bluuebunny/crossref_metadata_2025_split huggingface dataset:
The invariance of the total direct DNA strand break yield
Authors: Bernal M. A. , deAlmeida C. E. , Sampaio C. , Incerti S. , Champion C. , Nieminen P. 
Published: June 2011

Purpose:The invariance of the total direct strand break yield when DNA is irradiated by different types of particles and energies has been reported by previous works. This study is intended to explain the physical causes of this behavior.Methods:Thegeant4‐dna extension of the geant4 general purpose Monte Carlo simulation toolkit has been used to determine direct strand break yields induced by protons and alpha particles impacting on a B‐DNA geometrical model, including five organization levels of the human genetic material. The linear energy transfer (LET) of such particles ranges from 4.8 keV/μm (10 MeV protons) to about 235 keV/μm (2 MeV alpha particles), at 5.225 μm depth (near the center of the region of interest). Direct total, single and double strand break probabilities have been determined in a liquid water homogeneous medium with a 1.06 g/cm density. The energetic spectra of single strand breaks (SSB), the number of energy deposition events, and the SSB/event ratio were determined.Results:The target‐hit probability was found to be independent of both the type and the energy of the incident particle, even if this latter is a secondary electron. This probability is determined by the geometrical properties of the system. The total strand break yield and the number of energy deposition events required to reach a certain absorbed dose were found nearly independent of the type and energy of the incident ion (proton or alpha). In contrast, the double strand break (DSB) yield was found strongly dependent on the LET of the incident radiation.Conclusions:The SSB generation process is homogeneous and independent of the LET of the particles involved, at least within the proton and alpha particle energy range here studied. The target‐hit probability is only determined by the ratio between the total volume occupied by targets and that of the ROI where the radiation deposits its energy. The maximum separation distance between two adjacent SSBs to produce a DSB is the parameter that breaks the homogeneity of the target‐hit process, making the DSB production process strongly heterogeneous.
Daptomycin Antibiotic Lock Therapy in a Rat Model of Staphylococcal Central Venous Catheter Biofilm Infections
Authors: Van Praagh Andrew D. G. , Li Tongchuan , Zhang Shuxin , Arya Anu , Chen Liping , Zhang Xi-Xian , Bertolami Shellie , Mortin Lawrence I. 
Published: June 2011

ABSTRACT

Antibiotic lock therapy (ALT) is an adjunctive procedure to prevent or treat central venous catheter infections, ensuing catheter-related bacteremia, and catheter-related metastatic infections. Daptomycin is a cyclic lipopeptide that is rapidly bactericidal against methicillin-susceptible and -resistant
Staphylococcus aureus
. The efficacies of daptomycin against central venous catheter biofilms, catheter-related bacteremia, and catheter-related metastatic infections were evaluated by adapting a previously reported central venous catheter biofilm model in rats. Combined daptomycin ALT and systemic dosing resulted in the clearance of an established
in vivo S. aureus
central venous catheter biofilm after just two daily ALT treatments (30 min with daptomycin at 5 mg/ml) with concurrent systemic daptomycin dosing (40 mg/kg of body weight/day subcutaneously [s.c.]; equivalent exposure of 6 mg/kg/day in people). Daptomycin ALT solutions formulated in either saline or lactated Ringer's solution were equally fast in eradicating established
in vivo
methicillin-resistant
Staphylococcus epidermidis
(MRSE) central venous catheter biofilms. However, the lactated Ringer's formulation was superior to that of saline in sustaining the bacterial clearance of treated central venous catheters (83% versus 50%). In MRSE-infected central venous catheter studies, 3 days of daptomycin or vancomycin ALT (18 h at 5 mg/ml) with systemic s.c. dosing (40 mg/kg/day daptomycin or 100 mg/kg/day vancomycin) was equally effective 1 week posttherapy in maintaining cleared central venous catheters (90% [
n
= 10] versus 100% [
n
= 8]). These results suggest that daptomycin ALT, along with systemic dosing, could be an effective treatment option for the prevention or eradication of staphylococcal central venous catheter biofilm infections, thereby reducing the occurrence of catheter-related bacteremia or catheter-related metastatic infections.
Novel Trichomonacidal Spermicides
Authors: Jain Ashish , Lal Nand , Kumar Lokesh , Verma Vikas , Kumar Rajeev , Kumar Lalit , Singh Vishal , Mishra Raghav K. , Sarswat Amit , Jain S. K. , Maikhuri J. P. , Sharma V. L. , Gupta Gopal 
Published: June 2011

ABSTRACT

Metronidazole, the U.S. Food and Drug Administration-approved drug against trichomoniasis, is nonspermicidal and thus cannot offer pregnancy protection when used vaginally. Furthermore, increasing resistance of
Trichomonas vaginalis
to 5-nitro-imidazoles is a cause for serious concern. On the other hand, the vaginal spermicide nonoxynol-9 (N-9) does not protect against sexually transmitted diseases and HIV in clinical situations but may in fact increase their incidence due to its nonspecific, surfactant action. We therefore designed dually active, nonsurfactant molecules that were capable of killing
Trichomonas vaginalis
(both metronidazole-susceptible and -resistant strains) and irreversibly inactivating 100% human sperm at doses that were noncytotoxic to human cervical epithelial (HeLa) cells and vaginal microflora (lactobacilli)
in vitro
. Anaerobic energy metabolism, cell motility, and defense against reactive oxygen species, which are key to survival of both sperm and
Trichomonas
in the host after intravaginal inoculation, depend crucially on availability of free thiols. Consequently, molecules were designed with carbodithioic acid moiety as the major pharmacophore, and chemical variations were incorporated to provide high excess of reactive thiols for interacting with accessible thiols on sperm and
Trichomonas
. We report here the
in vitro
activities, structure-activity relationships, and safety profiles of these spermicidal antitrichomonas agents, the most promising of which was more effective than N-9 (the OTC spermicide) in inactivating human sperm and more efficacious than metronidazole in killing
Trichomonas vaginalis
(including metronidazole-resistant strain). It also significantly reduced the available free thiols on human sperm and inhibited the cytoadherence of
Trichomonas
on HeLa cells. Experimentally
in vitro
, the new compounds appeared to be safer than N-9 for vaginal use.
Melatonin Attenuates Colistin-Induced Nephrotoxicity in Rats
Authors: Yousef Jumana M. , Chen Gong , Hill Prue A. , Nation Roger L. , Li Jian 
Published: June 2011

ABSTRACT

Colistin-induced nephrotoxicity is a dose-limiting adverse effect when colistin is used against Gram-negative pathogens. This study examined the nephroprotective effect of melatonin against colistin in rats. Rats (
n
= 7 per group) were treated intravenously twice daily with saline, colistin (at increasing doses from 0.5 to 4.0 mg/kg), melatonin (5 mg/kg), or both melatonin and colistin for 7 days. The severity of renal alteration was examined both biochemically and histologically. The effect of coadministration of melatonin on colistin pharmacokinetics was investigated. Significantly lower urinary
N
-acetyl-β-
d
-glucosaminidase excretion was observed from day 1 in the colistin-melatonin group compared to the colistin group (
P
< 0.0001). Plasma creatinine increased significantly (
P
= 0.023) only in the colistin group on day 6. Significant histological abnormalities (
P
< 0.0001) were detected only in the kidneys of the colistin group. Melatonin altered colistin pharmacokinetics; the total body clearance in the colistin-melatonin group (1.82 ± 0.26 ml/min/kg) was lower than in the colistin group (4.28 ± 0.93 ml/min/kg). This is the first study demonstrating the protective effect of melatonin against colistin-induced nephrotoxicity, which indicates that colistin-induced nephrotoxicity is mediated through oxidative stress. It also highlights the potential of coadministering an antioxidant to widen the therapeutic window of this very important last-line antibiotic.
Polymorphisms in Isoniazid and Prothionamide Resistance Genes of the Mycobacterium tuberculosis Complex
Authors: Projahn Michaela , Köser Claudio U. , Homolka Susanne , Summers David K. , Archer John A. C. , Niemann Stefan 
Published: June 2011

ABSTRACT

Sequence analyses of 74 strains that encompassed major phylogenetic lineages of the
Mycobacterium tuberculosis
complex revealed 10 polymorphisms in
mshA
(
Rv0486
) and four polymorphisms in
inhA
(
Rv1484
) that were not responsible for isoniazid or prothionamide resistance. Instead, some of these mutations were phylogenetically informative. This genetic diversity must be taken into consideration for drug development and for the design of molecular tests for drug resistance.
Coresistance to Isoniazid and Ethionamide Maps to Mycothiol Biosynthetic Genes in Mycobacterium bovis
Authors: Vilchèze Catherine , Av-Gay Yossef , Barnes S. Whitney , Larsen Michelle H. , Walker John R. , Glynne Richard J. , Jacobs William R. 
Published: June 2011

ABSTRACT

A search to identify new mechanisms of isoniazid resistance in
Mycobacterium bovis
led to the isolation of mutants defective in mycothiol biosynthesis due to mutations in genes coding for the glycosyltransferase (
mshA
) or the cysteine ligase (
mshC
). These mutants showed low-level resistance to isoniazid but were highly resistant to ethionamide. This study further illustrates that mutations in mycothiol biosynthesis genes may contribute to isoniazid or ethionamide resistance across mycobacterial species.
Identification of a Novel Benzimidazole That Inhibits Bacterial Biofilm Formation in a Broad-Spectrum Manner
Authors: Sambanthamoorthy Karthik , Gokhale Ankush A. , Lao Weiwei , Parashar Vijay , Neiditch Matthew B. , Semmelhack Martin F. , Lee Ilsoon , Waters Christopher M. 
Published: June 2011

ABSTRACT

Bacterial biofilm formation causes significant industrial economic loss and high morbidity and mortality in medical settings. Biofilms are defined as multicellular communities of bacteria encased in a matrix of protective extracellular polymers. Because biofilms have a high tolerance for treatment with antimicrobials, protect bacteria from immune defense, and resist clearance with standard sanitation protocols, it is critical to develop new approaches to prevent biofilm formation. Here, a novel benzimidazole molecule, named antibiofilm compound 1 (ABC-1), identified in a small-molecule screen, was found to prevent bacterial biofilm formation in multiple Gram-negative and Gram-positive bacterial pathogens, including
Pseudomonas aeruginosa
and
Staphylococcus aureus
, on a variety of different surface types. Importantly, ABC-1 itself does not inhibit the growth of bacteria, and it is effective at nanomolar concentrations. Also, coating a polystyrene surface with ABC-1 reduces biofilm formation. These data suggest ABC-1 is a new chemical scaffold for the development of antibiofilm compounds.
In Vitro
Spectrum of Activity of Finafloxacin, a Novel, pH-Activated Fluoroquinolone, under Standard and Acidic Conditions
Authors: Stubbings Will , Leow Pamela , Yong Goh Chee , Goh Falicia , Körber-Irrgang Barbara , Kresken Michael , Endermann Rainer , Labischinski Harald 
Published: June 2011

ABSTRACT

Finafloxacin is a novel fluoroquinolone that exhibits enhanced antibacterial activity under acidic conditions. The aim of this study was to define the
in vitro
pH-activity relationship. Finafloxacin exhibited optimal antibacterial activity between pH 5.0 and 6.0 at which MICs were 4- to 8-fold lower than those determined at neutral pH. These observations were then confirmed against a larger collection of bacteria. These data suggest that finafloxacin could potentially offer a therapeutic advantage within acidic foci of infection.
The
SLCO1B1
rs4149032 Polymorphism Is Highly Prevalent in South Africans and Is Associated with Reduced Rifampin Concentrations: Dosing Implications
Authors: Chigutsa Emmanuel , Visser Marianne E. , Swart Elizabeth C. , Denti Paolo , Pushpakom Sudeep , Egan Deirdre , Holford Nicholas H. G. , Smith Peter J. , Maartens Gary , Owen Andrew , McIlleron Helen 
Published: June 2011

ABSTRACT

Among patients with tuberculosis, rifampin plasma concentrations and sputum conversion rates have been reported to be lower in Africans. Rifampin is a substrate of P-glycoprotein (coded for by the
ABCB1
gene) and organic anion-transporting polypeptide 1B1 (coded for by
SLCO1B1
). The objectives were to identify genetic polymorphisms of drug transporters and the transcriptional regulators pregnane X receptor (PXR) and constitutive androstane receptor (CAR) with an impact on rifampin pharmacokinetics in South Africans. Fifty-seven patients with tuberculosis from Cape Town underwent pharmacokinetic sampling during treatment with rifampin, pyrazinamide, isoniazid, and ethambutol. DNA was genotyped for
ABCB1
,
SLCO1B1
,
PXR
, and
CAR
polymorphisms by using real-time PCR. NONMEM was used for data analysis. The allele frequency of the
SLCO1B1
rs4149032 polymorphism was 0.70. Patients heterozygous and homozygous for this polymorphism had reductions in the bioavailability (and, thus, the area under the curve [AUC]) of rifampin of 18% and 28%, respectively. Simulations showed that increasing the daily rifampin dose by 150 mg in patients with the polymorphism would result in plasma concentrations similar to those of wild-type individuals and reduce the percentage of patients with peak plasma concentrations (
C
max
) below 8 mg/liter from 63% to 31%.
ABCB1
,
PXR
, and
CAR
polymorphisms were not associated with differences in rifampin pharmacokinetics.
SLCO1B1
rs4149032 was present in most patients and was associated with substantially reduced rifampin exposure. These data suggest that the standard recommended dose of rifampin should be reconsidered for South Africans.
Complement-Mediated Bactericidal Activity of Anti-Factor H Binding Protein Monoclonal Antibodies against the Meningococcus Relies upon Blocking Factor H Binding
Authors: Giuntini Serena , Reason Donald C. , Granoff Dan M. 
Published: June 2011

ABSTRACTBinding of the complement-downregulating protein factor H (fH) to the surface of the meningococcus is important for survival of the organism in human serum. The meningococcal vaccine candidate factor H binding protein (fHbp) is an important ligand for human fH. While some fHbp-specific monoclonal antibodies (MAbs) block binding of fH to fHbp, the stoichiometry of blocking in the presence of high serum concentrations of fH and its effect on complement-mediated bactericidal activity are unknown. To investigate this question, we constructed chimeric antibodies in which the human IgG1 constant region was paired with three murine fHbp-specific binding domains designated JAR 3, JAR 5, and MAb502. By surface plasmon resonance, the association rates for binding of all three MAbs to immobilized fHbp were >50-fold higher than that for binding of fH to fHbp, and the MAb dissociation rates were >500-fold lower than that for fH. While all three MAbs elicited similar C1q-dependent C4b deposition on live bacteria (classical complement pathway), only those antibodies that inhibited binding of fH to fHbp (JAR 3 and JAR 5) had bactericidal activity with human complement. MAb502, which did not inhibit fH binding, had complement-mediated bactericidal activity only when tested with fH-depleted human complement. When an IgG1 anti-fHbp MAb binds to sparsely exposed fHbp on the bacterial surface, there appears to be insufficient complement activation for bacteriolysis unless fH binding also is inhibited. The ability of fHbp vaccines to elicit protective antibodies, therefore, is likely to be enhanced if the antibody repertoire is of high avidity and includes fH-blocking activity.
Caspase-1 Activation of Interleukin-1β (IL-1β) and IL-18 Is Dispensable for Induction of Experimental Cerebral Malaria
Authors: Kordes Maximilian , Matuschewski Kai , Hafalla Julius Clemence R. 
Published: June 2011

ABSTRACT

Malaria infection is initiated by sporozoite invasion of hepatocytes and asexual reproduction of liver stages, processes that are regarded to be “clinically and diagnostically silent.” Merozoites, which egress from hepatocytes, infect erythrocytes in periodic cycles and induce disease. How the host innate immune system contributes to disease outcomes and to the induction of effector cells during malaria remains unclear. Likewise, how the initial liver stages may shape responses to blood-stage parasites is unknown. Here, using both sporozoite- and blood-stage-induced infections with the rodent malaria parasite
Plasmodium berghei
ANKA, we show that the MyD88 and Toll-like receptor 2/4 (TLR2/4) pathways play critical roles in the development of experimental cerebral malaria (ECM). Strikingly, an absolute dependence on MyD88 and TLR2/4 was observed when infections were initiated with sporozoites. In addition, we show that caspase-1 activation of interleukin-1β (IL-1β) and IL-18, which is associated with the inflammasome pathway, does not contribute to
P. berghei
ANKA-induced immunopathology. Consistent with these data, prophylactic cover with the IL-1β antagonist anakinra did not reduce the incidence of ECM. Therefore, we propose that protection against ECM due to loss of TLR signaling functions is caused by effector mechanisms other than IL-1β activation.
Alcohol-induced memory blackouts as an indicator of injury risk among college drinkers
Authors: Mundt Marlon P , Zakletskaia Larissa I , Brown David D , Fleming Michael F 
Published: June 2011

BackgroundAn alcohol-induced memory blackout represents an amnesia to recall events but does not involve a loss of consciousness. Memory blackouts are a common occurrence among college drinkers, but it is not clear if a history of memory blackouts is predictive of future alcohol-related injury above and beyond the risk associated with heavy drinking episodes.ObjectiveTo determine whether baseline memory blackouts can prospectively identify college students with alcohol-related injury in the next 24 months after controlling for heavy drinking days.MethodsData were analysed from the College Health Intervention Project Study (CHIPS), a randomised controlled trial of screening and brief physician intervention for problem alcohol use among 796 undergraduate and 158 graduate students at four university sites in the USA and one in Canada, conducted from 2004 to 2009. Multivariate analyses used generalised estimating equations with the logit link.ResultsThe overall 24-month alcohol-related injury rate was 25.6%, with no significant difference between men and women (p=0.51). Alcohol-induced memory blackouts at baseline exhibited a significant dose–response on odds of alcohol-related injury during follow-up, increasing from 1.57 (95% CI 1.13 to 2.19) for subjects reporting 1–2 memory blackouts at baseline to 2.64 (95% CI 1.65 to 4.21) for students acknowledging 6+ memory blackouts at baseline. The link between memory blackouts and injury was mediated by younger age, prior alcohol-related injury, heavy drinking, and sensation-seeking disposition.ConclusionsMemory blackouts are a significant predictor of future alcohol-related injury among college drinkers after adjusting for heavy drinking episodes.
SOME PHYSICAL PROPERTIES OFBaTiO3–CoFe2O4COMPOSITE
Authors: HEMEDA D. M. , TAWFIK A. , EL-SHAHAWY M. M. 
Published: June 2011

[X]% BaTiO3[100-x]% CoFe2O4composites (x = 0, 20, 40, 60, 80, and 100) were prepared by the general ceramic method. X-ray diffraction patterns and IR spectra confirmed the presence of two phases beside identified phase in the composites with (x% = 40-80% BaTiO3).The temperature variation of conductivity was mainly attributed to change of the drift mobility rather than to the variation of charge carrier concentration. All the composites showed p-type behaviors in the range of temperature 300–400 K. For T > 400 K all composites showed n-type behavior. At this high temperature, the conduction is mainly due to Fe3+→ Fe2+. Hence, there is a p–n transition.The variation of dielectric constant as a function of temperature showed a peak value at the Curie temperature (around 390 K) of ferroelectric phase in composites. It is also noted that the phase transition temperature Tcvaried for different composites.The relation between charge carrier mobility log (μd) versus (1/T) is nearly linear supporting the polaron hopping model for the conduction. The activation energies calculated from resistivity and that from mobility are in close agreement indicating localized model of charge carrier.The initial permeability increased with increasing temperature which is due to the activation of hopping electrons between Fe3+and Fe2+giving rise to the magnetic moment of the composites.
Tectonic re-interpretation of the Banggai-Sula–Molucca Sea margin, Indonesia
Authors: Watkinson Ian M. , Hall Robert , Ferdian Farid 
Published: June 2011

Abstract
High resolution multibeam bathymetric and seismic data from the area north of the Banggai-Sula Islands, Indonesia, provide a new insight into the geological history of the boundary between the East Sulawesi ophiolite, the Banggai-Sula microcontinent and the Molucca Sea collision zone. Major continuous faults such as the Sula Thrust and the North Sula–Sorong Fault, previously interpreted to bound and pass through the area are not seen. The south-verging Batui Thrust previously interpreted offshore to the east of Poh Head cannot be identified. In the areas where the thrust was interpreted there is a north-vergent thrust and fold zone overlain by almost undeformed sediments. Gently dipping strata of the Banggai-Sula microcontinent margin can be traced northwards beneath younger rocks. In the east, rocks of the Molucca Sea collision complex are deformed by multigenerational folds, thrusts and strike-slip faults. There is a series of small thrusts between the leading edge of the collision complex and the foot of the slope. In the west a zone of transpression close to the East Arm of Sulawesi is the termination of the dextral strike-slip Balantak Fault extending east from Poh Head.
Neogene climate history of the Makassar Straits, Indonesia
Authors: Morley Robert J. , Morley Harsanti P. 
Published: June 2011

Abstract
The Neogene climate history of the Makassar Straits has been assessed by combining palynological studies of two Late Quaternary cores from the ocean floor with analyses of petroleum exploration wells from the Makassar Straits, Indonesia, penetrating the Early Pleistocene to Middle Miocene.
The two Late Quaternary cores span 30 ka, located offshore the Mahakam Delta, east Kalimantan, and 95 ka, from offshore south Sulawesi. The first provides a record of the vegetation and climate history of the Mahakam catchment, and indicates rain forests through the last 30 ka, but with a cooler last glacial maximum, whereas the second provides a record of vegetation of the Java Sea region and south Sulawesi, and indicates extensive grasslands, suggesting a distinctly seasonal climate, during the last glacial maximum.
Based on a climate model constructed from the cores which link sea level change with changes of temperature and seasonality, the history of vegetation and climate for the Makassar Straits is then extrapolated back to the Middle Miocene using the record obtained from the two exploration wells. Results show that the equatorial climate has been everwet since the Middle Miocene, but at subequatorial latitudes seasonal climates became established from the Late Pliocene onward.