bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discovery and Characterization of Substituted Diphenyl Heterocyclic Compounds as Potent and Selective Inhibitors of Hepatitis C Virus Replication
Authors: Huang Peiyong , Goff Dane A. , Huang Qi , Martinez Anthony , Xu Xiang , Crowder Scott , Issakani Sarkiz D. , Anderson Emily , Sheng Ning , Achacoso Philip , Yen Ann , Kinsella Todd , Darwish Ihab S. , Kolluri Rao , Hong Hui , Qu Kunbin , Stauffer Emily , Goldstein Eileen , Singh Rajinder , Payan Donald G. , Lu H. Henry 
Published: January 2008

ABSTRACT
A novel small-molecule inhibitor, referred to here as R706, was discovered in a high-throughput screen of chemical libraries against Huh-7-derived replicon cells carrying autonomously replicating subgenomic RNA of hepatitis C virus (HCV). R706 was highly potent in blocking HCV RNA replication as measured by real-time reverse transcription-PCR and Western blotting of R706-treated replicon cells. Structure-activity iterations of the R706 series yielded a lead compound, R803, that was more potent and highly specific for HCV replication, with no significant inhibitory activity against a panel of HCV-related positive-stranded RNA viruses. Furthermore, HCV genotype 1 replicons displayed markedly higher sensitivity to R803 treatment than a genotype 2a-derived replicon. In addition, R803 was tested by a panel of biochemical and cell-based assays for on-target and off-target activities, and the data suggested that the compound had a therapeutic window close to 100-fold, while its exact mechanism of action remained elusive. We found that R803 was more effective than alpha interferon (IFN-α) at blocking HCV RNA replication in the replicon model. In combination studies, R803 showed a weak synergistic effect with IFN-α/ribavirin but only additive effects with a protease inhibitor and an allosteric inhibitor of RNA-dependent RNA polymerase (20). We conclude that R803 and related heterocyclic compounds constitute a new class of HCV-specific inhibitors that could potentially be developed as a treatment for HCV infection.
Killing of
Neisseria gonorrhoeae, Streptococcus agalactiae
(Group B Streptococcus),
Haemophilus ducreyi
, and Vaginal
Lactobacillus
by 3-
O
-Octyl-
sn
-Glycerol
Authors: Moncla B. J. , Pryke K. , Isaacs Charles E. 
Published: January 2008

ABSTRACT
The microbicide candidate octylglycerol inactivates sexually transmitted bacterial pathogens at concentrations which spare normal vaginal flora (lactobacillus). Standard minimum microbicidal concentration assays and time-kill assays revealed the drug concentrations and times required for inactivation. Octylglycerol concentrations must exceed the binding capacity of any human serum albumin to be effective.
Pharmacodynamics of the Antibacterial Effect and Emergence of Resistance to Tomopenem, Formerly RO4908463/CS-023, in an In Vitro Pharmacokinetic Model of
Staphylococcus aureus
Infection
Authors: MacGowan Alasdair P. , Bowker Karen E. , Noel Alan R. 
Published: January 2008

ABSTRACT

The antibacterial effects (ABE) of tomopenem (formerly RO4908463/CS-023) against seven
Staphylococcus aureus
strains (methicillin-resistant
S. aureus
[MRSA] strain tomopenem MICs, 0.5 to 16 mg/liter; methicillin-sensitive
S. aureus
[MSSA] strain tomopenem MIC, 0.06 mg/liter) were studied in an in vitro pharmacokinetic model. Initially, two human doses were simulated, 750 mg every 8 hours (8hly) and 1,500 mg 8hly intravenously, using
S. aureus
at a standard inoculum of 10
6
CFU/ml. There was a rapid clearance of bacteria from the model by 12 h after drug exposure with most strains. Clearance was not related to the tomopenem MIC. The ABE of these two tomopenem dose regimens were also tested at a high inoculum, 10
8
CFU/ml; in all simulations, there was a >4-log drop in viable count at 24 h. Strains were not cleared from the model at 10
8
CFU/ml, in contrast to what was seen for the standard inoculum. When the ABE of tomopenem at 750 mg 8hly was compared to those of vancomycin, tomopenem was seen to have a superior effect, as measured by the area under the bacterial kill curve at 24 h (AUBKC
24
) and 48 h (
P
< 0.05). Dose ranging studies were performed to provide time-above-MIC (T>MIC) drug exposures of 0 to 100% (8 to 10 doses per strain) with five MRSA/MSSA strains. The T>MIC for a 24-h bacteriostatic effect was 8% ± 5% (range, 1.3% to 15.4%); the T>MIC for a 4-log drop in viable count was 32% ± 18% (range, 12.8% to 36.2%). The T>MIC for a 90% maximum response using AUBKC
24
as ABE was 24.9% ± 15.7%. Inoculum had little impact on T>MIC exposures for ABE. There was emergence of resistance to tomopenem in the dose ranging studies, with increased growth of subpopulations on plates containing tomopenem at 2× and 4× the MIC compared to what was seen for preexposure population analysis at T>MICs of <20%. The pharmacodynamics of tomopenem against
S. aureus
is similar to those of other members of the carbapenem class, with the exception that MRSA is included. These data indicate that tomopenem will have clinically useful activity against MRSA at T>MICs achievable in humans.
In Vitro and In Vivo Antifungal Activities of T-2307, a Novel Arylamidine
Authors: Mitsuyama Junichi , Nomura Nobuhiko , Hashimoto Kyoko , Yamada Eio , Nishikawa Hiroshi , Kaeriyama Makoto , Kimura Akiko , Todo Yozo , Narita Hirokazu 
Published: January 2008

ABSTRACT

The in vitro and in vivo antifungal activities of T-2307, a novel arylamidine, were evaluated and compared with those of fluconazole, voriconazole, micafungin, and amphotericin B. T-2307 exhibited broad-spectrum activity against clinically significant pathogens, including
Candida
species (MIC range, 0.00025 to 0.0078 μg/ml),
Cryptococcus neoformans
(MIC range, 0.0039 to 0.0625 μg/ml), and
Aspergillus
species (MIC range, 0.0156 to 4 μg/ml). Furthermore, T-2307 exhibited potent activity against fluconazole-resistant and fluconazole-susceptible-dose-dependent
Candida albicans
strains as well as against azole-susceptible strains. T-2307 exhibited fungicidal activity against some
Candida
and
Aspergillus
species and against
Cryptococcus neoformans
. In mouse models of disseminated candidiasis, cryptococcosis, and aspergillosis, the 50% effective doses of T-2307 were 0.00755, 0.117, and 0.391 mg·kg
−1
·dose
−1
, respectively. This agent was considerably more active than micafungin and amphotericin B against candidiasis and than amphotericin B against cryptococcosis, and its activity was comparable to the activities of micafungin and amphotericin B against aspergillosis. The results of preclinical in vitro and in vivo evaluations performed thus far indicate that T-2307 could represent a potent injectable agent for the treatment of candidiasis, cryptococcosis, and aspergillosis.
In Vitro Phenotypic Susceptibility of Human Immunodeficiency Virus Type 2 Clinical Isolates to Protease Inhibitors
Authors: Desbois Delphine , Roquebert Bénédicte , Peytavin Gilles , Damond Florence , Collin Gilles , Bénard Antoine , Campa Pauline , Matheron Sophie , Chêne Geneviève , Brun-Vézinet Françoise , Descamps Diane 
Published: January 2008

ABSTRACTWe determine phenotypic susceptibility of human immunodeficiency virus type 2 (HIV-2) isolates to amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, saquinavir, and tipranavir. Saquinavir, lopinavir, and darunavir are potent against wild-type HIV-2 isolates and should be preferred as first-line options for HIV-2-infected patients. Other protease inhibitors are less active against HIV-2 than against HIV-1.
MyD88 Negatively Controls Hypergammaglobulinemia with Autoantibody Production during Bacterial Infection
Authors: Woods Anne , Soulas-Sprauel Pauline , Jaulhac Benoit , Arditi Bérénice , Knapp Anne-Marie , Pasquali Jean-Louis , Korganow Anne-Sophie , Martin Thierry 
Published: January 2008

ABSTRACT

A large body of evidence has convincingly shown that Toll-like receptors are necessary sensors for infections with pathogens, but their activation was also suggested to generate autoimmunity. During experimental infections, the lack of these sensors or of their signaling molecules should lead to a deficient immune response. We found out that MyD88, the major adaptor of the Toll/interleukin-1 (Toll/IL-1) receptor signaling pathway, can actually act as a negative regulator of B-cell function in some settings. MyD88-deficient mice infected by
Borrelia burgdorferi
developed extreme hypergammaglobulinemia compared to wild-type animals, with high levels of immunoglobulin M (IgM) autoantibodies. In vivo, cell transfer experiments and cell blocking assays showed that this phenotype was not linked to the absence of MyD88 in B cells but rather to CD4 T-cell and likely dendritic cell dysfunctions leading to a Th1-to-Th2 cytokine switch. In addition, our results suggest a relative defect in the Ig class switch recombination process, since MyD88 knockout mice developed mostly IgM antibodies. Collectively, these data emphasize the complex role of the Toll/IL-1 receptor pathway in tuning the immune response against infection and avoiding autoimmunity.
Capsular Antigen Fraction 1 and Pla Modulate the Susceptibility of
Yersinia pestis
to Pulmonary Antimicrobial Peptides Such as Cathelicidin
Authors: Galván Estela M. , Lasaro Melissa A. S. , Schifferli Dieter M. 
Published: January 2008

ABSTRACT

Inhaled
Yersinia pestis
produces a severe primary pneumonia known as pneumonic plague, which is contagious and highly lethal to humans and animals. In this study, we first determined the susceptibility of
Y. pestis
KIM6 to antimicrobial molecules of the airways. We found that (i) rat bronchoalveolar lavage fluid (rBALF) effectively killed KIM6 cells growing at 37°C; (ii) the antibacterial components of rBALF were small peptides (<10 kDa) that included two cationic antimicrobial peptides (CAMPs), the rat cathelicidin rCRAMP, and β-defensin RBD-1; (iii) the human cathelicidin LL-37 killed KIM6 cells as well as rBALF did; and (iv) the bactericidal property of LL-37 was synergistically amplified by human β-defensin 1, another constitutively expressed pulmonary CAMP. Second, the effects of three major surface proteins of
Y. pestis
, namely, the capsular antigen fraction 1 (F1), the pH 6 antigen (Psa fimbriae), and the outer membrane protease Pla, on the bactericidal effect of the antimicrobial rBALF peptides was determined with corresponding deletion mutants. We showed that (i) a
Y. pestis psa
mutant was only slightly more susceptible to rBALF than the parental KIM6 strain, (ii) a
caf
(F1 gene) mutant and a
caf psa
mutant were resistant to rBALF or LL-37, (iii) a
caf pla
mutant was as susceptible to the effect of rBALF or LL-37 as KIM6 was (
caf
+
pla
+
), and (iv) only the single
caf
mutant (
pla
+
), but not KIM6 or the
caf pla
double mutant, degraded LL-37. The activity of Pla toward LL-37 was confirmed with
pla
mutants carrying a single-residue substitution affecting plasminogen cleavage. Taken together, our data indicated that Pla might act as a virulence factor not only by processing plasminogen but also by inactivating CAMPs, particularly when F1 is not expressed.
Mining the
Moraxella catarrhalis
Genome: Identification of Potential Vaccine Antigens Expressed during Human Infection
Authors: Ruckdeschel Elizabeth A. , Kirkham Charmaine , Lesse Alan J. , Hu Zihua , Murphy Timothy F. 
Published: January 2008

ABSTRACT

Moraxella catarrhalis
is an important cause of respiratory infections in adults and otitis media in children. Developing an effective vaccine would reduce the morbidity, mortality, and costs associated with such infections. An unfinished genome sequence of a strain of
M. catarrhalis
available in the GenBank database was analyzed, and open reading frames predicted to encode potential vaccine candidates were identified. Three genes encoding proteins having molecular masses of approximately 22, 75, and 78 kDa (designated Msp [
Moraxella s
urface
p
roteins]) (
msp22
,
msp75
, and
msp78
, respectively) were determined to be conserved by competitive hybridization using a microarray, PCR, and sequencing of the genes in clinical isolates of
M. catarrhalis
. The genes were transcribed when
M. catarrhalis
was grown in vitro. These genes were amplified by PCR and cloned into
Escherichia coli
expression vectors. Recombinant proteins were generated and then studied using enzyme-linked immunosorbent assays with preacquisition and postclearance serum and sputum samples from 31 adults with chronic obstructive pulmonary disease (COPD) who acquired and cleared
M. catarrhalis
. New antibody responses to the three proteins were observed for a small proportion of the patients with COPD, indicating that these proteins were expressed during human infection. These studies indicate that the Msp22, Msp75, and Msp78 proteins, whose genes were discovered using genome mining, are highly conserved among strains, are expressed during human infection with
M. catarrhalis
, and represent potential vaccine antigens.
αB-Crystallin Protects Retinal Tissue during
Staphylococcus aureus
- Induced Endophthalmitis
Authors: Whiston Emily A. , Sugi Norito , Kamradt Merideth C. , Sack Coralynn , Heimer Susan R. , Engelbert Michael , Wawrousek Eric F. , Gilmore Michael S. , Ksander Bruce R. , Gregory Meredith S. 
Published: January 2008

ABSTRACT

Bacterial infections of the eye highlight a dilemma that is central to all immune-privileged sites. On the one hand, immune privilege limits inflammation to prevent bystander destruction of normal tissue and loss of vision. On the other hand, bacterial infections require a robust inflammatory response for rapid clearance of the pathogen. We demonstrate that the retina handles this dilemma, in part, by activation of a protective heat shock protein. During
Staphylococcus aureus
-induced endophthalmitis, the small heat shock protein αB-crystallin is upregulated in the retina and prevents apoptosis during immune clearance of the bacteria. In the absence of αB-crystallin, mice display increased retinal apoptosis and retinal damage. We found that
S. aureus
produces a protease capable of cleaving αB-crystallin to a form that coincides with increased retinal apoptosis and tissue destruction. We conclude that αB-crystallin is important in protecting sensitive retinal tissue during destructive inflammation that occurs during bacterial endophthalmitis.
Vibrio vulnificus
Biotype 2 Serovar E
gne
but Not
galE
Is Essential for Lipopolysaccharide Biosynthesis and Virulence
Authors: Valiente Esmeralda , Jiménez Natalia , Merino Susana , Tomás Juan M. , Amaro Carmen 
Published: January 2008

ABSTRACT

This work aimed to establish the role of
gne
(encoding UDP-GalNAc 4-epimerase activity) and
galE
(encoding UDP-Gal-4-epimerase activity) in the biosynthesis of surface polysaccharides, as well as in the virulence for eels and humans of the zoonotic serovar of
Vibrio vulnificus
biotype 2, serovar E. DNA sequence data revealed that
gne
and
galE
are quite homologous within this species (≥90% homology). Mutation in
gne
of strain CECT4999 increased the surface hydrophobicity, produced deep alterations in the outer membrane architecture, and resulted in noticeable increases in the sensitivity to microcidal peptides (MP), to eel and human sera, and to phagocytosis/opsonophagocytosis. Furthermore, significant attenuation of virulence for eels and mice was observed. By contrast, mutation in
galE
did not alter the cellular surface, did not increase the sensitivity to MP, serum, or phagocytosis, and did not affect the virulence for fish and mice. The change in the attenuated-virulence phenotype produced by a mutation in
gne
was correlated with the loss of the O-antigen lipopolysaccharide (LPS), while the capsule was maintained. Complementation of a
gne
-deficient mutant restored the LPS structure together with the whole virulence phenotype. In conclusion,
gne
, but not
galE
, is essential for LPS biosynthesis and virulence in the zoonotic serovar of
V. vulnificus
biotype 2.
The Sho1 Sensor Regulates Growth, Morphology, and Oxidant Adaptation in
Aspergillus fumigatus
but Is Not Essential for Development of Invasive Pulmonary Aspergillosis
Authors: Ma Yan , Qiao Jianjun , Liu Wei , Wan Zhe , Wang Xiaohong , Calderone Richard , Li Ruoyu 
Published: January 2008

ABSTRACT

Aspergillus fumigatus
is an important opportunistic fungal pathogen. This organism must be able to adapt to stress changes in the microenvironment during host invasion and systemic spread. The high-osmolarity-glycerol (HOG) mitogen-activated protein kinase (HOG-MAPK) signaling pathway plays an important role in regulating morphology, growth, and adaptation to stress and virulence in a number of fungal pathogens. The Sho1 adaptor protein is one important element of the two upstream branches of the HOG-MAPK pathway in
Saccharomyces cerevisiae
, a signal transduction cascade involved in adaptation to stress. We constructed a
sho1
mutant of
A. fumigatus
, MA21. Both the growth and germination rates of the mutant were reduced, and the MA21 strain had an irregular hyphal morphology characterized by reduced production of phialides and conidia. This gene deletion mutant was sensitive to 2.5 mM hydrogen peroxide and 15 μM menadione, but it appeared to be minimally sensitive to diamide compared to the wild-type strain. In an immunosuppressed mouse model, the mutant was as virulent as the wild-type or complemented strains. These data support the idea that the loss of
sho1
, a highly conserved gene among fungi, regulates radial hyphal growth and delays germination of
A. fumigatus
conidia. In addition, the
sho1
gene has a visible effect in the adaptation to oxidative stress in
A. fumigatus
similar to that in
S. cerevisiae
.
Braun Lipoprotein (Lpp) Contributes to Virulence of Yersiniae: Potential Role of Lpp in Inducing Bubonic and Pneumonic Plague
Authors: Sha Jian , Agar Stacy L. , Baze Wallace B. , Olano Juan P. , Fadl Amin A. , Erova Tatiana E. , Wang Shaofei , Foltz Sheri M. , Suarez Giovanni , Motin Vladimir L. , Chauhan Sadhana , Klimpel Gary R. , Peterson Johnny W. , Chopra Ashok K. 
Published: January 2008

ABSTRACTYersinia pestisevolved fromY. pseudotuberculosisto become the causative agent of bubonic and pneumonic plague. We identified a homolog of theSalmonella entericaserovar Typhimurium lipoprotein (lpp) gene inYersiniaspecies and preparedlppgene deletion mutants ofY. pseudotuberculosisYPIII,Y. pestisKIM/D27 (pigmentation locus minus), andY. pestisCO92 with reduced virulence. Mice injected via the intraperitoneal route with 5 × 107CFU of the ΔlppKIM/D27 mutant survived a month, even though this would have constituted a lethal dose for the parental KIM/D27 strain. Subsequently, these ΔlppKIM/D27-injected mice were solidly protected against an intranasally administered, highly virulentY. pestisCO92 strain when it was given as five 50% lethal doses (LD50). In a parallel study with the pneumonic plague mouse model, after 72 h postinfection, the lungs of animals infected with wild-type (WT)Y. pestisCO92 and given a subinhibitory dose of levofloxacin had acute inflammation, edema, and masses of bacteria, while the lung tissue appeared essentially normal in mice inoculated with the Δlppmutant of CO92 and given the same dose of levofloxacin. Importantly, while WTY. pestisCO92 could be detected in the bloodstreams and spleens of infected mice at 72 h postinfection, the Δlppmutant of CO92 could not be detected in those organs. Furthermore, the levels of cytokines/chemokines detected in the sera were significantly lower in animals infected with the Δlppmutant than in those infected with WT CO92. Additionally, the Δlppmutant was more rapidly killed by macrophages than was the WT CO92 strain. These data provided evidence that the Δlppmutants of yersiniae were significantly attenuated and could be useful tools in the development of new vaccines.
High-power (80 W) potassium titanyl phosphate laser prostatectomy in 128 high-risk patients
Authors: Yuan J , Wang H , Wu G , Liu H , Zhang Y , Yang L 
Published: January 2008

Abstract

Objective
To evaluate the safety and merits of 80 W potassium titanyl phosphate (KTP) laser prostatectomy in men with high cardiovascular or pulmonary risk, receiving oral anticoagulant medication, or with bleeding disorders.

Methods
A prospective clinical trial was performed in 128 high-risk men with benign prostatic hyperplasia who underwent photoselective vaporisation of the prostate (PVP). The operation time, postoperative serum sodium and packed cell volume were recorded. The International Prostate Symptom Score (IPSS), maximal flow rate (Qmax) and post-void residual urine volume (PVR) were measured at every follow-up visit.

Results
In all patients, KTP laser prostatectomy was performed successfully. The mean (SD) operation time was 51.6 (22.8) min. No blood transfusions were required. No major complications occurred during surgery, and there was no mortality. The mean (SD) catheterisation time was 2.8 (1.6) days. IPSS decreased from 19.2 (6.1) before surgery to 11.5 (8.2), 7.8 (6.4), 6.7 (5.3) and 6.1 (4.6), respectively, at 1, 3, 6 and 12 months after. Qmax increased from 7.0 (2.8) ml/s to 14.5 (9.3), 20.2 (11.5), 21.3 (8.6) and 24.8 (8.0) ml/s, respectively. PVR decreased from 168 (89) ml to 35 (29), 30 (26), 27 (21) and 23 (34) ml, respectively.

Conclusions
80 W KTP laser prostatectomy is a virtually bloodless, safe and effective procedure for men with high cardiovascular or pulmonary risk or bleeding disorders or taking oral anticoagulant medication.
Multiple physical urticarias
Authors: Torchia D , Francalanci S , Bellandi S , Fabbri P 
Published: January 2008

Abstract
Physical urticarias are a group of mucocutaneous disorders characterised by the appearance of whealing and/or angioedema and induced by physical stimuli. A 24-year-old Caucasian male affected by ultraviolet A-induced solar urticaria, specific food-dependent exercise-induced anaphylaxis, symptomatic dermographism and allergic rhinoconjunctivitis is described.
Sleep-disordered breathing and cardiovascular disease
Authors: Amit Benjamin J , Lewis K E 
Published: January 2008

Abstract
Sleep-disordered breathing (SDB) describes a group of disorders characterised by abnormalities in the frequency and/or depth of breathing while asleep. The most common type is the obstructive sleep apnoea/hypopnoea syndrome (OSAHS); it affects 2–4% of the adult population and is an independent risk factor for hypertension. Another type is central sleep apnoea (CSA), which includes Cheyne–Stokes respiration; it is most commonly seen in patients with congestive heart failure and other critical illnesses including cerebrovascular accidents. There is accumulating evidence that both these types of SDB are associated with cardiac failure, arrhythmias and coronary artery disease. Treatment of OSAHS with continuous positive airway pressure (CPAP) has lowered blood pressure, reduced the frequency and severity of some arrhythmias, and improved markers of endovascular inflammation. CPAP has had a mild positive effect on left ventricular function in chronic heart failure by treating co-existent SDB, but it has not improved mortality, possibly because it does not fully treat associated CSA. Clinicians need to be aware of the increasing associations of SDB, especially OSAHS, with cardiovascular dysfunction, as treatment of co-existent SDB will not only improve sleepiness, quality of life, and driving risk, but there is growing evidence that it may also improve cardiovascular risk itself, even in non-sleepy subjects.