bluuebunny/crossref_metadata_2025_split huggingface dataset:
The neural interaction between the arterial baroreflex and muscle metaboreflex is preserved in older men
Authors: Greaney Jody L. , Schwartz Christopher E. , Edwards David G. , Fadel Paul J. , Farquhar William B. 
Published: June 2013

New Findings
What is the central question of this study?Sympathetic baroreflex sensitivity increases during isolated skeletal muscle metaboreflex activation in young adults, but whether this neural interaction between the arterial baroreflex and the muscle metaboreflex is altered in healthy ageing remains unclear.
What is the main finding and its importance?The collective findings indicate that the neural interaction between the arterial baroreflex and the skeletal muscle metaboreflex in the regulation of muscle sympathetic nerve activity is preserved in healthy ageing. This has potential implications for the regulation of blood pressure during exercise in older adults.
Sympathetic baroreflex sensitivity is increased during selective activation of the skeletal muscle metaboreflex with postexercise ischaemia (PEI) in young adults. However, to date, there are no data demonstrating this neural interaction between the arterial baroreflex and the muscle metaboreflex in healthy older adults. Therefore, the goal of the present study was to examine the influence of healthy ageing on the metabolic component of the exercise pressor reflex and its interaction with the arterial baroreflex in the control of sympathetic outflow. Postexercise ischaemia following static hand grip performed at 30% maximal voluntary contraction was used to isolate muscle metaboreflex activation in young [n= 10; 24 ± 1 years old; resting blood pressure (BP) 116 ± 3/64 ± 3 mmHg] and older men (n= 9; 59 ± 2 years old; resting BP 120 ± 2/77 ± 2 mmHg). Arterial BP (Finometer) and muscle sympathetic nerve activity (MSNA) were measured continuously. Weighted linear regression analysis between MSNA and diastolic BP was used to estimate arterial baroreflex MSNA gain. There were no age‐related differences in the increase in mean BP (young, Δ14 ± 3 mmHg versus older, Δ15 ± 2 mmHg; P > 0.05) or MSNA burst frequency (young, Δ11 ± 2 bursts min−1 versus older, Δ9 ± 1 bursts min−1; P > 0.05) during PEI. Likewise, the gain of arterial baroreflex control of total MSNA increased to a similar extent in both groups during PEI (young, −4.2 ± 0.9 baseline versus−6.3 ± 1.1 PEI a.u. beat−1 mmHg−1; and older, −3.7 ± 1.1 baseline versus−6.7 ± 1.4 PEI a.u. beat−1 mmHg−1; P < 0.05 for both). Collectively, these findings indicate that the neural interaction between the arterial baroreflex and the skeletal muscle metaboreflex in the regulation of MSNA is preserved in healthy ageing.
The du2J mouse model of ataxia and absence epilepsy has deficient cannabinoid CB1 receptor‐mediated signalling
Authors: Wang Xiaowei , Whalley Benjamin J. , Stephens Gary J. 
Published: June 2013

Key points
Cerebellar ataxias are progressive debilitating diseases with no known treatment and are associated with defective motor function and, in particular, abnormalities to Purkinje cells.
Mutant mice with deficits in Ca2+ channel auxiliary α2δ‐2 subunits are used as models of cerebellar ataxia.
Our data in the du2J mouse model shows an association between the ataxic phenotype exhibited by homozygous du2J/du2J mice and increased irregularity of Purkinje cell firing.
We show that both heterozygous +/du2J and homozygous du2J/du2J mice completely lack the strong presynaptic modulation of neuronal firing by cannabinoid CB1 receptors which is exhibited by litter‐matched control mice.
These results show that the du2J ataxia model is associated with deficits in CB1 receptor signalling in the cerebellar cortex, putatively linked with compromised Ca2+ channel activity due to reduced α2δ‐2 subunit expression. Knowledge of such deficits may help design therapeutic agents to combat ataxias.
Abstract  Cerebellar ataxias are a group of progressive, debilitating diseases often associated with abnormal Purkinje cell (PC) firing and/or degeneration. Many animal models of cerebellar ataxia display abnormalities in Ca2+ channel function. The ‘ducky’du2J mouse model of ataxia and absence epilepsy represents a clean knock‐out of the auxiliary Ca2+ channel subunit α2δ‐2, and has been associated with deficient Ca2+ channel function in the cerebellar cortex. Here, we investigate effects of du2J mutation on PC layer (PCL) and granule cell layer (GCL) neuronal spiking activity and, also, inhibitory neurotransmission at interneurone–Purkinje cell (IN‐PC) synapses. Increased neuronal firing irregularity was seen in the PCL and, to a less marked extent, in the GCL in du2J/du2J, but not +/du2J, mice; these data suggest that the ataxic phenotype is associated with lack of precision of PC firing, that may also impinge on GC activity and requires expression of two du2J alleles to manifest fully. The du2J mutation had no clear effect on spontaneous inhibitory postsynaptic current (sIPSC) frequency at IN‐PC synapses, but was associated with increased sIPSC amplitudes. du2J mutation ablated cannabinoid CB1 receptor (CB1R)‐mediated modulation of spontaneous neuronal spike firing and CB1R‐mediated presynaptic inhibition of synaptic transmission at IN‐PC synapses in both +/du2J and du2J/du2J mutants, effects that occurred in the absence of changes in CB1R expression. These results demonstrate that the du2J ataxia model is associated with deficient CB1R signalling in the cerebellar cortex, putatively linked with compromised Ca2+ channel activity and the ataxic phenotype.
Increased apical Na+ permeability in cystic fibrosis is supported by a quantitative model of epithelial ion transport
Authors: O’Donoghue Donal L. , Dua Vivek , Moss Guy W. J. , Vergani Paola 
Published: June 2013

Key points
Cystic fibrosis (CF) is a common genetic disease caused by loss‐of‐function mutations in the cystic fibrosis transmembrane conductance regulator gene, which encodes a channel protein, selective for anions.
In the lungs, the site of the most severe symptoms, CF causes abnormal electrolyte transport in epithelial cells which line the airways.
Airway epithelial ion transport can be assessed by measuring the trans‐epithelial potential difference (Vt) which shows characteristic changes in CF individuals. We developed a biophysical model of ion transport in human nasal epithelia, in order to investigate quantitatively which transport parameters underlie these observed bioelectric changes.
We found that loss of apical Cl− permeability alone is insufficient to explain the bioelectric properties of CF epithelia. An increase of apical Na+ permeability must also occur.
This insight has important implications for our understanding of the physiology of CF disease, and hence for potential therapies aimed at correcting the CF ion transport defect.
Abstract  Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes an anion channel. In the human lung CFTR loss causes abnormal ion transport across airway epithelial cells. As a result CF individuals produce thick mucus, suffer persistent bacterial infections and have a much reduced life expectancy. Trans‐epithelial potential difference (Vt) measurements are routinely carried out on nasal epithelia of CF patients in the clinic. CF epithelia exhibit a hyperpolarised basal Vt and a larger Vt change in response to amiloride (a blocker of the epithelial Na+ channel, ENaC). Are these altered bioelectric properties solely a result of electrical coupling between the ENaC and CFTR currents, or are they due to an increased ENaC permeability associated with CFTR loss? To examine these issues we have developed a quantitative mathematical model of human nasal epithelial ion transport. We find that while the loss of CFTR permeability hyperpolarises Vt and also increases amiloride‐sensitive Vt, these effects are too small to account for the magnitude of change observed in CF epithelia. Instead, a parallel increase in ENaC permeability is required to adequately fit observed experimental data. Our study provides quantitative predictions for the complex relationships between ionic permeabilities and nasal Vt, giving insights into the physiology of CF disease that have important implications for CF therapy.
Eccentric contractions increase the phosphorylation of tuberous sclerosis complex‐2 (TSC2) and alter the targeting of TSC2 and the mechanistic target of rapamycin to the lysosome
Authors: Jacobs Brittany L. , You Jae‐Sung , Frey John W. , Goodman Craig A. , Gundermann David M. , Hornberger Troy A. 
Published: June 2013

Key points
Mechanical stimuli play a major role in the regulation of skeletal muscle mass.
Signalling through a protein kinase called the mechanistic target of rapamycin (mTOR) is essential for mechanically induced changes in muscle mass; however, the mechanism(s) via which mechanical stimuli regulate mTOR signalling have not been defined.
In this study, mouse skeletal muscles were stimulated with eccentric contractions (ECs) to determine if the mechanical activation of mTOR signalling is associated with changes in the phosphorylation of the tuberous sclerosis complex‐2 (TSC2) and the targeting of both mTOR and TSC2 to the lysosome.
Our results demonstrate that ECs induce hyper‐phosphorylation of TSC2, enhanced lysosomal targeting of mTOR and nearly abolish the lysosomal targeting of TSC2.
These novel observations suggest that alterations in the lysosomal targeting of mTOR/TSC2 could play a fundamental role in the mechanism via which mechanical stimuli regulate mTOR signalling and ultimately skeletal muscle mass.
Abstract  The goal of this study was to determine whether the mechanical activation of mechanistic target of rapamycin (mTOR) signalling is associated with changes in phosphorylation of tuberous sclerosis complex‐2 (TSC2) and targeting of mTOR and TSC2 to the lysosome. As a source of mechanical stimulation, mouse skeletal muscles were subjected to eccentric contractions (ECs). The results demonstrated that ECs induced hyper‐phosphorylation of TSC2 and at least part of this increase occurred on residue(s) that fall within RxRxxS/T consensus motif(s). Furthermore, in control muscles, we found that both mTOR and TSC2 are highly enriched at the lysosome. Intriguingly, ECs enhanced the lysosomal association of mTOR and almost completely abolished the lysosomal association of TSC2. Based on these results, we developed a new model that could potentially explain how mechanical stimuli activate mTOR signalling. Furthermore, this is the first study to reveal that the activation of mTOR is associated with the translocation of TSC2 away from the lysosome. Since a large number of signalling pathways rely on TSC2 to control mTOR signalling, our results have potentially revealed a fundamental mechanism via which not only mechanical, but also various other types of stimuli, control mTOR signalling.
Virulence of Vancomycin-Resistant Enterococcus faecium According to Linezolid Resistance and Clinical Outbreak Status
Authors: McLaughlin Milena , Malczynski Michael , Qi Chao , Barajas Grace , Radetski Jordan , Zembower Teresa , Scheetz Marc H. 
Published: June 2013

ABSTRACT

Assessing clinical virulence differences between vancomycin-resistant
Enterococcus faecium
(VREF) strains resistant to linezolid (LRVRE) and linezolid-susceptible VRE (LSVRE) strains is difficult due to confounding patient variables.
Galleria mellonella
is a validated host interaction model allowing straightforward organism virulence assessment. The objective of this study was to assess the virulence of VREF in
G. mellonella
according to linezolid resistance and clinical outbreak status. A genetically related pair of VREF strains with and without genotypically confirmed linezolid resistance was selected for analysis. Additionally, six strains of LSVRE and two strains of LRVRE were selected according to epidemiologic outbreak status. Mortality of
G. mellonella
was assessed daily over a 5-day period and analyzed using Kaplan-Meier survival curves and log rank tests. Linezolid resistance did not have a significant effect on
G. mellonella
mortality in the genetically related pair (
P
= 0.93). There was no significant difference in mortality over time between strains (non-outbreak [i.e., no patient transmissions were recorded] [
n
= 2] versus outbreak [i.e., transmission occurred between 3 or more patients in a period of 30 days] [
n
= 6],
P
= 0.84; extensive transmission [i.e., the isolate was transmitted between at least 80 patients] [
n
= 2] versus limited transmission [i.e., the isolate was transmitted between fewer than 10 patients] [
n
= 4],
P
= 0.78). These results suggest that patients infected with LRVRE or outbreak strains of VREF are at no greater risk of poor outcomes mediated by organism virulence than those infected with LSVRE or non-outbreak strains.
Role of the LytSR Two-Component Regulatory System in Adaptation to Cationic Antimicrobial Peptides in Staphylococcus aureus
Authors: Yang Soo-Jin , Xiong Yan Q. , Yeaman Michael R. , Bayles Kenneth W. , Abdelhady Wessam , Bayer Arnold S. 
Published: June 2013

ABSTRACT

Many host defense cationic antimicrobial peptides (HDPs) perturb the staphylococcal cell membrane (CM) and alter transmembrane potential (ΔΨ) as key parts of their lethal mechanism. Thus, a sense-response system for detecting and mediating adaptive responses to such stresses could impact organism survival; the
Staphylococcus aureus
LytSR two-component regulatory system (TCRS) may serve as such a ΔΨ sensor. One well-known target of this system is the
lrgAB
operon, which, along with the related
cidABC
operon, has been shown to be a regulator in the control of programmed cell death and lysis. We used an isogenic set of
S. aureus
strains: (i) UAMS-1, (ii) its isogenic Δ
lytS
and Δ
lrgAB
mutants, and (iii) plasmid-complemented Δ
lytSR
and Δ
lrgAB
mutants. The Δ
lytS
strain displayed significantly increased
in vitro
susceptibilities to all HDPs tested (neutrophil-derived human neutrophil peptide 1 [hNP-1], platelet-derived thrombin-induced platelet microbicidal proteins [tPMPs], and the tPMP-mimetic peptide RP-1), as well as to calcium-daptomycin (DAP), a cationic antimicrobial peptide (CAP). In contrast, the Δ
lrgAB
strain exhibited no significant changes in susceptibilities to these cationic peptides, indicating that although
lytSR
positively regulates transcription of
lrgAB
, increased HDP/CAP susceptibilities in the Δ
lytS
mutant were
lrgAB
independent. Further, parental UAMS-1 (but not the Δ
lytS
mutant) became more resistant to hNP-1 and DAP following pretreatment with carbonyl cyanide
m
-chlorophenylhydrazone (CCCP) (a CM-depolarizing agent). Of note,
lytSR
-dependent survival against CAP/HDP killing was not associated with changes in either surface positive charge, expression of
mprF
and
dlt
, or CM fluidity. The Δ
lytS
strain (but not the Δ
lrgAB
mutant) displayed a significant reduction in target tissue survival in an endocarditis model during DAP treatment. Collectively, these results suggest that the
lytSR
TCRS plays an important role in adaptive responses of
S. aureus
to CM-perturbing HDPs/CAPs, likely by functioning as a sense-response system for detecting subtle changes in ΔΨ.
Lethal Hydroxyl Radical Accumulation by a Lactococcal Bacteriocin, Lacticin Q
Authors: Li Mengqi , Yoneyama Fuminori , Toshimitsu Nayu , Zendo Takeshi , Nakayama Jiro , Sonomoto Kenji 
Published: June 2013

ABSTRACT
The antimicrobial mechanism of a lactococcal bacteriocin, lacticin Q, can be described by the toroidal pore model without any receptor. However, lacticin Q showed different degrees of activity (selective antimicrobial activity) against Gram-positive bacteria even among related species. The ability of lacticin Q to induce pore formation in liposomes composed of lipids from different indicator strains indicated that its selective antimicrobial activity could not be attributed only to membrane lipid composition. We investigated the accumulation of deleterious hydroxyl radicals after exposure to lacticin Q as a contributing factor to cell death in the indicator strains. When lacticin Q of the same concentration as the MIC or minimum bactericidal concentration was added to the indicator cultures, high levels of hydroxyl radical accumulation were detected. Treatment with hydroxyl radical scavengers, thiourea and 2,2′-bipyridyl, decreased the levels of hydroxyl radical accumulation and recovered cell viability. These results suggest that, with or without pore formation, the final antimicrobial mechanism of lacticin Q is the accumulation of hydroxyl radicals, which varies by strain, resulting in the selective antimicrobial activity of lacticin Q.
Efficacy of Humanized Carbapenem Exposures against New Delhi Metallo-β-Lactamase (NDM-1)-Producing Enterobacteriaceae in a Murine Infection Model
Authors: Wiskirchen Dora E. , Nordmann Patrice , Crandon Jared L. , Nicolau David P. 
Published: June 2013

ABSTRACT

Enterobacteriaceae
producing the novel carbapenemase New Delhi metallo-β-lactamase (NDM-1) are emerging worldwide. While these organisms often display high levels of
in vitro
resistance to multiple antibiotics,
in vivo
efficacy data are lacking. Here, the activities of humanized ertapenem and doripenem exposures were characterized against a wild-type
K. pneumoniae
and its derived isogenic strains harboring either an NDM-1 or KPC-2 plasmid in immunocompetent mice. In addition, four clinical isolates expressing NDM-1 were evaluated. Human-simulated regimens of ertapenem at 1 g every 24 h and high-dose, prolonged infusion of doripenem at 2 g every 8 h as a 4-h infusion were evaluated over 24 h, and efficacy was determined by the change in bacterial density compared to that in 24-h growth controls. CFU reductions in bacterial density of greater than 1 log unit were observed against the wild-type strain as well as the derived isogenic NDM-1 strain, while no reduction was observed against the derived KPC-2 strain. Postexposure MICs confirmed the
in vitro
maintenance of the ertapenem resistance marker in both the NDM-1 and KPC-2 strains. Similar to the case for the isogenically derived NDM-1 strain, bacterial density was reduced at 24 h against all four clinical NDM-1 isolates showing variable levels of MICs for carbapenems, with near-maximal activity of both agents occurring when the doripenem MIC was ≤8 μg/ml. While carbapenem monotherapy does not appear to be an option against KPC-based infections, these data suggest that carbapenem monotherapy may be a viable option for treating NDM-1-producing
Enterobacteriaceae
under certain conditions, and this warrants further
in vivo
exploration.
Efficacy and Safety of Metronidazole for Pulmonary Multidrug-Resistant Tuberculosis
Authors: Carroll Matthew W. , Jeon Doosoo , Mountz James M. , Lee Jong Doo , Jeong Yeon Joo , Zia Nadeem , Lee Myungsun , Lee Jongseok , Via Laura E. , Lee Soyoung , Eum Seok-Yong , Lee Sung-Joong , Goldfeder Lisa C. , Cai Ying , Jin Boyoung , Kim Youngran , Oh Taegwon , Chen Ray Y. , Dodd Lori E. , Gu Wenjuan , Dartois Veronique , Park Seung-Kyu , Kim Cheon Tae , Barry Clifton E. , Cho Sang-Nae 
Published: June 2013

ABSTRACT

Pulmonary lesions from active tuberculosis patients are thought to contain persistent, nonreplicating bacilli that arise from hypoxic stress. Metronidazole, approved for anaerobic infections, has antituberculosis activity against anoxic bacilli
in vitro
and in some animal models and may target persistent, nonreplicating bacilli. In this double-blind, placebo-controlled trial, pulmonary multidrug-resistant tuberculosis subjects were randomly assigned to receive metronidazole (500 mg thrice daily) or placebo for 8 weeks in addition to an individualized background regimen. Outcomes were measured radiologically (change on high-resolution computed tomography [HRCT]), microbiologically (time to sputum smear and culture conversion), and clinically (status 6 months after stopping therapy). Enrollment was stopped early due to excessive peripheral neuropathies in the metronidazole arm. Among 35 randomized subjects, 31 (15 metronidazole, 16 placebo) were included in the modified intent-to-treat analysis. There were no significant differences by arm in improvement of HRCT lesions from baseline to 2 or 6 months. More subjects in the metronidazole arm converted their sputum smear (
P
= 0.04) and liquid culture (
P
= 0.04) to negative at 1 month, but these differences were lost by 2 months. Overall, 81% showed clinical success 6 months after stopping therapy, with no differences by arm. However, 8/16 (50%) of subjects in the metronidazole group and 2/17 (12%) of those in the placebo group developed peripheral neuropathy. Subjects who received metronidazole were 4.3-fold (95% confidence interval [CI], 1.1 to 17.1) more likely to develop peripheral neuropathies than subjects who received placebo. Metronidazole may have increased early sputum smear and culture conversion but was too neurotoxic to use over the longer term. Newer nitroimidazoles with both aerobic and anaerobic activity, now in clinical trials, may increase the sterilizing potency of future treatment regimens.
Candida albicans Mucin Msb2 Is a Broad-Range Protectant against Antimicrobial Peptides
Authors: Swidergall Marc , Ernst Andreas M. , Ernst Joachim F. 
Published: June 2013

ABSTRACT

The human fungal pathogen
Candida albicans
releases a large glycofragment of the Msb2 surface protein (Msb2*) into the growth environment, which protects against the action of human antimicrobial peptides (AMPs) LL-37 and histatin-5. Quantitation of Msb2*/LL-37 interactions by microscale thermophoresis revealed high-affinity binding (dissociation constant [

K
D

] = 73 nM), which was lost or greatly diminished by lack of
O
-glycosylation or by Msb2* denaturation. Msb2* also interacted with human α- and β-defensins and protected
C. albicans
against these AMPs. In addition, the lipopeptide antibiotic daptomycin was bound and inactivated by Msb2*, which prevented the killing of bacterial pathogens
Staphylococcus aureus
,
Enterococcus faecalis
, and
Corynebacterium pseudodiphtheriticum
. In coculturings or mixed biofilms of
S. aureus
with
C. albicans
wild-type but not
msb2
mutant strains, the protective effects of Msb2* on the bactericidal action of daptomycin were demonstrated. These results suggest that tight binding of shed Msb2* to AMPs that occurs during bacterial coinfections with
C. albicans
compromises antibacterial therapy by inactivating a relevant reserve antibiotic.