-item Short Form Health Survey (SF-36) and Montreal Cognitive Assessment (MoCA). Results There were significant improvements in the scores of all outcome measures after treatment with both acupuncture and clonazepam, except for MoCA. There were no significant differences between the two therapeutic regimens regarding the scores of the performed tests. Conclusions Acupuncture and clonazepam are similarly effective for patients with BMS.
Contribution of recurrent admissions in children and young people to emergency hospital admissions: retrospective cohort analysis of hospital episode statistics
Authors: Wijlaars Linda PMM , Hardelid Pia , Woodman Jenny , Allister Janice , Cheung Ronny , Gilbert Ruth 
Published: May 2015

ObjectiveTo examine the contribution of recurrent admissions to the high rate of emergency admissions among children and young people (CYP) in England, and to what extent readmissions are accounted for by patients with chronic conditions.DesignAll hospital admissions to the National Health Service (NHS) in England using hospital episode statistics (HES) from 2009 to 2011 for CYP aged 0–24 years. We followed CYP for 2 years from discharge of their first emergency admission in 2009. We determined the number of subsequent emergency admissions, time to next admission, length of stay and the proportion of injury and chronic condition admissions measured by diagnostic codes in all following admissions.Results869 895 children had an index emergency admission in 2009, resulting in a further 939 710 admissions (of which 600 322, or 64%, were emergency admissions) over the next 2 years. After discharge from the index admission, 32% of 274,986 (32%) children were readmitted within 2 years, 26% of these readmissions occurring within 30 days of discharge. Recurrent emergency admission accounted for 41% of all emergency admissions in the 2-year cohort and 66% of inpatient days. 41% of index admissions, but 76% of the recurrent emergency admissions, were in children with a chronic condition.ConclusionsRecurrent admissions contribute substantially to total emergency admissions. They often occur soon after discharge, and disproportionately affect CYP with chronic conditions. Policies aiming to discourage readmissions should consider whether they could undermine necessary inpatient care for children with chronic conditions.