bluuebunny/crossref_metadata_2025_split huggingface dataset:
New Insight into the Mechanism of Accumulation and Intraerythrocytic Compartmentation of Albitiazolium, a New Type of Antimalarial
Authors: Wein Sharon , Tran Van Ba Christophe , Maynadier Marjorie , Bordat Yann , Perez Julie , Peyrottes Suzanne , Fraisse Laurent , Vial Henri J. 
Published: July 2014

ABSTRACT

Bis-thiazolium salts constitute a new class of antihematozoan drugs that inhibit parasite phosphatidylcholine biosynthesis. They specifically accumulate in
Plasmodium
- and
Babesia
-infected red blood cells (IRBC). Here, we provide new insight into the choline analogue albitiazolium, which is currently being clinically tested against severe malaria. Concentration-dependent accumulation in
P. falciparum
-infected erythrocytes reached steady state after 90 to 120 min and was massive throughout the blood cycle, with cellular accumulation ratios of up to 1,000. This could not occur through a lysosomotropic effect, and the extent did not depend on the food vacuole pH, which was the case for the weak base chloroquine. Analysis of albitiazolium accumulation in
P. falciparum
IRBC revealed a high-affinity component that was restricted to mature stages and suppressed by pepstatin A treatment, and thus likely related to drug accumulation in the parasite food vacuole. Albitiazolium also accumulated in a second high-capacity component present throughout the blood cycle that was likely not related to the food vacuole and also observed with
Babesia divergens
-infected erythrocytes. Accumulation was strictly glucose dependent, drastically inhibited by H
+
/K
+
and Na
+
ionophores upon collapse of ionic gradients, and appeared to be energized by the proton-motive force across the erythrocyte plasma membrane, indicating the importance of transport steps for this permanently charged new type of antimalarial agent. This specific, massive, and irreversible accumulation allows albitiazolium to restrict its toxicity to hematozoa-infected erythrocytes. The intraparasitic compartmentation of albitiazolium corroborates a dual mechanism of action, which could make this new type of antimalarial agent resistant to parasite resistance.
In Vitro
Synergism Observed with Azithromycin, Clarithromycin, Minocycline, or Tigecycline in Association with Antifungal Agents against Pythium insidiosum
Authors: Jesus Francielli P. K. , Ferreiro Laerte , Loreto Érico S. , Pilotto Maiara B. , Ludwig Aline , Bizzi Karine , Tondolo Juliana S. M. , Zanette Régis A. , Alves Sydney H. , Santurio Janio M. 
Published: July 2014

ABSTRACT

We describe here the
in vitro
activities of azithromycin, clarithromycin, minocycline, or tigecycline alone and in combination with amphotericin B, itraconazole, terbinafine, voriconazole, anidulafungin, caspofungin, or micafungin against 30 isolates of the oomycete
Pythium insidiosum
. The assays were based on the CLSI M38-A2 technique and the checkerboard microdilution method. The main synergisms observed were through the combination of minocycline with amphotericin B (73.33%), itraconazole (70%), and micafungin (70%) and of clarithromycin with micafungin (73.33%).
Pyocyanin Production by Pseudomonas aeruginosa Confers Resistance to Ionic Silver
Authors: Muller Michael , Merrett Neil D. 
Published: July 2014

ABSTRACT

Silver in its ionic form (Ag
+
), but not the bulk metal (Ag
0
), is toxic to microbial life forms and has been used for many years in the treatment of wound infections. The prevalence of bacterial resistance to silver is considered low due to the nonspecific nature of its toxicity. However, the recent increased use of silver as an antimicrobial agent for medical, consumer, and industrial products has raised concern that widespread silver resistance may emerge.
Pseudomonas aeruginosa
is a common pathogen that produces pyocyanin, a redox toxin and a reductant for molecular oxygen and ferric (Fe
3+
) ions. The objective of this study was to determine whether pyocyanin reduces Ag
+
to Ag
0
, which may contribute to silver resistance due to lower bioavailability of the cation. Using surface plasmon resonance spectroscopy and scanning electron microscopy, pyocyanin was confirmed to be a reductant for Ag
+
, forming Ag
0
nanoparticles and reducing the bioavailability of free Ag
+
by >95% within minutes. Similarly, a pyocyanin-producing strain of
P. aeruginosa
(PA14) reduced Ag
+
but not a pyocyanin-deficient (Δ
phzM
) strain of the bacterium. Challenge of each strain with Ag
+
(as AgNO
3
) gave MICs of 20 and 5 μg/ml for the PA14 and Δ
phzM
strains, respectively. Removal of pyocyanin from the medium strain PA14 was grown in or its addition to the medium that Δ
phzM
mutant was grown in gave MICs of 5 and 20 μg/ml, respectively. Clinical isolates demonstrated similar pyocyanin-dependent resistance to Ag
+
. We conclude that pseudomonal silver resistance exists independently of previously recognized intracellular mechanisms and may be more prevalent than previously considered.
Binding Mode Characterization of NBD Series CD4-Mimetic HIV-1 Entry Inhibitors by X-Ray Structure and Resistance Study
Authors: Curreli Francesca , Kwon Young Do , Zhang Hongtao , Yang Yongping , Scacalossi Daniel , Kwong Peter D. , Debnath Asim K. 
Published: July 2014

ABSTRACTWe previously identified two small-molecule CD4 mimetics—NBD-556 and NBD-557—and synthesized a series of NBD compounds that resulted in improved neutralization activity in a single-cycle HIV-1 infectivity assay. For the current investigation, we selected several of the most active compounds and assessed their antiviral activity on a panel of 53 reference HIV-1 Env pseudoviruses representing diverse clades of clinical isolates. The selected compounds inhibited tested clades with low-micromolar potencies. Mechanism studies indicated that they act as CD4 agonists, a potentially unfavorable therapeutic trait, in that they can bind to the gp120 envelope glycoprotein and initiate a similar physiological response as CD4. However, one of the compounds, NBD-09027, exhibited reduced agonist properties, in both functional and biophysical studies. To understand the binding mode of these inhibitors, we first generated HIV-1-resistant mutants, assessed their behavior with NBD compounds, and determined the X-ray structures of two inhibitors, NBD-09027 and NBD-10007, in complex with the HIV-1 gp120 core at ∼2-Å resolution. Both studies confirmed that the NBD compounds bind similarly to NBD-556 and NBD-557 by inserting their hydrophobic groups into the Phe43 cavity of gp120. The basic nitrogen of the piperidine ring is located in close proximity to D368 of gp120 but it does not form any H-bond or salt bridge, a likely explanation for their nonoptimal antagonist properties. The results reveal the structural and biological character of the NBD series of CD4 mimetics and identify ways to reduce their agonist properties and convert them to antagonists.
Latitudinal Distribution of Ammonia-Oxidizing Bacteria and Archaea in the Agricultural Soils of Eastern China
Authors: Jiang Hongchen , Huang Liuqin , Deng Ye , Wang Shang , Zhou Yu , Liu Li , Dong Hailiang 
Published: July 2014

ABSTRACT

The response of soil ammonia-oxidizing bacterial (AOB) and archaeal (AOA) communities to individual environmental variables (e.g., pH, temperature, and carbon- and nitrogen-related soil nutrients) has been extensively studied, but how these environmental conditions collectively shape AOB and AOA distributions in unmanaged agricultural soils across a large latitudinal gradient remains poorly known. In this study, the AOB and AOA community structure and diversity in 26 agricultural soils collected from eastern China were investigated by using quantitative PCR and bar-coded 454 pyrosequencing of the
amoA
gene that encodes the alpha subunit of ammonia monooxygenase. The sampling locations span over a 17° latitude gradient and cover a range of climatic conditions. The
Nitrosospira
and
Nitrososphaera
were the dominant clusters of AOB and AOA, respectively; but the subcluster-level composition of
Nitrosospira
-related AOB and
Nitrososphaera
-related AOA varied across the latitudinal gradient. Variance partitioning analysis showed that geography and climatic conditions (e.g., mean annual temperature and precipitation), as well as carbon-/nitrogen-related soil nutrients, contributed more to the AOB and AOA community variations (∼50% in total) than soil pH (∼10% in total). These results are important in furthering our understanding of environmental conditions influencing AOB and AOA community structure across a range of environmental gradients.
Developmental Cell Fate and Virulence Are Linked to Trehalose Homeostasis in Cryptococcus neoformans
Authors: Botts Michael R. , Huang Mingwei , Borchardt Regen K. , Hull Christina M. 
Published: July 2014

ABSTRACT

Among pathogenic environmental fungi, spores are thought to be infectious particles that germinate in the host to cause disease. The meningoencephalitis-causing yeast
Cryptococcus neoformans
is found ubiquitously in the environment and sporulates in response to nutrient limitation. While the yeast form has been studied extensively, relatively little is known about spore biogenesis, and spore germination has never been evaluated at the molecular level. Using genome transcript analysis of spores and molecular genetic approaches, we discovered that trehalose homeostasis plays a key role in regulating sporulation of
C. neoformans
, is required for full spore viability, and influences virulence. Specifically, we found that genes involved in trehalose metabolism, including a previously uncharacterized secreted trehalase (
NTH2
), are highly overrepresented in dormant spores. Deletion of the two predicted trehalases in the
C. neoformans
genome,
NTH1
and
NTH2
, resulted in severe defects in spore production, a decrease in spore germination, and an increase in the production of alternative developmental structures. This shift in cell types suggests that trehalose levels modulate cell fate decisions during sexual development. We also discovered that deletion of the
NTH2
trehalase results in hypervirulence in a murine model of infection. Taken together, these data show that the metabolic adaptations that allow this fungus to proliferate ubiquitously in the environment play unexpected roles in virulence in the mammalian host and highlight the complex interplay among the processes of metabolism, development, and pathogenesis.
Retinoid Levels Influence Enterohemorrhagic Escherichia coli Infection and Shiga Toxin 2 Susceptibility in Mice
Authors: Cabrera Gabriel , Fernández-Brando Romina J. , Abrey-Recalde María Jimena , Baschkier Ariela , Pinto Alipio , Goldstein Jorge , Zotta Elsa , Meiss Roberto , Rivas Marta , Palermo Marina S. 
Published: July 2014

ABSTRACT

Enterohemorrhagic
Escherichia coli
(EHEC) is a food-borne pathogen that produces Shiga toxin (Stx) and causes hemorrhagic colitis. Under some circumstances, Stx produced within the intestinal tract enters the bloodstream, leading to systemic complications that may cause the potentially fatal hemolytic-uremic syndrome. Although retinoids like vitamin A (VA) and retinoic acid (RA) are beneficial to gut integrity and the immune system, the effect of VA supplementation on gastrointestinal infections of different etiologies has been controversial. Thus, the aim of this work was to study the influence of different VA status on the outcome of an EHEC intestinal infection in mice. We report that VA deficiency worsened the intestinal damage during EHEC infection but simultaneously improved survival. Since death is associated mainly with Stx toxicity, Stx was intravenously inoculated to analyze whether retinoid levels affect Stx susceptibility. Interestingly, while VA-deficient (VA-D) mice were resistant to a lethal dose of Stx2, RA-supplemented mice were more susceptible to it. Given that peripheral blood polymorphonuclear cells (PMNs) are known to potentiate Stx2 toxicity, we studied the influence of retinoid levels on the absolute number and function of PMNs. We found that VA-D mice had decreased PMN numbers and a diminished capacity to produce reactive oxygen species, while RA supplementation had the opposite effect. These results are in line with the well-known function of retinoids in maintaining the homeostasis of the gut but support the idea that they have a proinflammatory effect by acting, in part, on the PMN population.
Folding LacZ in the Periplasm of Escherichia coli
Authors: Dwyer Robert S. , Malinverni Juliana C. , Boyd Dana , Beckwith Jon , Silhavy Thomas J. 
Published: July 2014

ABSTRACT

Targeted, translational LacZ fusions provided the initial support for the signal sequence hypothesis in prokaryotes and allowed for selection of the mutations that identified the Sec translocon. Many of these selections relied on the fact that expression of targeted, translational
lacZ
fusions like
malE-lacZ
and
lamB-lacZ42-1
causes lethal toxicity as folded LacZ jams the translocation pore. However, there is another class of targeted LacZ fusions that do not jam the translocon. These targeted, nonjamming fusions also show toxic phenotypes that may be useful for selecting mutations in genes involved in posttranslocational protein folding and targeting; however, they have not been investigated to the same extent as their jamming counterparts. In fact, it is still unclear whether LacZ can be fully translocated in these fusions. It may be that they simply partition into the inner membrane where they can no longer participate in folding or assembly. In the present study, we systematically characterize the nonjamming fusions and determine their ultimate localization. We report that LacZ can be fully translocated into the periplasm, where it is toxic. We show that this toxicity is likely due to LacZ misfolding and that, in the absence of the periplasmic disulfide bond catalyst DsbA, LacZ folds in the periplasm. Using the novel phenotype of periplasmic β-galactosidase activity, we show that the periplasmic chaperone FkpA contributes to LacZ folding in this nonnative compartment. We propose that targeted, nonjamming LacZ fusions may be used to further study folding and targeting in the periplasm of
Escherichia coli
.
Oral drug treatments in patients with erectile dysfunction and multiple comorbidities: a retrospective observational study
Authors: Zaman Huri Hasniza , Lian Choo Tee , Sulaiman Che Zuraini , Mark Raymond , Abdul Razack Azad Hassan 
Published: July 2014

ObjectiveTo investigate factors associated with demographic/clinical characteristics and drug selection in patients with erectile dysfunction (ED). The prevalence of ED is increasing worldwide. Studies have shown that ED is associated with age, lifestyle and comorbidities. However, the factors associated with patient characteristics as well as drug selection are incompletely understood.SettingA tertiary medical centre in Kuala Lumpur, Malaysia.ParticipantsA total of 219 patients (range 23–80 years) who had received phosphodiesterase type-5 (PDE-5) inhibitors as ED treatment were evaluated.Inclusion criteriaAdult patients aged ≥18 years, diagnosed with ED, and prescribed with sildenafil, tadalafil or vardenafil.Exclusion criteriaPatients diagnosed with ED but who did not receive any PDE-5 inhibitor, or those with missing data.Primary and secondary outcome measuresFactors associated with demographic and clinical characteristics as well as drug selection were assessed.ResultsIschaemic heart disease (p=0.025), benign prostatic hyperplasia (p<0.001), obesity (p=0.005), lower urinary tract symptoms (LUTS) (p=0.006) and α-blockers (p<0.001) were significantly associated with elderly patients with ED. Additionally, LUTS (p=0.038) and α-blockers (p=0.008) were significantly associated with the selection of PDE-5 inhibitor.ConclusionsThese data showed that elderly patients with ED were significantly associated with comorbidities and α-blockers, whereas LUTS and α blockers were associated with drug selection.
IMPROVED POINTER MACHINE AND I/O LOWER BOUNDS FOR SIMPLEX RANGE REPORTING AND RELATED PROBLEMS
Authors: AFSHANI PEYMAN 
Published: July 2014

We investigate one of the fundamental areas in computational geometry: lower bounds for range reporting problems in the pointer machine and the external memory models. We develop new techniques that lead to new and improved lower bounds for simplex range reporting as well as some other geometric problems. Simplex range reporting is the problem of storing n points in the d-dimensional space in a data structure such that the k points that lie inside a query simplex can be found efficiently. This is one of the fundamental and extensively studied problems in computational geometry. Currently, the best data structures for the problem achieve Q(n) + O(k) query time using [Formula: see text] space in which the [Formula: see text] notation either hides a polylogarithmic or an nε factor for any constant ε > 0, (depending on the data structure and Q(n)). The best lower bound on this problem is due to Chazelle and Rosenberg who showed any pointer machine data structure that can answer queries in O(nγ + k) time must use Ω(nd-ε-dγ) space. Observe that this bound is a polynomial factor away from the best known data structures. In this article, we improve the space lower bound to [Formula: see text]. Not only this bridges the gap from polynomial to sub-polynomial, it also offers a smooth trade-off curve. For instance, for polylogarithmic values of Q(n), our space lower bound almost equals Ω((n/Q(n))d); the latter is generally believed to be the “right” bound. By a simple geometric transformation, we also improve the best lower bounds for the halfspace range reporting problem. Furthermore, we study the external memory model and offer a new simple framework for proving lower bounds in this model. We show that answering simplex range reporting queries with Q(n)+O(k/B) I/Os requires [Formula: see text]) space or [Formula: see text] blocks, in which B is the block size.
Impacts of Dem Uncertainty on Estimated Surface Solar Radiation and Extracted River Network
Authors: Wang Laigang , Wang Kaicun 
Published: July 2014

Abstract
Digital elevation models (DEMs) have important meteorological, hydrological, and climatological applications. This research studies the uncertainties of six widely accepted global DEM datasets over China and their derivative parameters, including slope and aspect, in calculating the surface-received solar radiation and extracting the river networks. The authors’ results indicate that, although the absolute height values of the six DEM data are nearly identical, substantial and significant differences are introduced when estimating the surface-received solar radiation. The extracted drainage streamflows of the Pearl River basin in South China are close to the actual river networks in general but are quite different in some details that cannot be ignored. Results herein highlight that the uncertainties of DEM themselves as well as their derived parameters must be considered in analogous study.
Genesis of Late Miocene-Pliocene lacustrine palygorskite and calcretes from Kırşehir, central Anatolia, Turkey
Authors: Kadİr S. , Eren M. , Külah T. , Önalgİl N. , Cesur M. , Gürel A. 
Published: July 2014

AbstractThis paper addresses the mineralogy, geochemistry, and genesis of palygorskite and associated calcretes in the Kırşehir region. In this area, the Quaternary calcretes are present within and/or on lacustrine mudstones of the Kızılırmak Formation (Late Miocene-Pliocene). The calcretes occur in the form of nodules, tubes, fracture-infills, and hard laminated crusts (hardpans). Calcrete samples are predominantly composed of calcite associated with smectite, quartz, feldspar, and minor palygorskite. The lacustrine mudstone samples consist mainly of smectite and palygorskite with minor calcite, quartz, feldspar, illite, kaolinite and amorphous material. Petrographic studies revealed that the calcrete samples are predominantly micrites that were partially converted to microsparites by recrystallization. Scanning and transmission electron microscopy images indicate that palygorskite fibres formed authigenically on and between calcite rhombs in the calcrete samples and at the edges of smectite flakes of host rocks adjacent to the calcretes. The oxygen and hydrogen stable isotope values of the calcite suggest that it precipitated from meteoric water under arid or seasonally arid climatic conditions. Calcite precipitation occurred in the vadose zone, as evidenced by desiccation cracks and vadose pisolites. The enrichment of Rb+Ba±Sr and Light Rare Earth Elements (LREE) relative to Heavy Rare Earth Elements (HREE)with a distinct negative Eu anomaly are responses to the fractionation of volcanogenic feldspar and hornblende under the influence of meteoric water. The palygorskite associated with calcretes was precipitated from alkaline water rich in Si, Al and Fe and low in Mg. The palygorskite precipitation occurred at increased temperatures, characterising the advanced stage of calcrete formation which lowers the Ca content in the soil water. The required chemical elements for palygorskite and calcite were most likely derived from the dissolution of smectitic clays, ignimbrites and carbonate minerals.
The antiviral immune response in human conventional dendritic cells is controlled by the mammalian target of rapamycin
Authors: Fekete Tünde , Pazmandi Kitti , Szabo Attila , Bacsi Attila , Koncz Gabor , Rajnavölgyi Eva 
Published: July 2014

AbstractType I and III IFNs are crucial, soluble components of potent antiviral responses. It has been explored recently that mTOR is involved in the regulation of IFN-α/β production by pDCs, albeit its role in the induction of IFN responses in cDCs remained unrevealed. In this study, we demonstrate that the PI3K/mTOR pathway is indispensable for eliciting intact type I and III IFN responses in moDCs stimulated with polyI:C. The inhibition of mTOR functionality by rapamycin impairs the pIRF3 and also a few members of the MAPK family, suggesting that mTOR contributes to the activation of multiple signaling pathways in the presence of viral antigens. Furthermore, rapamycin-treated moDCs show decreased capacity to prime IFN-γ secretion by naive CD8+ T-lymphocytes. As in moDCs, mTOR-mediated regulation is also essential for the production of type I and III IFNs in circulating CD1c+ DCs. To our best knowledge, these results demonstrate for the first time that mTOR has an impact on the functional activities of cDCs via modulating the outcome of IFN secretion.