bluuebunny/crossref_metadata_2025_split huggingface dataset:
First Pharmacokinetic and Safety Study in Humans of the Novel Lipid Antiviral Conjugate CMX001, a Broad-Spectrum Oral Drug Active against Double-Stranded DNA Viruses
Authors: Painter Wendy , Robertson Alice , Trost Lawrence C. , Godkin Susan , Lampert Bernhard , Painter George 
Published: March 2012

ABSTRACT
CMX001 is a novel, broad-spectrum lipid antiviral conjugate (LAC) that produces high intracellular levels of the active antiviral agent cidofovir diphosphate (CDV-PP). Study CMX001-102 was a randomized, double-blind, placebo-controlled, parallel group, dose-escalating study in healthy volunteers. The objectives of the study were to evaluate the safety and pharmacokinetic parameters of CMX001 after single and multiple doses. Single doses ranging from 0.25 to 2.0 mg/kg of body weight and multiple doses ranging from 0.1 to 1.0 mg/kg (3 total doses, administered every 6 days) were given orally. Safety was assessed using comprehensive clinical and laboratory evaluations, including enhanced monitoring for potential gastrointestinal (GI) effects using wireless capsule endoscopy (WCE). Serial plasma and pooled urine samples were collected to estimate pharmacokinetic parameters for both CMX001 and cidofovir (CDV). No adverse events occurred that prevented dose escalation. No clinically significant drug-related changes in blood chemistry, hematology, renal function, or intraocular pressure were observed. No CMX001-related gastrointestinal mucosal changes were observed by WCE. CMX001 was absorbed rapidly, with maximum plasma concentrations observed 2 to 3 h postdose. Maximum plasma drug concentration and systemic exposure of CMX001 increased approximately in proportion to dose following single and multiple doses; no significant accumulation of CMX001 or CDV was observed following multiple doses. We conclude that CMX001 is orally bioavailable and well tolerated in healthy volunteers at doses up to 2 mg/kg, approximately 140 mg in a typical adult. This is the first demonstration of the use of phospholipid conjugation technology to achieve plasma drug exposures that are expected to result in activity against multiple double-stranded DNA viruses.
In Vitro
Interactions between Aspirin and Amphotericin B against Planktonic Cells and Biofilm Cells of Candida albicans and C. parapsilosis
Authors: Zhou Yabin , Wang Ganggang , Li Yutang , Liu Yang , Song Yu , Zheng Wenshuai , Zhang Ning , Hu Xiaoyan , Yan Shikun , Jia Jihui 
Published: March 2012

ABSTRACT

The increase in drug resistance and invasion caused by biofilm formation brings enormous challenges to the management of
Candida
infection. Aspirin's antibiofilm activity
in vitro
was discovered recently. The spectrophotometric method and the XTT {2,3-
bis
(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2
H
-tetrazolium hydroxide} reduction assay used for data generation make it possible to evaluate fungal biofilm growth accurately. The combined use of the most commonly used methods, the fractional inhibitory concentration index (FICI) and a newly developed method, the Δ
E
model, which uses the concentration-effect relationship over the whole concentration range instead of using the MIC index alone, makes the interpretation of results more reliable. As an attractive tool for studying the pharmacodynamics of antimicrobial agents, time-kill curves can provide detailed information about antimicrobial efficacy as a function of both time and concentration. In the present study,
in vitro
interactions between aspirin (acetylsalicylic acid [ASA]) and amphotericin B (AMB) against planktonic cells and biofilm cells of
Candida albicans
and
C. parapsilosis
were evaluated by the checkerboard microdilution method and the time-kill test. Synergistic and indifferent effects were found for the combination of ASA and AMB against planktonic cells, while strong synergy was found against biofilm cells analyzed by FICI. The Δ
E
model gave more consistent results with FICI. The positive interactions in concentration were also confirmed by the time-kill test. Moreover, this approach also revealed the pharmacodynamics changes of ASA and synergistic action on time. Our findings suggest a potential clinical use for combination therapy with ASA and AMB to augment activity against biofilm-associated infections.
Recurrent Episodes of Candidemia Due to Candida glabrata with a Mutation in Hot Spot 1 of the
FKS2
Gene Developed after Prolonged Therapy with Caspofungin
Authors: Durán-Valle María Teresa , Gago Sara , Gómez-López Alicia , Cuenca-Estrella Manuel , Jiménez Díez-Canseco Leticia , Gómez-Garcés José Luis , Zaragoza Oscar 
Published: March 2012

ABSTRACT

We report two episodes of recurrent candidemia caused by echinocandin-resistant
Candida glabrata
in a 69-year-old patient who underwent repeated abdominal surgery. In the first episode of candidemia, an echinocandin-susceptible
Candida glabrata
strain was isolated, and the patient was treated with caspofungin. The isolates from the later episodes showed resistance to echinocandins. Analysis of the HS1 region of the
FKS2
gene showed the amino acid substitution S663P. Microsatellite analysis demonstrated a strong genetic relationship between the isolates.
Cryptococcus neoformans-Cryptococcus gattii Species Complex: an International Study of Wild-Type Susceptibility Endpoint Distributions and Epidemiological Cutoff Values for Amphotericin B and Flucytosine
Authors: Espinel-Ingroff A. , Chowdhary A. , Cuenca-Estrella M. , Fothergill A. , Fuller J. , Hagen F. , Govender N. , Guarro J. , Johnson E. , Lass-Flörl C. , Lockhart S. R. , Martins M. A. , Meis J. F. , Melhem M. S. C. , Ostrosky-Zeichner L. , Pelaez T. , Pfaller M. A. , Schell W. A. , Trilles L. , Kidd S. , Turnidge J. 
Published: March 2012

ABSTRACTClinical breakpoints (CBPs) are not available for theCryptococcus neoformans-Cryptococcus gattiispecies complex. MIC distributions were constructed for the wild type (WT) to establish epidemiologic cutoff values (ECVs) forC. neoformansandC. gattiiversus amphotericin B and flucytosine. A total of 3,590 amphotericin B and 3,045 flucytosine CLSI MICs forC. neoformans(including 1,002 VNI isolates and 8 to 39 VNII, VNIII, and VNIV isolates) and 985 and 853 MICs forC. gattii, respectively (including 42 to 259 VGI, VGII, VGIII, and VGIV isolates), were gathered in 9 to 16 (amphotericin B) and 8 to 13 (flucytosine) laboratories (Europe, United States, Australia, Brazil, Canada, India, and South Africa) and aggregated for the analyses. Additionally, 442 amphotericin B and 313 flucytosine MICs measured by using CLSI-YNB medium instead of CLSI-RPMI medium and 237 Etest amphotericin B MICs forC. neoformanswere evaluated. CLSI-RPMI ECVs for distributions originating in ≥3 laboratories (with the percentages of isolates for which MICs were less than or equal to ECVs given in parentheses) were as follows: for amphotericin B, 0.5 μg/ml forC. neoformansVNI (97.2%) andC. gattiiVGI and VGIIa (99.2 and 97.5%, respectively) and 1 μg/ml forC. neoformans(98.5%) andC. gattiinontyped (100%) and VGII (99.2%) isolates; for flucytosine, 4 μg/ml forC. gattiinontyped (96.4%) and VGI (95.7%) isolates, 8 μg/ml for VNI (96.6%) isolates, and 16 μg/ml forC. neoformansnontyped (98.6%) andC. gattiiVGII (97.1%) isolates. Other molecular types had apparent variations in MIC distributions, but the number of laboratories contributing data was too low to allow us to ascertain that the differences were due to factors other than assay variation. ECVs may aid in the detection of isolates with acquired resistance mechanisms.
Strand Length-Dependent Antimicrobial Activity and Membrane-Active Mechanism of Arginine- and Valine-Rich β-Hairpin-Like Antimicrobial Peptides
Authors: Dong Na , Ma Qingquan , Shan Anshan , Lv Yinfeng , Hu Wanning , Gu Yao , Li Yuzhi 
Published: March 2012

ABSTRACT

Antimicrobial peptides with amphipathic β-hairpin-like structures have potent antimicrobial properties and low cytotoxicity. The effect of VR or RV motifs on β-hairpin-like antimicrobial peptides has not been investigated. In this study, a series of β-hairpin-like peptides, Ac-C(VR)

n

D
PG (RV)

n

C-NH
2
(
n
= 1, 2, 3, 4, or 5), were synthesized, and the effect of chain length on antimicrobial activity was evaluated. The antimicrobial activity of the peptides initially increased and then decreased with chain length. Longer peptides stimulated the toxicity to mammalian cells. VR3, a 16-mer peptide with seven amino acids in the strand, displayed the highest therapeutic index and represents the optimal chain length. VR3 reduced bacterial counts in the mouse peritoneum and increased the survival rate of mice at 7 days after
Salmonella enterica
serovar Typhimurium infection
in vivo
. The circular dichroism (CD) spectra demonstrated that the secondary structure of the peptides was a β-hairpin or β-sheet in the presence of an aqueous and membrane-mimicking environment. VR3 had the same degree of penetration into the outer and inner membranes as melittin. Experiments simulating the membrane environment showed that Trp-containing VRW3 (a VR3 analog) tends to interact preferentially with negatively charged vesicles in comparison to zwitterionic vesicles, which supports the biological activity data. Additionally, VR3 resulted in greater membrane damage than melittin as determined using a flow cytometry-based membrane integrity assay. Collectively, the data for synthetic lipid vesicles and whole bacteria demonstrated that the VR3 peptide killed bacteria via targeting the cell membrane. This assay could be an effective pathway to screen novel candidates for antibiotic development.
Emerging Role of Ubiquitination in Antiviral RIG-I Signaling
Authors: Maelfait Jonathan , Beyaert Rudi 
Published: March 2012

SUMMARY
Detection of viruses by the innate immune system involves the action of specialized pattern recognition receptors. Intracellular RIG-I receptors sense the presence of viral nucleic acids in infected cells and trigger signaling pathways that lead to the production of proinflammatory and antiviral proteins. Over the past few years, posttranslational modification of RIG-I and downstream signaling proteins by different types of ubiquitination has been found to be a key event in the regulation of RIG-I-induced NF-κB and interferon regulatory factor 3 (IRF3) activation. Multiple ubiquitin ligases, deubiquitinases, and ubiquitin binding scaffold proteins contribute to both positive and negative regulation of the RIG-I-induced antiviral immune response. A better understanding of the function and activity of these proteins might eventually lead to the development of novel therapeutic approaches for management of viral diseases.
Asphyxiation and entombment mechanisms in fines rich spawning substrates: experimental evidence with brook trout (Salvelinus fontinalis) embryos
Authors: Franssen Jan , Blais Catherine , Lapointe Michel , Bérubé Francis , Bergeron Normand , Magnan Pierre 
Published: March 2012

We investigated the distinct physical controls causing entombment and asphyxiation, the key mechanisms influencing salmonid egg-to-emergence (EtE) survival. Entombment occurs when sediment blocks the interstitial pathways (macropores) that larvae use to emerge from the streambed, while asphyxiation is related to low oxygen flux, which is a function of interstitial flow velocity. EtE survival has been related to substrate composition and flow velocity. However, in streambed sediments these variables are correlated, and few studies have examined the sensitivity of EtE survival to changes in velocity and oxygen flux at fixed substrate composition. EtE survival has not yet been directly related to the size and density of macropores. We incubated brook trout ( Salvelinus fontinalis ) embryos in artificial redds with different sediment compositions and hydraulic gradients to examine independently the effects of substrate composition, macropore geometry, and flow velocity on EtE survival, emergence timing, and fry condition. In situ measurements of macropore size were obtained using a computed tomography scanner. Despite high oxygen concentrations, we observed that entombment or blockage effects caused high embryo mortality in fines-rich substrates with few large macropores, and triggered early emergence of rare survivors. These outcomes could not be mitigated by increased flow velocity and oxygen flux to the egg pocket.
Life history schedule and periodic recruitment of female snow crab (Chionoecetes opilio) in the eastern Bering Sea
Authors: Ernst Billy , Armstrong David A. , Burgos Julián , Orensanz J.M. (Lobo) 
Published: March 2012

Snow crab ( Chionoecetes opilio ) populations have fluctuated cyclically in eastern Canada and the eastern Bering Sea, where recruitment to the mature female pool has occurred over a period of three decades (1978–2007) in pulses with a mean period of 7 years. It has been hypothesized that this was the result of a parent–offspring relation between sequentially linked strong cohorts of mature primiparous females, which requires that periodicity matches the time lapsed between egg extrusion by the maternal broodstock and the offspring reaching maturity. We show that female age at maturity (post-settlement) varies between 4.5 and 7.5 years, with most females maturing at 5.5–6.5 years (7–8 years after egg extrusion). Pulses of female recruitment to the mature population do not show a latitudinal trend, consistent with uniformity in age-at-maturity. Results of tracking crab abundance and size–frequency distributions in cod stomach and trawl samples between successive pulses of the cycle are consistent with the hypothesis of serial linkage among pulses. Periodicity is reflected in trends of clutch fullness and average shell condition and in the negative correlation between the strength of primiparous female cohorts and the mean size of their members.
Three-dimensional kernel utilization distributions improve estimates of space use in aquatic animals
Authors: Simpfendorfer Colin A. , Olsen Esben M. , Heupel Michelle R. , Moland Even 
Published: March 2012

Tracking data have previously been used to define animal movement patterns through two-dimensional (2D) kernel utilization distributions and separate analysis of vertical locations. Here we describe the use of three-dimensional (3D) kernel utilization distributions to estimate the volumetric space use of individuals based on tracking data and to estimate the overlap in activity space between individuals. Data from European eels ( Anguilla anguilla ) from Norwegian coastal waters were used to compare the information conveyed by 2D and 3D activity space estimates and the utility of this approach for aquatic species. The use of 3D kernels produced detailed representations of space use in A. anguilla that permitted examination of depth use in a geographic context. Comparison of 2D and 3D home ranges showed that 2D analyses overestimated the amount of overlap between individuals by 13%–20%, because individuals sometimes occurred in the same location but used different depths. Hence, the 3D approach provided more comprehensive representations of animal movement in three dimensions while producing a metric that can be used for testing hypotheses relating to scientific descriptions of activity space, habitat use, and movement parameters.
Stereodynamics study of the O+ + D2 (υ = 0, j = 0–2) → OD+ + D reaction
Authors: Chen Jiawu , Liu Xinguo , Zhang Qinggang 
Published: March 2012

The vector correlations between products and reagents for the ion–molecule reaction O+ + D2 → OD+ + D with different rotational quantum numbers (j = 0, 1, or 2) were explored theoretically using the quasi-classical trajectory method (QCT) on a Martìnez–Millán–González (MMG) surface. The three angular distributions P(θr), P([Formula: see text]), and P(θr,[Formula: see text]), as well as four polarization-dependent differential cross sections (PDDCSs) were calculated. The results indicate that a reagent’s rotational excitation greatly influences both the vector correlations of k–k′, k–j′, and k–k′–j′ and the PDDCSs of the title reaction, which means the reactivity is very sensitive to the rotational quantum number.
RELIABLE INTERNET-BASED MASTER-WORKER COMPUTING IN THE PRESENCE OF MALICIOUS WORKERS
Authors: ANTA ANTONIO FERNÁNDEZ , GEORGIOU CHRYSSIS , LÓPEZ LUIS , SANTOS AGUSTÍN 
Published: March 2012

We consider a Master-Worker distributed system where a master processor assigns, over the Internet, tasks to a collection of n workers, which are untrusted and might act maliciously. In addition, a worker may not reply to the master, or its reply may not reach the master, due to unavailabilities or failures of the worker or the network. Each task returns a value, and the goal is for the master to accept only correct values with high probability. Furthermore, we assume that the service provided by the workers is not free; for each task that a worker is assigned, the master is charged with a work-unit. Therefore, considering a single task assigned to several workers, our objective is to have the master processor to accept the correct value of the task with high probability, with the smallest possible amount of work (number of workers the master assigns the task). We probabilistically bound the number of faulty processors by assuming a known probability p < 1/2 of any processor to be faulty. Our work demonstrates that it is possible to obtain, with provable analytical guarantees, high probability of correct acceptance with low work. In particular, we first show lower bounds on the minimum amount of (expected) work required, so that any algorithm accepts the correct value with probability of success 1 - ε, where ε ≪ 1 (e.g., 1/n). Then we develop and analyze two algorithms, each using a different decision strategy, and show that both algorithms obtain the same probability of success 1 - ε, and in doing so, they require similar upper bounds on the (expected) work. Furthermore, under certain conditions, these upper bounds are asymptotically optimal with respect to our lower bounds.
The third porosity system
Authors: Corbett P. W. M. , Geiger S. , Borges L. , Garayev M. , Valdez C. 
Published: March 2012

Well testing is a critical part of any evaluation of a carbonate reservoir discovery. Well-test interpretation in carbonate reservoirs poses additional challenges to those normally faced in the interpretation process in clastic reservoirs. The range of different boundary and crossflow relationships that are generated during well testing by the complex porosity systems are often poorly quantified and understood. The volume over which the pressure response is effective is also a source of great uncertainty and could be critical at the exploration/appraisal stage in any project.
In this paper, which describes a generic modelling approach, we consider carbonate reservoirs which contain three pore sytems (or porosity types): (1) microporosity (end-member) with low permeability and high porosity; (2) macroporosity (end-member) with high permeability and high porosity; and (3) fracture porosity with high permeability and low porosity. These occur in various nested geometrical distributions and varying contrasts. The observed well-test responses (i.e. fracture flow, fracture–matrix interactions) tend to ‘obscure’ one of these systems when compared with theoretical models. Micro- (meso-) and macroporosity can merge into a single matrix porosity system where the permeability contrasts are not great and the correlation lengths short (which can often be the case in carbonates). Macroporosity can also appear in well testing to ‘merge’ with the fracture response, i.e. the contributions of flow in the fractures and (high-permeability) porous matrix are indistinguishable. As a result of the homogenizing attributes of pressure dissipation away from the well, it is not generally possible to see the effects of a ‘triple-porosity’ response (i.e. where three different pore systems have a separate and identifiable signature on the well-test response) and a classical double-porosity response in the well test, despite three different pore systems being present, is possible. The apparent double-porosity response, which might obscure a triple-porosity system, therefore needs careful interpretation in order to attribute the appropriate properties during reservoir characterization in carbonates.
In this work we use ‘geological’ well testing (i.e. well testing through numerical simulation of hypothetical geological models) to systematically analyse the effects of microporosity, macroporosity and fracture porosity on pressure dissipation and their apparent homogenization. While recent studies have proposed that a triple-porosity system should result in a ‘W-shaped’ response, we do not observe this behaviour in our simulations, although we specifically designed our geological models with a triple-porosity system. Instead we observe how macroporosity merges with the fractures or micro- and macroporosity merge, creating a ‘sub-dominant’ matrix or a ‘dominant’ fracture system, respectively and follow a traditional ‘V-shaped’ double-porosity response.
A new method for top seals predictions in high-pressure hydrocarbon plays
Authors: Casabianca Davide , Cosgrove John 
Published: March 2012

The current model describing the sealing mechanism of high-pressure hydrocarbon traps and the ensuing methodology for predicting top seal integrity and capacity in high-pressure plays assumes that the caprock, defined as the low matrix permeability formation immediately overlying the reservoir, is the seal.
This study challenges this assumption and proposes the existence within the caprock of a fluid waste zone consisting of a system of fractures cutting from the reservoir upwards into the caprock and, therefore, charged with reservoir fluids. Because of the waste zone fractures the reservoir fluids are not sealed at the base of the caprock. Instead the seal coincides with the fracture waste zone tip point, which occurs at an important stress and stratigraphic boundary termed the ultimate seal. Six case studies demonstrate that in the UK Central Graben the top seal for Mesozoic high pressure hydrocarbon accumulations lies between the Base Cretaceous Unconformity and the base of the Chalk Group and that the Jurassic Kimmeridge Clay Formation is not necessarily the seal for these traps. The data used for the construction of structural and stress models for the case studies include pore pressure measurements, formation integrity measurements, well logs and reflection seismic profiles.
An important conclusion of this study is that the shorter the waste zone the higher the chance of finding a hydrocarbon column in the reservoir.
A fast screening method for tricyclic antidepressants and their urinary metabolites by FAB‐tandem mass spectrometry
Authors: Schäfer M. , Budzikiewicz H. , Brzezinka H. , Schifferdecker M. 
Published: March 2012

A screening method for tricyclic antidepressants (TCA) and their urinary metabolites by FAB tandem mass spectrometry (FAB MS/MS) is presented. The collision induced dissociation (CID) behavior of pure dibenzocycloheptadienes (amitriptyline 1, nortriptyline 2), dibenzoxepines (doxepine 3, dosulepine 4), dibenzazepines (imipramine 5, desipramine 6, trimipramine 7) and the iminostilbene derivative opipramol 8 is described and used for the specific determination of these tricyclics by MS/MS.For the screening procedure a methanolic extract of the urine sample is passed through a XAD‐2 column and the eluate is examined without further purification after evaporation of the solvent. Identification of the TCA is achieved by constant neutral loss (CNL) scans for 173 u, 195 u and 193 u and subsequent daughter ion spectra of the molecular ions [M+H]+. Glucuronide conjugate metabolites of the tricyclic antidepressants 1, 2, 3, 6, 8 could be identified by CNL‐scans (176 u) and the assignments were confirmed by daughter ion mass spectra. A urine sample of a fatal 1, 2, 8 overdose and samples of three patients under therapeutic dosage with 1, 3 or 6 are presented as examples for application.