bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synthetic Histidine-Rich Peptides Inhibit
Candida
Species and Other Fungi In Vitro: Role of Endocytosis and Treatment Implications
Authors: Zhu Jingsong , Luther Paul W. , Leng Qixin , Mixson A. James 
Published: July 2006

ABSTRACT

A family of histidine-rich peptides, histatins, is secreted by the parotid gland in mammals and exhibits marked inhibitory activity against a number of
Candida
species. We were particularly interested in the mechanism by which histidine-rich peptides inhibit fungal growth, because our laboratory has synthesized a variety of such peptides for drug and nucleic acid delivery. In contrast to naturally occurring peptides that are linear, peptides made on synthesizers can be varied with respect to their degrees of branching. Using this technology, we explored whether histidine-lysine (HK) polymers of different complexities and degrees of branching affect the growth of several species of
Candida
. Polymers with higher degrees of branching were progressively more effective against
Candida albicans
, with the four-branched polymer, H2K4b, most effective. Furthermore, H2K4b accumulated efficiently in
C. albicans
, which may indicate its ability to transport other antifungal agents intracellularly. Although H2K4b had greater antifungal activity than histatin 5, their mechanisms were similar. Toxicity in
C. albicans
induced by histatin 5 or branched HK peptides was markedly reduced by 4,4′-diisothiocyanato-stilbene-2,2′-disulfonate, an inhibitor of anion channels. We also determined that bafilomycin A1, an inhibitor of endosomal acidification, significantly decreased the antifungal activity of H2K4b. This suggests that the pH-buffering and subsequent endosomal-disrupting properties of histidine-rich peptides have a role in their antifungal activity. Moreover, the ability of the histidine component of these peptides to disrupt endosomes, which allows their escape from the lysosomal pathway, may explain why these peptides are both effective antifungal agents and nucleic acid delivery carriers.
Development of an Orogastrointestinal Mucosal Model of Candidiasis with Dissemination to Visceral Organs
Authors: Clemons Karl V. , Gonzalez Gloria M. , Singh Gaurav , Imai Jackie , Espiritu Marife , Parmar Rachana , Stevens David A. 
Published: July 2006

ABSTRACT

Studies were done to develop a murine model that mimics the pattern of mucosal candidiasis followed by disseminated disease seen in patients given cytotoxic chemotherapy. Developmental studies showed that suppression of mice with 5-fluorouracil beginning 3 days prior to infection and given every 7 days thereafter necessitated antibacterial treatment but resulted in a reproducible model.
Candida albicans
given in the drinking water resulted in oral infection by day 3 that significantly increased from days 10 to 15 and mucosal infection with 4 to 7 log
10
Candida
CFU in the esophagus, stomach, small intestine, and cecum. Dissemination to livers occurred and was 100% on days 5 to 15; fewer animals had kidney infection. The median kidney or liver CFU were 2 or 3 log
10
CFU, respectively, on day 15; despite this, mortality was low through 21 days of infection. As a demonstration of the utility of the model to test antifungal activity, daily treatment with 10 or 50 mg/kg itraconazole significantly reduced dissemination to the liver and kidneys and reduced tongue CFU compared to controls. Overall, these studies indicate that a nonlethal model of oral and gastrointestinal mucosal candidiasis with dissemination can be established in mice. Drug efficacy in treating localized infection and in preventing or treating disseminated infection can be studied.
Comparative Pharmacodynamics of Gentamicin against
Staphylococcus aureus
and
Pseudomonas aeruginosa
Authors: Tam Vincent H. , Kabbara Samer , Vo Giao , Schilling Amy N. , Coyle Elizabeth A. 
Published: July 2006

ABSTRACT

Aminoglycosides are often used to treat severe infections with gram-positive organisms. Previous studies have shown concentration-dependent killing by aminoglycosides of gram-negative bacteria, but limited data are available for gram-positive bacteria. We compared the in vitro pharmacodynamics of gentamicin against
Staphylococcus aureus
and
Pseudomonas aeruginosa
. Five
S. aureus
strains were examined (ATCC 29213 and four clinical isolates). Time-kill studies (TKS) in duplicate (baseline inocula of 10
7
CFU/ml) were conducted to evaluate bacterial killing in relation to increasing gentamicin concentrations (0 to 16 times the MIC). Serial samples were obtained over 24 h to quantify bacterial burden. Similar TKS with
P. aeruginosa
ATCC 27853 were conducted, and the time courses of the all bacterial strains were mathematically modeled for quantitative comparison. A dose fractionation study (using identical daily doses of gentamicin) in an in vitro hollow-fiber infection model (HFIM) over 5 days was subsequently used for data validation for the two ATCC strains. Model fits to the data were satisfactory;
r
2
values for the
S. aureus
and
P. aeruginosa
ATCC strains were 0.915 and 0.956, respectively. Gentamicin was found to have a partially concentration-dependent killing effect against
S. aureus
; concentrations beyond four to 8 times the MIC did not result in significantly faster bacterial killing. In contrast, a concentration-dependent profile was demonstrated in suppressing
P. aeruginosa
regrowth after initial decline in bacterial burden. In HFIM, thrice-daily gentamicin dosing appeared to be superior to once-daily dosing for
S. aureus
, but they were similar for
P. aeruginosa
. Different killing profiles of gentamicin were demonstrated against
S. aureus
and
P. aeruginosa
. These results may guide optimal dosing strategies of gentamicin in
S. aureus
infections and warrant further investigations.
Cisplatin Inhibition of Anthrax Lethal Toxin
Authors: Moayeri Mahtab , Wiggins Jason F. , Lindeman Robin E. , Leppla Stephen H. 
Published: July 2006

ABSTRACT

Bacillus anthracis
lethal toxin (LT) produces symptoms of anthrax in mice and induces rapid lysis of macrophages derived from certain inbred strains. LT is comprised of a receptor binding component, protective antigen (PA), which delivers the enzymatic component, lethal factor (LF), into cells. We found that mouse macrophages were protected from toxin by the antitumor drug
cis
-diammineplatinum (II) dichloride (cisplatin). Cisplatin was shown to inhibit LT-mediated cleavage of cellular mitogen-activated protein kinases (MEKs) without inhibiting LF's in vitro proteolytic activity. Cisplatin-treated PA lost 100% of its ability to function in toxicity assays when paired with untreated LF, despite maintaining the ability to bind to cells. Cisplatin-treated PA was unable to form heptameric oligomers required for LF binding and translocation. The drug was shown to modify PA in a reversible noncovalent manner. Not surprisingly, cisplatin also blocked the actions of anthrax edema toxin and of LF-
Pseudomonas aeruginosa
exotoxin A fusion peptide (FP59), both of which require PA for translocation. Treatment of BALB/cJ mice or Fischer F344 rats with cisplatin at biologically relevant concentrations completely protected the animals from a coadministered lethal dose of LT. However, treatment with cisplatin 2 hours before or after animals received a lethal bolus of toxin did not protect them.
New Azasterols against
Trypanosoma brucei
: Role of 24-Sterol Methyltransferase in Inhibitor Action
Authors: Gros Ludovic , Castillo-Acosta Victor Manuel , Jiménez Carmen Jiménez , Sealey-Cardona Marco , Vargas Sofia , Manuel Estévez Antonio , Yardley Vanessa , Rattray Lauren , Croft Simon L. , Ruiz-Perez Luis M. , Urbina Julio A. , Gilbert Ian H. , Pacanowska Dolores González 
Published: July 2006

ABSTRACT

A series of azasterol derivatives, designed as potential inhibitors of the Δ
24
-sterol methyltransferase enzyme (24-SMT), were synthesized and evaluated for their activities against parasitic protozoa. Values in the nanomolar range were obtained for 50% effective dose against the
Trypanosoma brucei
subsp.
rhodesiense
bloodstream form cultured in vitro. In order to investigate the mode of action,
Trypanosoma brucei
subsp.
brucei
24-SMT was cloned and overexpressed and compounds were assayed for inhibitory activity. None of the inhibitors tested appeared to be active against the enzyme. Sterol composition analysis showed that only cholestane type sterols are present in membranes of bloodstream forms while ergosterol is a major component of procyclic sterol extracts. Interestingly, Northern blot analysis showed the presence of 24-SMT mRNA in both the procyclic and the bloodstream forms of the parasite, although levels of mRNA were threefold lower in the latter. Likewise, Western blot analysis and activity determinations evidenced the existence of active enzyme in both forms of the parasite. We conclude that the designed compounds act at sites other than 24-SMT in
Trypanosoma brucei
.
Comparative Analysis of Sequences Flanking
tet
(W) Resistance Genes in Multiple Species of Gut Bacteria
Authors: Kazimierczak Katarzyna A. , Flint Harry J. , Scott Karen P. 
Published: July 2006

ABSTRACT

tet
(W) is one of the most abundant tetracycline resistance genes found in bacteria from the mammalian gut and was first identified in the rumen anaerobe
Butyrivibrio fibrisolvens
1.230, where it is highly mobile and its transfer is associated with the transposable chromosomal element Tn
B1230
. In order to compare the genetic basis for
tet
(W) carriage in different bacteria, we studied sequences flanking
tet
(W) in representatives of seven bacterial genera originating in diverse gut environments. The sequences 657 bp upstream and 43 bp downstream of
tet
(W) were 96 to 100% similar in all strains examined. A common open reading frame (ORF) was identified downstream of
tet
(W) in five different bacteria, while another conserved ORF that flanked
tet
(W) in
B. fibrisolvens
1.230 was also present upstream of
tet
(W) in a human colonic
Roseburia
isolate and in another rumen
B. fibrisolvens
isolate. In one species,
Bifidobacterium longum
(strain F8), a novel transposase was located within the conserved 657-bp region upstream of
tet
(W) and was flanked by imperfect direct repeats. Additional direct repeats 6 bp long were identified on each end of a chromosomal ORF interrupted by the insertion of the putative transposase and the
tet
(W) gene. This
tet
(W) gene was transferable at low frequencies between
Bifidobacterium
strains. A putative minielement carrying a copy of
tet
(W) was identified in
B. fibrisolvens
transconjugants that had acquired the
tet
(W) gene on Tn
B1230
. Several different mechanisms, including mechanisms involving plasmids and conjugative transposons, appear to be involved in the horizontal transfer of
tet
(W) genes, but small core regions that may function as minielements are conserved.
Hydrophobic α-Helices 1 and 2 of Herpes Simplex Virus gH Interact with Lipids, and Their Mimetic Peptides Enhance Virus Infection and Fusion
Authors: Gianni Tatiana , Fato Romana , Bergamini Christian , Lenaz Giorgio , Campadelli-Fiume Gabriella 
Published: July 2006

ABSTRACT

Entry of herpes simplex virus into cells occurs by fusion and requires four glycoproteins. gD serves as the receptor binding glycoprotein. Of the remaining glycoproteins, gH carries structural and functional elements typical of class 1 fusion glycoproteins, in particular α-helix 1 (α-H1), with properties of a candidate fusion peptide, and two heptad repeats. Here, we characterized α-H2 and compared it to α-H1. α-H2 (amino acids 513 to 531) is of lower hydrophobicity than α-H1. Its deletion or mutation decreased virus infection and cell fusion. Its replacement with heterologous fusion peptides did not rescue infection and cell fusion beyond the levels exhibited by the α-H2-deleted gH. This contrasts with α-H1, which cannot be deleted and can be functionally replaced with heterologous fusion peptides (T. Gianni et al., J. Virol.
79:
2931-2940, 2005). Synthetic peptides mimicking α-H1 and α-H2 induced fusion of nude lipid vesicles. Importantly, they increased infection of herpes simplex virus, pseudorabies virus, bovine herpesvirus 1, and vesicular stomatitis virus. The α-H1 mimetic peptide was more effective than the α-H2 peptide. Consistent with the findings that gH carries membrane-interacting segments, a soluble form of gH, but not of gD or gB, partitioned with lipid vesicles. Current findings highlight that α-H2 is an important albeit nonessential region for virus entry and fusion. α-H1 and α-H2 share the ability to target the membrane lipids; they contribute to virus entry and fusion, possibly by destabilizing the membranes. However, α-H2 differs from α-H1 in that it is of lower hydrophobicity and cannot be replaced with heterologous fusion peptides.
Dynamics of Synoptic Eddy and Low-Frequency Flow Interaction. Part I: A Linear Closure
Authors: Jin F-F. , Pan L-L. , Watanabe M. 
Published: July 2006

Abstract
The interaction between synoptic eddy and low-frequency flow (SELF) has been recognized for decades to play an important role in the dynamics of the low-frequency variability of the atmospheric circulation. In this three-part study a linear framework with a stochastic basic flow capturing both the climatological mean flow and climatological measures of the synoptic eddy flow is proposed. Based on this linear framework, a set of linear dynamic equations is derived for the ensemble-mean eddy forcing that is generated by anomalous time-mean flows. By assuming that such dynamically determined eddy-forcing anomalies approximately represent the time-mean anomalies of the synoptic eddy forcing and by using a quasi-equilibrium approximation, an analytical nonlocal dynamical closure is obtained for the two-way SELF feedback. This linear closure, directly relating time-mean anomalies of the synoptic eddy forcing to the anomalous time–mean flow, becomes an internal part of a new linear dynamic system for anomalous time–mean flow that is referred to as the low-frequency variability of the atmospheric circulation in this paper.
In Part I, the basic approach for the SELF closure is illustrated using a barotropic model. The SELF closure is tested through the comparison of the observed eddy-forcing patterns associated with the leading low-frequency modes with those derived using the SELF feedback closure. Examples are also given to illustrate an important role played by the SELF feedback in regulating the atmospheric responses to remote forcing. Further applications of the closure for understanding the dynamics of low-frequency modes as well as the extension of the closure to a multilevel primitive equation model will be given in Parts II and III, respectively.
Empirical Mode Reduction in a Model of Extratropical Low-Frequency Variability
Authors: Kondrashov D. , Kravtsov S. , Ghil M. 
Published: July 2006

Abstract
This paper constructs and analyzes a reduced nonlinear stochastic model of extratropical low-frequency variability. To do so, it applies multilevel quadratic regression to the output of a long simulation of a global baroclinic, quasigeostrophic, three-level (QG3) model with topography; the model's phase space has a dimension of O(104).
The reduced model has 45 variables and captures well the non-Gaussian features of the QG3 model's probability density function (PDF). In particular, the reduced model's PDF shares with the QG3 model its four anomalously persistent flow patterns, which correspond to opposite phases of the Arctic Oscillation and the North Atlantic Oscillation, as well as the Markov chain of transitions between these regimes. In addition, multichannel singular spectrum analysis identifies intraseasonal oscillations with a period of 35–37 days and of 20 days in the data generated by both the QG3 model and its low-dimensional analog.
An analytical and numerical study of the reduced model starts with the fixed points and oscillatory eigenmodes of the model's deterministic part and uses systematically an increasing noise parameter to connect these with the behavior of the full, stochastically forced model version. The results of this study point to the origin of the QG3 model's multiple regimes and intraseasonal oscillations and identify the connections between the two types of behavior.
The Response of Damaging Winds of a Simulated Tropical Cyclone to Finite-Amplitude Perturbations of Different Variables
Authors: Hoffman R. N. , Henderson J. M. , Leidner S. M. , Grassotti C. , Nehrkorn T. 
Published: July 2006

Abstract
Four-dimensional variational data assimilation (4DVAR) is an established data assimilation method that finds the finite-amplitude perturbation that best fits observations consistent with a priori information and model dynamics. The response of a simulated tropical cyclone to specially designed finite perturbations of selected model variables was studied with a modified version of 4DVAR. The usual goal of minimizing data misfits was replaced with a goal of reducing damaging surface winds at the end of six hours of forecast time. For this purpose a property value cost function based on topography was defined. The case studied was a 20-km simulation of a hurricane approaching the Hawaiian Islands. Each prognostic variable in turn—temperature, winds, humidity, vertical velocity, and perturbation pressure—and all prognostic variables at once were used as the control vector for the optimization problem. Of all prognostic variables examined, temperature and the horizontal wind were the most effective at reducing damaging surface winds. The wind-only perturbation was very similar to the wind component of the perturbation calculated when all prognostic variables were used at once. Calculated perturbations had scales of 0.25°C or 1 m s−1, but changes at a few grid points near the center of the storm were an order of magnitude greater. Vertical velocity and humidity perturbations alone were ineffective at reducing damaging winds. The perturbation pressure experiment failed to converge but did substantially reduce the damaging winds.
An Estimate of Tidal Energy Lost to Turbulence at the Hawaiian Ridge
Authors: Klymak Jody M. , Moum James N. , Nash Jonathan D. , Kunze Eric , Girton James B. , Carter Glenn S. , Lee Craig M. , Sanford Thomas B. , Gregg Michael C. 
Published: July 2006

Abstract
An integrated analysis of turbulence observations from four unique instrument platforms obtained over the Hawaiian Ridge leads to an assessment of the vertical, cross-ridge, and along-ridge structure of turbulence dissipation rate and diffusivity. The diffusivity near the seafloor was, on average, 15 times that in the midwater column. At 1000-m depth, the diffusivity atop the ridge was 30 times that 10 km off the ridge, decreasing to background oceanic values by 60 km. A weak (factor of 2) spring–neap variation in dissipation was observed. The observations also suggest a kinematic relationship between the energy in the semidiurnal internal tide (E) and the depth-integrated dissipation (D), such that D ∼ E1±0.5 at sites along the ridge. This kinematic relationship is supported by combining a simple knife-edge model to estimate internal tide generation, with wave–wave interaction time scales to estimate dissipation. The along-ridge kinematic relationship and the observed vertical and cross-ridge structures are used to extrapolate the relatively sparse observations along the length of the ridge, giving an estimate of 3 ± 1.5 GW of tidal energy lost to turbulence dissipation within 60 km of the ridge. This is roughly 15% of the energy estimated to be lost from the barotropic tide.
Tidally Forced Internal Waves and Overturns Observed on a Slope: Results from HOME
Authors: Levine Murray D. , Boyd Timothy J. 
Published: July 2006

Abstract
Tidal mixing over a slope was explored using moored time series observations on Kaena Ridge extending northwest from Oahu, Hawaii, during the Survey component of the Hawaii Ocean Mixing Experiment (HOME). A mooring was instrumented to sample the velocity and density field of the lower 500 m of the water column to look for indirect evidence of tidally induced mixing and was deployed on a slope in 1453-m water depth for 2 months beginning in November 2000. The semidiurnal barotropic tidal currents at this site have a significant cross-ridge component, favorable for exciting an internal tidal response. A large-amplitude response is expected, given that the slope of the topography (4.5°) is nearly the same as the slope of the internal wave group velocity at semidiurnal frequency. Density overturns were inferred from temperature profiles measured every 2 min. The number and strength of the overturns are greater in the 200 m nearest the bottom, with overturns exceeding 24 m present at any depth nearly 10% of the time. Estimates of turbulent dissipation rate ɛ were made for each overturn by associating the measured Thorpe scale with the Ozmidov scale. The average ɛ between 1300 and 1450 m for the entire experiment is about 10−8 m2 s−3, corresponding to an average Kρ of 10−3 m2 s−1. Both ɛ and Kρ decrease by about an order of magnitude by 1200 m. The occurrence of overturns and the magnitude of ɛ are both highly correlated with the tide: both with the spring–neap cycle as well as the phase of the semidiurnal tide itself. Dissipation rate varies by at least an order of magnitude over the spring–neap cycle. It appears that tidal frequency vertical shear within 200 m of the boundary leads to significant strain (vertical divergence). Most of the overturns occur during the few hours when the vertical strain is greatest. The buoyancy frequency N calculated from reordering these overturns is a factor of 3 lower than the background N. This is consistent with the following kinematic description: the internal tide first strains the mean density field, leading to regions of low N that subsequently overturn. Less regularly, overturns also occur when the internal tide strain has created relatively high stratification within 200 m of the bottom.
Propagation of Low-Mode Internal Waves through the Ocean
Authors: Rainville Luc , Pinkel Robert 
Published: July 2006

Abstract
The baroclinic tides play a significant role in the energy budget of the abyssal ocean. Although the basic principles of generation and propagation are known, a clear understanding of these phenomena in the complex ocean environment is only now emerging. To advance this effort, a ray model is developed that quantifies the effects of spatially variable topography, stratification, and planetary vorticity on the horizontal propagation of internal gravity modes. The objective is to identify “baroclinic shoals” where wave energy is spatially concentrated and enhanced dissipation might be expected. The model is then extended to investigate the propagation of internal waves through a barotropic mesoscale current field. The refraction of tidally generated internal waves at the Hawaiian Ridge is examined using an ensemble of mesoscale background realizations derived from weekly Ocean Topography Experiment (TOPEX)/Poseidon altimetric measurements. The path of mode 1 is only slightly affected by typical currents, although its phase becomes increasingly random as the propagation distance from the source increases. The effect of the currents becomes more dramatic as mode number increases. For modes 3 and higher, wave phase can vary between realizations by ±π only a few wavelengths from the source. This phase variability reduces the magnitude of the baroclinic signal seen in altimetric data, creating a fictitious energy loss along the propagation path. In the TOPEX/Poseidon observations, the mode-1 M2 internal tide does appear to lose significant energy as it propagates southwestward from the Hawaiian Ridge. The simulations suggest that phase modulation by mesoscale flows could be responsible for a large fraction of this apparent loss. In contrast, northeast-propagating internal tides encounter a less energetic mesoscale and should experience limited refraction. The apparent energy loss seen in the altimetric data on the north side of the ridge might indeed be real.