bluuebunny/crossref_metadata_2025_split huggingface dataset:
GRL-04810 and GRL-05010, Difluoride-Containing Nonpeptidic HIV-1 Protease Inhibitors (PIs) That Inhibit the Replication of Multi-PI-Resistant HIV-1
In Vitro
and Possess Favorable Lipophilicity That May Allow Blood-Brain Barrier Penetration
Authors: Salcedo Gómez Pedro Miguel , Amano Masayuki , Yashchuk Sofiya , Mizuno Akira , Das Debananda , Ghosh Arun K. , Mitsuya Hiroaki 
Published: October 2013

ABSTRACT

We designed, synthesized, and identified two novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs), GRL-04810 and GRL-05010, containing the structure-based designed privileged cyclic ether-derived nonpeptide P2 ligand,
bis
-tetrahydrofuranylurethane (
bis
-THF), and a difluoride moiety, both of which are active against the laboratory strain HIV-1
LAI
(50% effective concentrations [EC
50
s], 0.0008 and 0.003 μM, respectively) with minimal cytotoxicity (50% cytotoxic concentrations [CC
50
s], 17.5 and 37.0 μM, respectively, in CD4
+
MT-2 cells). The two compounds were active against multi-PI-resistant clinical HIV-1 variants isolated from patients who had no response to various antiviral regimens. GRL-04810 and GRL-05010 also blocked the infectivity and replication of each of the HIV-1
NL4-3
variants selected by up to 5 μM lopinavir (EC
50
s, 0.03 and 0.03 μM, respectively) and atazanavir (EC
50
s, 0.02 and 0.04 μM, respectively). Moreover, they were active against darunavir (DRV)-resistant variants (EC
50
in 0.03 to 0.034 μM range for GRL-04810 and 0.026 to 0.043 μM for GRL-05010), while DRV had EC
50
s between 0.02 and 0.174 μM. GRL-04810 had a favorable lipophilicity profile as determined with the partition (log
P
) and distribution (log
D
) coefficients of −0.14 and −0.29, respectively. The
in vitro
blood-brain barrier (BBB) permeability assay revealed that GRL-04810 and GRL-05010 may have a greater advantage in terms of crossing the BBB than the currently available PIs, with apparent penetration indexes of 47.8 × 10
−6
and 61.8 × 10
−6
cm/s, respectively. The present data demonstrate that GRL-04810 and GRL-05010 exert efficient activity against a wide spectrum of HIV-1 variants
in vitro
and suggest that two fluorine atoms added to their
bis
-THF moieties may well enhance their penetration across the BBB.
IreB, a Ser/Thr Kinase Substrate, Influences Antimicrobial Resistance in Enterococcus faecalis
Authors: Hall Cherisse L. , Tschannen Michael , Worthey Elizabeth A. , Kristich Christopher J. 
Published: October 2013

ABSTRACT

Enterococcus faecalis
is a Gram-positive bacterium that is a major cause of hospital-acquired infections, in part due to its intrinsic resistance to cephalosporins. The mechanism that confers intrinsic cephalosporin resistance in enterococci remains incompletely defined. Previously, we have shown that the Ser/Thr protein kinase and phosphatase pair IreK and IreP act antagonistically to regulate cephalosporin resistance in
E. faecalis
. We hypothesize that IreK senses antibiotic-induced cell wall damage and activates a signaling pathway leading to antibiotic resistance. However, the factors downstream of IreK have not yet been identified. To discover such factors, suppressor mutations that restored resistance to a Δ
ireK
kinase mutant were identified. Mutations were found in IreB, a highly conserved gene of unknown function that is widespread among low-GC Gram-positive bacteria. We show that IreB plays a negative regulatory role in cephalosporin resistance and is an endogenous substrate of both IreK and IreP. IreB is phosphorylated on conserved threonine residues, and mutations at these sites impair cephalosporin resistance. Our results are consistent with a model in which the activity of IreB is modulated by IreK-dependent phosphorylation in a signaling pathway required for cephalosporin resistance and begin to shed light on the function of this previously uncharacterized protein.
Genotypic Analysis of the V3 Region of HIV from Virologic Nonresponders to Maraviroc-Containing Regimens Reveals Distinct Patterns of Failure
Authors: Swenson Luke C. , Chui Celia K. S. , Brumme Chanson J. , Chan Dennison , Woods Conan K. , Mo Theresa , Dong Winnie , Chapman Doug , Lewis Marilyn , Demarest James F. , James Ian , Portsmouth Simon , Goodrich James , Heera Jayvant , Valdez Hernan , Harrigan P. Richard 
Published: October 2013

ABSTRACTChanges in HIV tropism from R5 to non-R5 or development of drug resistance is often associated with virologic failure in patients treated with maraviroc, a CCR5 antagonist. We sought to examine changes in HIV envelope sequences and inferred tropism in patients who did not respond to maraviroc-based regimens. We selected 181 patients who experienced early virologic failure on maraviroc-containing therapy in the MOTIVATE trials. All patients had R5 HIV by the original Trofile assay before entry. We used population-based sequencing methods and the geno2pheno algorithm to examine changes in tropism and V3 sequences at the time of failure. Using deep sequencing, we assessed whether V3 sequences observed at failure emerged from preexisting subpopulations. From population genotyping data at failure, 90 patients had R5 results, and 91 had non-R5 results. Of the latter group, the geno2pheno false-positive rate (FPR) value fell from a median of 20 at screening to 1.1 at failure. By deep sequencing, the median percentage of non-R5 variants in these patients rose from 1.4% to 99.5% after a median of 4 weeks on maraviroc. In 70% of cases, deep sequencing could detect a pretreatment CXCR4-using subpopulation, which emerged at failure. Overall, there were two distinct patterns of failure of maraviroc. Patients failing with R5 generally had few V3 substitutions and low non-R5 prevalence by deep sequencing. Patients with non-R5 HIV who were failing developed very-high-prevalence non-R5 HIV (median, 99%) and had very low geno2pheno values.
Interactions between Bifidobacterium and Bacteroides Species in Cofermentations Are Affected by Carbon Sources, Including Exopolysaccharides Produced by Bifidobacteria
Authors: Rios-Covian David , Arboleya Silvia , Hernandez-Barranco Ana M. , Alvarez-Buylla Jorge R. , Ruas-Madiedo Patricia , Gueimonde Miguel , de los Reyes-Gavilan Clara G. 
Published: September 2013

ABSTRACT

Cocultures of strains from two
Bifidobacterium
and two
Bacteroides
species were performed with exopolysaccharides (EPS) previously purified from bifidobacteria, with inulin, or with glucose as the carbon source.
Bifidobacterium longum
NB667 and
Bifidobacterium breve
IPLA20004 grew in glucose but showed poor or no growth in complex carbohydrates (inulin, EPS E44, and EPS R1), whereas
Bacteroides
grew well in the four carbon sources tested. In the presence of glucose, the growth of
Bacteroides thetaiotaomicron
DSM-2079 was inhibited by
B. breve
, whereas it remained unaffected in the presence of
B. longum
.
Ba. fragilis
DSM-2151 contributed to a greater survival of
B. longum
, promoting changes in the synthesis of short-chain fatty acids (SCFA) and organic acids in coculture with respect to monocultures. In complex carbohydrates, cocultures of bifidobacterium strains with
Ba. thetaiotaomicron
did not modify the behavior of
Bacteroides
nor improve the poor growth of bifidobacteria. The metabolic activity of
Ba. fragilis
in coculture with bifidobacteria was not affected by EPS, but greater survival of bifidobacteria at late stages of incubation occurred in cocultures than in monocultures, leading to a higher production of acetic acid than in monocultures. Therefore, cocultures of
Bifidobacterium
and
Bacteroides
can behave differently against fermentable carbohydrates as a function of the specific characteristics of the strains from each species. These results stress the importance of considering specific species and strain interactions and not simply higher taxonomic divisions in the relationship among intestinal microbial populations and their different responses to probiotics and prebiotics.
Risk Factors Associated with Salmonella and Listeria monocytogenes Contamination of Produce Fields
Authors: Strawn Laura K. , Gröhn Yrjo T. , Warchocki Steven , Worobo Randy W. , Bihn Elizabeth A. , Wiedmann Martin 
Published: September 2013

ABSTRACT

Identification of management practices associated with preharvest pathogen contamination of produce fields is crucial to the development of effective Good Agricultural Practices (GAPs). A cross-sectional study was conducted to (i) determine management practices associated with a
Salmonella
- or
Listeria monocytogenes
-positive field and (ii) quantify the frequency of these pathogens in irrigation and nonirrigation water sources. Over 5 weeks, 21 produce farms in New York State were visited. Field-level management practices were recorded for 263 fields, and 600 environmental samples (soil, drag swab, and water) were collected and analyzed for
Salmonella
and
L. monocytogenes
. Management practices were evaluated for their association with the presence of a pathogen-positive field.
Salmonella
and
L. monocytogenes
were detected in 6.1% and 17.5% of fields (
n
= 263) and 11% and 30% of water samples (
n
= 74), respectively. The majority of pathogen-positive water samples were from nonirrigation surface water sources. Multivariate analysis showed that manure application within a year increased the odds of a
Salmonella
-positive field (odds ratio [OR], 16.7), while the presence of a buffer zone had a protective effect (OR, 0.1). Irrigation (within 3 days of sample collection) (OR, 6.0), reported wildlife observation (within 3 days of sample collection) (OR, 6.1), and soil cultivation (within 7 days of sample collection) (OR, 2.9) all increased the likelihood of an
L. monocytogenes
-positive field. Our findings provide new data that will assist growers with science-based evaluation of their current GAPs and implementation of preventive controls that reduce the risk of preharvest contamination.
Glycerol-3-Phosphate Acyltransferase Contributes to Triacylglycerol Biosynthesis, Lipid Droplet Formation, and Host Invasion in Metarhizium robertsii
Authors: Gao Qiang , Shang Yanfang , Huang Wei , Wang Chengshu 
Published: September 2013

ABSTRACT

Enzymes involved in the triacylglycerol (TAG) biosynthesis have been well studied in the model organisms of yeasts and animals. Among these, the isoforms of glycerol-3-phosphate acyltransferase (GPAT) redundantly catalyze the first and rate-limiting step in glycerolipid synthesis. Here, we report the functions of mrGAT, a GPAT ortholog, in an insect-pathogenic fungus,
Metarhizium robertsii
. Unlike in yeasts and animals, a single copy of the mrGAT gene is present in the fungal genome and the gene deletion mutant is viable. Compared to the wild type and the gene-rescued mutant, the Δ
mrGAT
mutant demonstrated reduced abilities to produce conidia and synthesize TAG, glycerol, and total lipids. More importantly, we found that mrGAT is localized to the endoplasmic reticulum and directly linked to the formation of lipid droplets (LDs) in fungal cells. Insect bioassay results showed that
mrGAT
is required for full fungal virulence by aiding fungal penetration of host cuticles. Data from this study not only advance our understanding of GPAT functions in fungi but also suggest that filamentous fungi such as
M. robertsii
can serve as a good model to elucidate the role of the glycerol phosphate pathway in fungal physiology, particularly to determine the mechanistic connection of GPAT to LD formation.
Impaired Innate Mucosal Immunity in Aged Mice Permits Prolonged Streptococcus pneumoniae Colonization
Authors: Krone Cassandra L. , Trzciński Krzysztof , Zborowski Tomasz , Sanders Elisabeth A. M. , Bogaert Debby 
Published: October 2013

ABSTRACT

Streptococcus pneumoniae
is a frequent asymptomatic colonizer of the nasopharyngeal niche and only occasionally progresses toward infection. The burden of pneumococcal disease is particularly high in the elderly, and the mechanisms behind this increased susceptibility are poorly understood. Here we used a mouse model of pneumococcal carriage to study immunosenescence in the upper respiratory tract (URT). Nasal mucosa-associated lymphoid tissue (NALT) showed increased expression of Toll-like receptor 1, interleukin-1β, NLRp3 inflammasome, and CCL2 in naive elderly compared to young animals. This suggests an increased proinflammatory expression profile in the NALT of aged mice at baseline. Simultaneously, we observed a more tolerogenic profile in respiratory epithelia of naive elderly compared to young adult mice with upregulation of the NF-κβ pathway inhibitor peroxisome proliferator-activated receptor gamma (PPARγ). After nasal instillation of pneumococci, pneumococcal colonization was prolonged in elderly mice compared to in young adults. The delay in clearance was associated with absent or delayed upregulation of a proinflammatory mediator(s) in the NALT, diminished influx of macrophages into the URT niche, and absent downregulation of PPARγ in respiratory epithelium, accompanied by diminished expression of cathelicidin (CRAMP) at the site of colonization. These findings suggest that unresponsiveness to pneumococcal challenge due to altered mucosal immune regulation is the key to increased susceptibility to disease in the elderly.
Surface Charge of Streptococcus pneumoniae Predicts Serotype Distribution
Authors: Li Yuan , Weinberger Daniel M. , Thompson Claudette M. , Trzciński Krzysztof , Lipsitch Marc 
Published: October 2013

ABSTRACT

Streptococcus pneumoniae
(pneumococcus) frequently colonizes the human nasopharynx and is an important cause of pneumonia, meningitis, sinusitis, and otitis media. The outer cell surface of pneumococcus may assume various degrees of negative charge depending on the polysaccharide capsule, of which more than 90 serotypes have been identified. The negative charge of capsular polysaccharides has been proposed to electrostatically repel pneumococci from phagocytic cells, and avoidance of phagocytosis correlates with higher carriage prevalence. We hypothesized that the surface charge of pneumococcus contributes to its success in nasopharyngeal carriage by modulating resistance to phagocyte-mediated killing. Here, we measured the surface charge (zeta potential) of laboratory-constructed strains that share a genetic background but differ in serotype and of clinical strains that differ in serotype and genetic background. A more negative surface charge correlated with higher resistance to nonopsonic killing by human neutrophils
in vitro
. In addition, a more negative zeta potential was associated with higher carriage prevalence in human populations before and after the widespread use of the pneumococcal conjugate vaccine PCV7. We also confirmed that capsule is the major determinant of net surface charge in clinical isolates with diverse backgrounds. We noted that exceptions exist to the idea that a higher magnitude of negative charge predicts higher prevalence. The results indicated that zeta potential is strongly influenced by pneumococcal capsule type but is unlikely to be the only important mechanism by which capsule interacts with host.
Capsular Sialic Acid of Streptococcus suis Serotype 2 Binds to Swine Influenza Virus and Enhances Bacterial Interactions with Virus-Infected Tracheal Epithelial Cells
Authors: Wang Yingchao , Gagnon Carl A. , Savard Christian , Music Nedzad , Srednik Mariela , Segura Mariela , Lachance Claude , Bellehumeur Christian , Gottschalk Marcelo 
Published: October 2013

ABSTRACT

Streptococcus suis
serotype 2 is an important swine bacterial pathogen, and it is also an emerging zoonotic agent. It is unknown how
S. suis
virulent strains, which are usually found in low quantities in pig tonsils, manage to cross the first host defense lines to initiate systemic disease. Influenza virus produces a contagious infection in pigs which is frequently complicated by bacterial coinfections, leading to significant economic impacts. In this study, the effect of a preceding swine influenza H1N1 virus (swH1N1) infection of swine tracheal epithelial cells (NTPr) on the ability of
S. suis
serotype 2 to adhere to, invade, and activate these cells was evaluated. Cells preinfected with swH1N1 showed bacterial adhesion and invasion levels that were increased more than 100-fold compared to those of normal cells. Inhibition studies confirmed that the capsular sialic acid moiety is responsible for the binding to virus-infected cell surfaces. Also, preincubation of
S. suis
with swH1N1 significantly increased bacterial adhesion to/invasion of epithelial cells, suggesting that
S. suis
also uses swH1N1 as a vehicle to invade epithelial cells when the two infections occur simultaneously. Influenza virus infection may facilitate the transient passage of
S. suis
at the respiratory tract to reach the bloodstream and cause bacteremia and septicemia.
S. suis
may also increase the local inflammation at the respiratory tract during influenza infection, as suggested by an exacerbated expression of proinflammatory mediators in coinfected cells. These results give new insight into the complex interactions between influenza virus and
S. suis
in a coinfection model.
Inequalities in avoidable hospitalisation by area income and the role of individual characteristics: a population-based register study in Stockholm County, Sweden
Authors: Löfqvist Therese , Burström Bo , Walander Anders , Ljung Rickard 
Published: October 2013

BackgroundAvoidable hospitalisations are hospital admissions for medical conditions that could potentially have been prevented by outpatient healthcare. They are used as an indicator of access to and quality of primary healthcare.AimTo investigate the association between median area income and avoidable hospitalisation and whether potential differences can be explained by contextual or compositional factors.MethodMedian area income was calculated for all 43 city districts and municipalities in Stockholm County during 2005–2007 and grouped into quintiles. The association between median area income and avoidable hospitalisation was studied by calculating age-adjusted rates. To disentangle contextual and compositional effects, ORs with 95% CIs were calculated, controlling for individual age, sex, country of birth, marital status and socioeconomic position.ResultsRates of avoidable hospitalisation were higher in areas with lower income, 1535 per 100 000 inhabitants in the lowest area income quintile compared with 1179 in the highest area income quintile after age standardisation. For the age group 18–64 years, comparing the lowest quintile with the highest quintile, adjustment for individual characteristics of residents (compositional factors) reduced the crude OR from 1.52 (95% CI 1.44 to 1.60) to 1.12 (95% CI 1.06 to 1.19). For the age group 65–79 years, the ORs were 1.28 (1.21 to 1.36) and 1.06 (1.00 to 1.13), respectively. For those aged 80+ years, no association was found with area median income.ConclusionsHigher rates of avoidable hospitalisation in low-income areas indicate greater healthcare needs of people living there. This should be addressed by investing in outpatient care for lower socioeconomic groups. The composition of individuals must be considered when studying area characteristics and avoidable hospitalisation.
Reducing unnecessary urinary catheter use and other strategies to prevent catheter-associated urinary tract infection: an integrative review
Authors: Meddings Jennifer , Rogers Mary A M , Krein Sarah L , Fakih Mohamad G , Olmsted Russell N , Saint Sanjay 
Published: September 2013

BackgroundCatheter-associated urinary tract infections (CAUTI) are costly, common and often preventable by reducing unnecessary urinary catheter (UC) use.MethodsTo summarise interventions to reduce UC use and CAUTIs, we updated a prior systematic review (through October 2012), and a meta-analysis regarding interventions prompting UC removal by reminders or stop orders. A narrative review summarises other CAUTI prevention strategies including aseptic insertion, catheter maintenance, antimicrobial UCs, and bladder bundle implementation.Results30 studies were identified and summarised with interventions to prompt removal of UCs, with potential for inclusion in the meta-analyses. By meta-analysis (11 studies), the rate of CAUTI (episodes per 1000 catheter-days) was reduced by 53% (rate ratio 0.47; 95% CI 0.30 to 0.64, p<0.001) using a reminder or stop order, with five studies also including interventions to decrease initial UC placement. The pooled (nine studies) standardised mean difference (SMD) in catheterisation duration (days) was −1.06 overall (p=0.065) including a statistically significant decrease in stop-order studies (SMD −0.37; p<0.001) but not in reminder studies (SMD, −1.54; p=0.071). No significant harm from catheter removal strategies is supported. Limited research is available regarding the impact of UC insertion and maintenance technique. A recent randomised controlled trial indicates antimicrobial catheters provide no significant benefit in preventing symptomatic CAUTIs.ConclusionsUC reminders and stop orders appear to reduce CAUTI rates and should be used to improve patient safety. Several evidence-based guidelines have evaluated CAUTI preventive strategies as well as emerging evidence regarding intervention bundles. Implementation strategies are important because reducing UC use involves changing well-established habits.
Continuing need for and provision of a service for non-standard implant removal
Authors: Pillai Mary , Gazet A Caroline , Griffiths Megan 
Published: October 2013

Background and methodologyInformation is presented on the management of women referred to a sexual health service during a 1-year period for management of a non-palpable contraceptive implant or of a palpable implant considered unsuitable for routine removal.ResultsFifty-two women were referred. Thirty-four implants were non-palpable and their depth on ultrasound ranged from 2.7 to 12 mm. Seventeen were fully or partly palpable and their depth ranged from 3 mm or less (16 cases) to 5.6 mm (one case). Nine had had previous failed attempts at removal, including three with two previous failed attempts. Three implants were located at sites other than the medial aspect of the arm, and were associated with long localisation times. Forty-seven implants were removed at a one-stop clinic appointment through a 2–3 mm incision using ring forceps. The mean time for removal from making the incision to complete extraction was 4.8 minutes. Three cases judged to be of higher risk were removed under local anaesthesia in theatre through a 15 mm incision. These included the only case where removal was attempted unsuccessfully in the outpatient clinic. Seven of the implants were Nexplanon®, including four cases seen during the last month of data collection.ConclusionsRemoval with the technique described is rapid, with an average time of 4–5 minutes, and less than 10 minutes in >90% of cases. Preliminary indications suggest that the introduction of Nexplanon has not resolved the problem of deep implant insertion. Based on our experience we suggest criteria for centres providing removal of deep implants.