bluuebunny/crossref_metadata_2025_split huggingface dataset:
Complementary functions of SK and Kv7/M potassium channels in excitability control and synaptic integration in rat hippocampal dentate granule cells
Authors: Mateos‐Aparicio Pedro , Murphy Ricardo , Storm Johan F. 
Published: December 2013

Key points
Previous studies showed that different firing patterns of hippocampal dentate granule cells (DGCs) can trigger different network responses. However, the intrinsic DGC mechanisms controlling their excitability, spike patterns and synaptic integration in DGCs, remain poorly understood.
SK and Kv7/M channels play important roles controlling neuronal integration and excitability, but their specific roles vary between cell types. Both channel types are expressed in DGCs, but their roles are unclear.
We found that SK channels are the main generators of medium afterhyperpolarizations in DGCs, thus causing negative feedback regulation of spiking (spike frequency adaptation) and calcium influx.
In contrast, Kv7/M perform subthreshold and ‘feed‐forward’ control of input resistance, postsynaptic integration, action potential threshold and excitability, thus weakening EPSP–spike coupling.
Thus, in DGCs, the SK and Kv7/M channels seem to perform complementary functions in postsynaptic integration and excitability control. This may have important consequences for dentate network physiology.
AbstractThe dentate granule cells (DGCs) form the most numerous neuron population of the hippocampal memory system, and its gateway for cortical input. Yet, we have only limited knowledge of the intrinsic membrane properties that shape their responses. Since SK and Kv7/M potassium channels are key mechanisms of neuronal spiking and excitability control, afterhyperpolarizations (AHPs) and synaptic integration, we studied their functions in DGCs. The specific SK channel blockers apamin or scyllatoxin increased spike frequency (excitability), reduced early spike frequency adaptation, fully blocked the medium‐duration AHP (mAHP) after a single spike or spike train, and increased postsynaptic EPSP summation after spiking, but had no effect on input resistance (Rinput) or spike threshold. In contrast, blockade of Kv7/M channels by XE991 increased Rinput, lowered the spike threshold, and increased excitability, postsynaptic EPSP summation, and EPSP–spike coupling, but only slightly reduced mAHP after spike trains (and not after single spikes). The SK and Kv7/M channel openers 1‐EBIO and retigabine, respectively, had effects opposite to the blockers. Computational modelling reproduced many of these effects. We conclude that SK and Kv7/M channels have complementary roles in DGCs. These mechanisms may be important for the dentate network function, as CA3 neurons can be activated or inhibition recruited depending on DGC firing rate.
The mitochondrial calcium uniporter complex: molecular components, structure and physiopathological implications
Authors: Marchi Saverio , Pinton Paolo 
Published: December 2013

AbstractAlthough it has long been known that mitochondria take up Ca2+, the molecular identities of the channels and transporters involved in this process were revealed only recently. Here, we discuss the recent work that has led to the characterization of the mitochondrial calcium uniporter complex, which includes the channel‐forming subunit MCU (mitochondrial calcium uniporter) and its regulators MICU1, MICU2, MCUb, EMRE, MCUR1 and miR‐25. We review not only the biochemical identities and structures of the proteins required for mitochondrial Ca2+ uptake but also their implications in different physiopathological contexts.
Bioluminescence and
19
F Magnetic Resonance Imaging Visualize the Efficacy of Lysostaphin Alone and in Combination with Oxacillin against Staphylococcus aureus in Murine Thigh and Catheter-Associated Infection Models
Authors: Hertlein Tobias , Sturm Volker , Lorenz Udo , Sumathy K. , Jakob Peter , Ohlsen Knut 
Published: December 2013

ABSTRACT

Staphylococci are the leading cause of hospital-acquired infections worldwide. Increasingly, they resist antibiotic treatment owing to the development of multiple antibiotic resistance mechanisms in most strains. Therefore, the activity and efficacy of recombinant lysostaphin as a drug against this pathogen have been evaluated. Lysostaphin exerts high levels of activity against antibiotic-resistant strains of
Staphylococcus aureus
, including methicillin-resistant
S. aureus
(MRSA). The therapeutic value of lysostaphin has been analyzed in two different clinically relevant
in vivo
models, a catheter-associated infection model and a thigh infection model. We infected mice with luciferase-expressing
S. aureus
Xen 29, and the efficacies of lysostaphin, vancomycin, oxacillin, and combined lysostaphin-oxacillin were investigated by determining numbers of CFU, detecting bioluminescent signals, and measuring the accumulation of perfluorocarbon emulsion at the site of infection by
19
F magnetic resonance imaging. Lysostaphin treatment significantly reduced the bacterial burden in infected thigh muscles and, after systemic spreading from the catheter, in inner organs. The efficiency of lysostaphin treatment was even more pronounced in combinatorial therapy with oxacillin. These results suggest that recombinant lysostaphin may have potential as an anti-
S. aureus
drug worthy of further clinical development. In addition, both imaging technologies demonstrated efficacy patterns similar to that of CFU determination, although they proved to be less sensitive. Nonetheless, they served as powerful tools to provide additional information about the course and gravity of infection in a noninvasive manner, possibly allowing a reduction in the number of animals needed for research evaluation of new antibiotics in future studies.
Pharmacokinetics of Orally Administered Oseltamivir in Healthy Obese and Nonobese Thai Subjects
Authors: Jittamala Podjanee , Pukrittayakamee Sasithon , Tarning Joel , Lindegardh Niklas , Hanpithakpong Warunee , Taylor Walter Robert John , Lawpoolsri Saranath , Charunwattana Prakaykaew , Panapipat Salwaluk , White Nicholas J. , Day Nicholas P. J. 
Published: December 2013

ABSTRACTOseltamivir is the most widely used anti-influenza drug. In the 2009 H1N1 pandemic, in which the influenza viruses were oseltamivir sensitive, obesity was identified as a risk factor for severe disease and unfavorable outcomes. The aim of this study was to investigate the pharmacokinetic properties of oseltamivir and its active metabolite, oseltamivir carboxylate, in obese and nonobese healthy subjects. A single-dose, randomized, two-sequence crossover study was conducted in 12 obese and 12 nonobese healthy Thai volunteers. Each volunteer was given 75 mg and 150 mg oseltamivir orally with an intervening washout period of more than 3 days. The pharmacokinetic properties of oseltamivir and oseltamivir carboxylate were evaluated using a noncompartmental approach. The median (range) body mass indexes (BMIs) for obese subjects were 33.8 kg/m2(30.8 to 43.2) and 22.2 (18.8 to 24.2) for nonobese subjects. The pharmacokinetic parameters of oseltamivir carboxylate, the active metabolite of oseltamivir, were not significantly different between obese and nonobese subjects for both 75-mg and 150-mg doses. Both doses were well tolerated. Despite the lower dose per kilogram body weight in obese subjects, there was no significant difference in the exposure of oseltamivir carboxylate between the obese and nonobese groups. Standard dosing is appropriate for obese subjects. (The study was registered at ClinicalTrials.gov under registration no. NCT 01049763.)
Outcome of Intravenous Azithromycin Therapy in Patients with Complicated Scrub Typhus Compared with That of Doxycycline Therapy Using Propensity-Matched Analysis
Authors: Jang Mi-Ok , Jang Hee-Chang , Kim Uh Jin , Ahn Joon Hwan , Kang Seung-Ji , Jung Sook-In , Shin Hee-Young , Park Kyung-Hwa 
Published: December 2013

ABSTRACT

There are no well-matched, controlled studies comparing azithromycin with doxycycline for the treatment of complicated scrub typhus. A retrospective propensity score-matched case-control study was performed for patients who presented with complicated scrub typhus and were treated with doxycycline or azithromycin between 2001 and 2011. Data on comorbidities, clinical manifestations, laboratory studies, treatments, and outcomes were extracted for analysis. The clinical characteristics and outcomes of the azithromycin-treated group (
n
= 73) were compared to those of the doxycycline-treated group (
n
= 108). Of 181 patients, 73 from each group were matched by propensity scores. There were no significant differences in baseline characteristics between the matched groups. The treatment success and survival rates were not significantly different (89% [65/73 patients] versus 96% [70/73 patients] and 96% [70/73 patients] versus 96% [70/73 patients], respectively [
P
> 0.05]). No difference was observed in the time to defervescence or length of hospital stay between the two groups (
P
> 0.05). In complicated scrub typhus patients (
n
= 181), multivariate analysis showed that only APACHE II score was an independent risk factor for mortality (95% confidence interval, 1.11 to 1.56;
P
< 0.001). Our data suggest that outcomes of azithromycin therapy are comparable to those of doxycycline therapy in patients with complicated scrub typhus.
Dihydroquinazolinone Inhibitors of Proliferation of Blood and Liver Stage Malaria Parasites
Authors: Derbyshire Emily R. , Min Jaeki , Guiguemde W. Armand , Clark Julie A. , Connelly Michele C. , Magalhães Andreia D. , Guy R. Kiplin , Clardy Jon 
Published: December 2013

ABSTRACT

Drugs that target both the liver and blood stages of malaria will be needed to reduce the disease's substantial worldwide morbidity and mortality. Evaluation of a 259-member library of compounds that block proliferation of the blood stage of malaria revealed several scaffolds—dihydroquinazolinones, phenyldiazenylpyridines, piperazinyl methyl quinolones, and bis-benzimidazoles—with promising activity against the liver stage. Focused structure-activity studies on the dihydroquinazolinone scaffold revealed several molecules with excellent potency against both blood and liver stages. One promising early lead with dual activity is 2-(
p
-bromophenyl)-3-(2-(diethylamino)ethyl)-2,3-dihydroquinazolin-4(1
H
)-one with 50% effective concentrations (EC
50
s) of 0.46 μM and 0.34 μM against liver stage
Plasmodium berghei
ANKA and blood stage
Plasmodium falciparum
3D7 parasites, respectively. Structure-activity relationships revealed that liver stage activity for this compound class requires a 3-dialkyl amino ethyl group and is abolished by substitution at the
ortho
-position of the phenyl moiety. These compounds have minimal toxicity to mammalian cells and are thus attractive compounds for further development.
In Vitro
Efficacy of Corifungin against Acanthamoeba castellanii Trophozoites and Cysts
Authors: Debnath Anjan , Tunac Josefino B. , Silva-Olivares Angélica , Galindo-Gómez Silvia , Shibayama Mineko , McKerrow James H. 
Published: December 2013

ABSTRACT

Painful blinding keratitis and fatal granulomatous amebic encephalitis are caused by the free-living amebae
Acanthamoeba
spp. Several prescription eye medications are used to treat
Acanthamoeba
keratitis, but the infection can be difficult to control because of recurrence of infection. For the treatment of encephalitis, no single drug was found useful, and in spite of the use of a combination of multiple drugs, the mortality rate remains high. Therefore, efficient, novel drugs are urgently needed for the treatment of amebic keratitis and granulomatous amebic encephalitis. In this study, we identified corifungin, a water-soluble polyene macrolide, as amebicidal.
In vitro
, it was effective against both the trophozoites and the cysts. Transmission electron microscopy of
Acanthamoeba castellanii
incubated with corifungin showed the presence of swollen mitochondria, electron-dense granules, degeneration of cytoplasm architecture, and loss of nuclear chromatin structure. These changes were followed by lysis of amebae. Corifungin also induced the encystment process of
A. castellanii
. There were alterations in the cyst cell wall followed by lysis of the cysts. Corifungin is a promising therapeutic option for keratitis and granulomatous amebic encephalitis.
Ceftaroline Restores Daptomycin Activity against Daptomycin-Nonsusceptible Vancomycin-Resistant Enterococcus faecium
Authors: Sakoulas George , Rose Warren , Nonejuie Poochit , Olson Joshua , Pogliano Joseph , Humphries Romney , Nizet Victor 
Published: December 2013

ABSTRACT

Daptomycin-nonsusceptible vancomycin-resistant
Enterococcus faecium
(VRE) strains are a formidable emerging threat to patients with comorbidities, leaving few therapeutic options in cases of severe invasive infections. Using a previously characterized isogenic pair of VRE strains from the same patient differing in their daptomycin susceptibilities (Etest MICs of 0.38 mg/liter and 10 mg/liter), we examined the effect of ceftaroline, ceftriaxone, and ampicillin on membrane fluidity and susceptibility of VRE to surface binding and killing by daptomycin and human cathelicidin antimicrobial peptide LL37. Synergy was noted
in vitro
between daptomycin, ampicillin, and ceftaroline for the daptomycin-susceptible VRE strain, but only ceftaroline showed synergy against the daptomycin-nonsusceptible VRE strain (∼2 log
10
CFU reduction at 24 h). Ceftaroline cotreatment increased daptomycin surface binding with an associated increase in membrane fluidity and an increase in the net negative surface charge of the bacteria as evidenced by increased poly-
l
-lysine binding. Consistent with the observed biophysical changes, ceftaroline resulted in increased binding and killing of daptomycin-nonsusceptible VRE by human cathelicidin LL37. Using a pair of daptomycin-susceptible/nonsusceptible VRE strains, we noted that VRE is ceftaroline resistant, yet ceftaroline confers significant effects on growth rate as well as biophysical changes on the cell surface of VRE that can potentiate the activity of daptomycin and innate cationic host defense peptides, such as cathelicidin. Although limited to just 2 strains, these finding suggest that additional
in vivo
and
in vitro
studies need to be done to explore the possibility of using ceftaroline as adjunctive anti-VRE therapy.
In Vitro
Characterization of a Sustained-Release Formulation for Enfuvirtide
Authors: Rothstein Sam N. , Huber Kelly D. , Sluis-Cremer Nicolas , Little Steven R. 
Published: December 2013

ABSTRACT

Although approved by the U.S. Food and Drug Administration, enfuvirtide is rarely used in combination antiretroviral therapies (cART) to treat HIV-1 infection, primarily because of its intense dosing schedule that requires twice-daily subcutaneous injection. Here, we describe the development of enfuvirtide-loaded, degradable poly(lactic-co-glycolic) acid microparticles that provide linear
in vitro
release of the drug over an 18-day period. This sustained-release formulation could make enfuvirtide more attractive for use in cART.
Fluxes of Ca
2+
and K
+
Are Required for the Listeriolysin O-Dependent Internalization Pathway of Listeria monocytogenes
Authors: Vadia Stephen , Seveau Stephanie 
Published: December 2013

ABSTRACT

Listeria monocytogenes
is responsible for the life-threatening food-borne disease listeriosis. This disease mainly affects elderly and immunocompromised individuals, causing bacteremia and meningoencephalitis. In pregnant women,
L. monocytogenes
infection leads to abortion and severe infection of the fetus or newborn. The
L. monocytogenes
intracellular life cycle is critical for pathogenesis. Previous studies have established that the major virulence factor of
L. monocytogenes
, the pore-forming toxin listeriolysin O (LLO), is sufficient to induce
L. monocytogenes
internalization into human epithelial cell lines. This internalization pathway strictly requires the formation of LLO pores in the plasma membrane and can be stimulated by the heterologous pore-forming toxin pneumolysin, suggesting that LLO acts nonspecifically by forming transmembrane pores. The present work tested the hypothesis that Ca
2+
and K
+
fluxes subsequent to perforation by LLO control
L. monocytogenes
internalization. We report that
L. monocytogenes
perforates the host cell plasma membrane in an LLO-dependent fashion at the early stage of invasion. In response to perforation, host cells undergo Ca
2+
-dependent but K
+
-independent resealing of their plasma membrane. In contrast to the plasma membrane resealing process, LLO-induced
L. monocytogenes
internalization requires both Ca
2+
and K
+
fluxes. Further linking ion fluxes to bacterial internalization, treating cells with a combination of Ca
2+
and K
+
ionophores but not with individual ionophores is sufficient to induce efficient internalization of large cargoes, such as 1-μm polystyrene beads and bacteria. We propose that LLO-induced
L. monocytogenes
internalization requires a Ca
2+
- and K
+
-dependent internalization pathway that is mechanistically distinct from the process of plasma membrane resealing.
Uropathogenic Escherichia coli Modulates Innate Immunity To Suppress Th1-Mediated Inflammatory Responses during Infectious Epididymitis
Authors: Lang Tali , Hudemann Christoph , Tchatalbachev Svetlin , Stammler Angelika , Michel Vera , Aslani Ferial , Bhushan Sudhanshu , Chakraborty Trinad , Renz Harald , Meinhardt Andreas 
Published: December 2013

ABSTRACTInfectious epididymitis in men, a frequent entity in urological outpatient settings, is commonly caused by bacteria originating from the anal region ascending the genitourinary tract. One of the most prevalent pathogens associated with epididymitis isEscherichia coli. In our previous study, we showed that semen quality is compromised in men following epididymitis associated with specificE. colipathovars. Thus, our aim was to investigate possible differences in immune responses elicited during epididymitis following infection with the uropathogenicE. coli(UPEC) strain CFT073 and the nonpathogenic entericE. coli(NPEC) strain 470. Employing anin vivoexperimental epididymitis model, C57BL/6 mice were infected with UPEC CFT073, NPEC 470, or phosphate-buffered saline (PBS) as a sham control for up to 7 days. After infection with NPEC 470, the expression of proinflammatory cytokines interleukin-1 (IL-1), IL-6, and tumor necrosis factor alpha in the epididymis was significantly increased. Conversely, UPEC CFT073-challenged mice displayed inflammatory gene expression at levels comparable to sham PBS-treated animals. Moreover, by day 7 only NPEC-infected animals showed activation of adaptive immunity evident by a substantial influx of CD3+and F4/80+cells in the epididymal interstitium. This correlated with enhanced production of Th1-associated cytokines IL-2 and gamma interferon (IFN-γ). Furthermore, splenocytes isolated from UPEC-infected mice exhibited diminished T-cell responses with significantly reduced secretion of IL-2 and IFN-γ in contrast to NPEC-infected animals. Overall, these findings provide new insights into understanding pathogen-specific modulation of host immunity during acute phases of epididymitis, which may influence severity of disease and clinical outcomes.
The Nod1, Nod2, and Rip2 Axis Contributes to Host Immune Defense against Intracellular Acinetobacter baumannii Infection
Authors: Bist Pradeep , Dikshit Neha , Koh Tse Hsien , Mortellaro Alessandra , Tan Thuan Tong , Sukumaran Bindu 
Published: December 2013

ABSTRACT

Acinetobacter baumannii
is a major extensively drug-resistant lethal human nosocomial bacterium. However, the host innate immune mechanisms controlling
A. baumannii
are not well understood. Although viewed as an extracellular pathogen,
A. baumannii
can also invade and survive intracellularly. However, whether host innate immune pathways sensing intracellular bacteria contribute to immunity against
A. baumannii
is not known. Here, we provide evidence for the first time that intracellular antibacterial innate immune receptors Nod1 and Nod2, and their adaptor Rip2, play critical roles in the sensing and clearance of
A. baumannii
by human airway epithelial cells
in vitro
.
A. baumannii
infection upregulated Rip2 expression. Silencing of Nod1, Nod2, and Rip2 expression profoundly increased intracellular invasion and prolonged the multiplication and survival of
A. baumannii
in lung epithelial cells. Notably, the Nod1/2-Rip2 axis did not contribute to the control of
A. baumannii
infection of human macrophages, indicating that they play cell type-specific roles. The Nod1/2-Rip2 axis was needed for
A. baumannii
infection-induced activation of NF-κB but not mitogen-activated protein kinases. Moreover, the Nod1/2-Rip2 axis was critical to induce optimal cytokine and chemokine responses to
A. baumannii
infection. Mechanistic studies showed that the Nod1/2 pathway contributed to the innate control of
A. baumannii
infection through the production of β-defensin 2 by airway epithelial cells. This study revealed new insights into the immune control of
A. baumannii
and may contribute to the development of effective immune therapeutics and vaccines against
A. baumannii
.
High-Temperature Protein G Is an Essential Virulence Factor of Leptospira interrogans
Authors: King Amy M. , Pretre Gabriela , Bartpho Thanatchaporn , Sermswan Rasana W. , Toma Claudia , Suzuki Toshihiko , Eshghi Azad , Picardeau Mathieu , Adler Ben , Murray Gerald L. 
Published: December 2013

ABSTRACT

Leptospira interrogans
is a global zoonotic pathogen and is the causative agent of leptospirosis, an endemic disease of humans and animals worldwide. There is limited understanding of leptospiral pathogenesis; therefore, further elucidation of the mechanisms involved would aid in vaccine development and the prevention of infection. HtpG (
h
igh-
t
emperature
p
rotein
G
) is the bacterial homolog to the highly conserved molecular chaperone Hsp90 and is important in the stress responses of many bacteria. The specific role of HtpG, especially in bacterial pathogenesis, remains largely unknown. Through the use of an
L. interrogans
htpG
transposon insertion mutant, this study demonstrates that
L. interrogans
HtpG is essential for virulence in the hamster model of acute leptospirosis. Complementation of the
htpG
mutant completely restored virulence. Surprisingly, the
htpG
mutant did not appear to show sensitivity to heat or oxidative stress, phenotypes common in
htpG
mutants in other bacterial species. Furthermore, the mutant did not show increased sensitivity to serum complement, reduced survival within macrophages, or altered protein or lipopolysaccharide expression. The underlying cause for attenuation thus remains unknown, but HtpG is a novel leptospiral virulence factor and one of only a very small number identified to date.
Novel Role for the
yceGH
Tellurite Resistance Genes in the Pathogenesis of Bacillus anthracis
Authors: Franks Sarah E. , Ebrahimi Celia , Hollands Andrew , Okumura Cheryl Y. , Aroian Raffi V. , Nizet Victor , McGillivray Shauna M. 
Published: December 2013

ABSTRACT

Bacillus anthracis
, the causative agent of anthrax, relies on multiple virulence factors to subvert the host immune defense. Using
Caenorhabditis elegans
as an infection model, we screened approximately 5,000 transposon mutants of
B. anthracis
Sterne for decreased virulence. One of the attenuated mutants resulted in loss of expression of
yceG
and
yceH
, the last two genes in a six-gene cluster of tellurite resistance genes. We generated an analogous insertional mutant to confirm the phenotype and characterize the role of
yceGH
in resistance to host defenses. Loss of
yceGH
rendered the mutants more sensitive to tellurite toxicity as well as to host defenses such as reactive oxygen species and the cathelicidin family of antimicrobial peptides. Additionally, we see decreased survival in mammalian models of infection, including human whole blood and in mice. We identify a novel role for the
yceGH
genes in
B. anthracis
Sterne virulence and suggest that
C. elegan
s is a useful infection model to study anthrax pathogenesis.