bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nosocomial Infections after Aneurysmal Subarachnoid Hemorrhage: Time Course and Causative Pathogens
Authors: Laban Kamil G. , Rinkel Gabriel J. E. , Vergouwen Mervyn D. I. 
Published: April 2015

Background Nosocomial infections after aneurysmal subarachnoid hemorrhage (aSAH) are associated with prolonged length of stay and poor functional outcome. It remains unclear if infections result in prolonged length of stay or, vice versa, if prolonged length of stay results in more infections. Before strategies can be designed to reduce infections after aneurysmal subarachnoid hemorrhage, more data are needed on time course and causative pathogens of infections. Aim To investigate the time course of infection onset and bacterial microorganisms that cause nosocomial infections after aSAH. Methods In consecutive patients with aneurysmal subarachnoid hemorrhage admitted to the University Medical Center Utrecht between 2009 and 2011, we analyzed the proportion of patients with infections, day of infection onset, and culture results. Results Of the 291 included patients, 107 (37%) patients developed 115 nosocomial infections. Fifty-six patients (19%) developed an infection within the first week. Median day of infection onset was for pneumonia ( n = 49; 17%) day 4 (interquartile range 3–9), respiratory tract infection ( n = 16; 6%) day 4 (interquartile range 1–7), urinary tract infection ( n = 27; 9%) day 11 (interquartile range 7–14), and meningitis/ventriculitis ( n = 10; 3%) day 19 (interquartile range 9–33). Cultures of infections mostly yielded Staphylococcus aureus (20%), Haemophilus influenzae (15%), and Escherichia coli (14%), Conclusion Nosocomial infections after subarachnoid hemorrhage are common and mostly occur in the first week after ictus. Future studies should investigate if general hygienic measures, infection awareness, minimizing the duration of mechanical ventilation and use of catheters/drains, or prophylactic antibiotics reduce infections and improve functional outcome.
Influence of complement on neutrophil extracellular trap release induced by bacteria
Authors: Palmer L. J. , Damgaard C. , Holmstrup P. , Nielsen C. H. 
Published: April 2015

Background and ObjectivesNeutrophil extracellular trap (NET) release has generally been studied in the absence of serum, or at low concentrations of untreated or heat‐inactivated serum. The influence of serum complement on NET release therefore remains unclear. We examined the DNA release induced by Staphylococcus aureus and three oral bacteria: Actinomyces viscosus, Aggregatibacter actinomycetemcomitans and Fusobacterium nucleatum subsp. vincettii.Material and MethodsBacteria‐stimulated NET release from the neutrophils of healthy donors was measured fluorometrically. Various complement containing and complement blocking conditions were used, including heat inactivation of the serum and antibody blockade of complement receptors 1 (CR1, CD35) and 3 (CR3, CD11b/CD18).ResultsWhile the presence of serum markedly enhanced NET release induced by S. aureus, A. actinomycetemcomitans, and to a lesser extent by A. viscosus, there was no enhancement of NET release induced by F. nucleatum. The serum‐mediated enhancement of NET release by A. actinomycetemcomitans was neutralized by heat inactivation of serum complement, while this was not the case for S. aureus. Blockade of CR1, significantly reduced NET release induced by S. aureus, A. actinomycetemcomitans and A. viscosus, while blockade of CR3, had no effect. However, opsonization of S. aureus with antibodies may also have contributed to the enhancing effect of serum, independently of complement, in that purified IgG promoted NET release.ConclusionsIn conclusion, complement opsonization promotes NET release induced by a variety of bacteria, including A. actinomycetemcomitans, and CR1 plays a dominant role in the process. Complement consumption or deficiency may compromise NETosis induced by some bacterial species, including A. actinomycetemcomitans. Within biofilms, the complement‐inactivating abilities of some bacteria may protect other species against NETosis, while these are more vulnerable when adopting a planktonic lifestyle.
Chronic sleep restriction induces long‐lasting changes in adenosine and noradrenaline receptor density in the rat brain
Authors: Kim Youngsoo , Elmenhorst David , Weisshaupt Angela , Wedekind Franziska , Kroll Tina , Mccarley Robert W. , Strecker Robert E. , Bauer Andreas 
Published: April 2015

SummaryAlthough chronic sleep restriction frequently produces long‐lasting behavioural and physiological impairments in humans, the underlying neural mechanisms are unknown. Here we used a rat model of chronic sleep restriction to investigate the role of brain adenosine and noradrenaline systems, known to regulate sleep and wakefulness, respectively. The density of adenosine A1 and A2a receptors and β‐adrenergic receptors before, during and following 5 days of sleep restriction was assessed with autoradiography. Rats (n = 48) were sleep‐deprived for 18 h day−1 for 5 consecutive days (SR1–SR5), followed by 3 unrestricted recovery sleep days (R1–R3). Brains were collected at the beginning of the light period, which was immediately after the end of sleep deprivation on sleep restriction days. Chronic sleep restriction increased adenosine A1 receptor density significantly in nine of the 13 brain areas analysed with elevations also observed on R3 (+18 to +32%). In contrast, chronic sleep restriction reduced adenosine A2a receptor density significantly in one of the three brain areas analysed (olfactory tubercle which declined 26–31% from SR1 to R1). A decrease in β‐adrenergic receptors density was seen in substantia innominata and ventral pallidum which remained reduced on R3, but no changes were found in the anterior cingulate cortex. These data suggest that chronic sleep restriction can induce long‐term changes in the brain adenosine and noradrenaline receptors, which may underlie the long‐lasting neurocognitive impairments observed in chronic sleep restriction.
Rhomboid proteases in invasion and replication of Apicomplexa
Authors: Stewart Rebecca J. , Tonkin Christopher J. 
Published: April 2015

SummaryIn this issue of Molecular Microbiology, Rugarabamu and colleagues investigate the role of rhomboid proteases responsible for adhesin shedding during invasion of the apicomplexan parasite Toxoplasma gondii. This study, together with several other recent publications, raises new questions about the function of these rhomboids in Toxoplasma, while also strongly arguing against other recently proposed roles for these proteases.
Carbon catabolite repression by seryl phosphorylated HPr is essential to Streptococcus pneumoniae in carbohydrate‐rich environments
Authors: Fleming Eleanor , Lazinski David W. , Camilli Andrew 
Published: April 2015

SummaryCarbon catabolite repression (CCR) is a regulatory phenomenon implemented by bacteria to hierarchically organize carbohydrate utilization in order to achieve maximal growth. CCR is likely of great importance to Streptococcus pneumoniae because the human host sites inhabited by this pathogen represent complex carbohydrate environments. In this species, inactivation of the prototypical Gram‐positive CCR master regulator, ccpA, attenuates virulence in mice but does not relieve CCR of most metabolic enzymes, suggesting CcpA‐independent CCR mechanisms predominate. Here we show the activities of three transcriptional regulators constitute the majority of transcriptional CCR of galactose metabolism operons. We determined seryl‐phosphorylated histidine phosphocarrier protein (HPr‐Ser∼P)‐mediated regulation is a major CCR mechanism and an essential activity in the pneumococcus, as an HPr point mutation abolishing HPrK/P‐dependent phosphorylation was not tolerated nor was deletion of hprk/p. The HPr‐Ser∼P phosphomimetic mutant HPr S46D had reduced phosphotransferase system transport rates and limited induction of CCR‐repressed genes. These results support a model of pneumococcal CCR in which HPr‐Ser∼P directly affects the activity of CcpA while indirectly affecting the activity of pathway‐specific transactional regulators. This report describes the first CcpA‐independent CCR mechanism identified in the pneumococcus and the first example of lethality from loss of HPr‐Ser∼P‐mediated CCR in any species.
The Psp system of Mycobacterium tuberculosis integrates envelope stress‐sensing and envelope‐preserving functions
Authors: Datta Pratik , Ravi Janani , Guerrini Valentina , Chauhan Rinki , Neiditch Matthew B. , Shell Scarlet S. , Fortune Sarah M. , Hancioglu Baris , Igoshin Oleg A. , Gennaro Maria Laura 
Published: April 2015

SummaryThe bacterial envelope integrates essential stress‐sensing and adaptive functions; thus, envelope‐preserving functions are important for survival. In Gram‐negative bacteria, envelope integrity during stress is maintained by the multi‐gene Psp response. Mycobacterium tuberculosis was thought to lack the Psp system since it encodes only pspA and no other psp ortholog. Intriguingly, pspA maps downstream from clgR, which encodes a transcription factor regulated by the MprAB‐σE envelope‐stress‐signaling system. clgR inactivation lowered ATP concentration during stress and protonophore treatment‐induced clgR‐pspA expression, suggesting that these genes express Psp‐like functions. We identified a four‐gene set – clgR, pspA (rv2744c), rv2743c, rv2742c – that is regulated by clgR and in turn regulates ClgR activity. Regulatory and protein–protein interactions within the set and a requirement of the four genes for functions associated with envelope integrity and surface‐stress tolerance indicate that a Psp‐like system has evolved in mycobacteria. Among Actinobacteria, the four‐gene module occurred only in tuberculous mycobacteria and was required for intramacrophage growth, suggesting links between its function and mycobacterial virulence. Additionally, the four‐gene module was required for MprAB‐σE stress‐signaling activity. The positive feedback between envelope‐stress‐sensing and envelope‐preserving functions allows sustained responses to multiple, envelope‐perturbing signals during chronic infection, making the system uniquely suited to tuberculosis pathogenesis.
Does Twitter Increase Perceived Police Legitimacy?
Authors: Grimmelikhuijsen Stephan G. , Meijer Albert J. 
Published: April 2015

AbstractSocial media use has become increasingly popular among police forces. The literature suggests that social media use can increase perceived police legitimacy by enabling transparency and participation. Employing data from a large and representative survey of Dutch citizens (N = 4,492), this article tests whether and how social media use affects perceived legitimacy for a major social media platform, Twitter. A negligible number of citizens engage online with the police, and thus the findings reveal no positive relationship between participation and perceived legitimacy. The article shows that by enhancing transparency, Twitter does increase perceived police legitimacy, albeit to a limited extent. Subsequent analysis of the mechanism shows both an affective and a cognitive path from social media use to legitimacy. Overall, the findings suggest that establishing a direct channel with citizens and using it to communicate successes does help the police strengthen their legitimacy, but only slightly and for a small group of interested citizens.
Serving Clients When the Server Crashes: How Frontline Workers Cope with E‐Government Challenges
Authors: Tummers Lars , Rocco Philip 
Published: April 2015

AbstractImplementing e‐government in the contemporary American state is challenging. E‐government places high technical demands on agencies and citizens in an environment of budget austerity and political polarization. Governments developing e‐government policies often mobilize frontline workers—also termed “street‐level bureaucrats”—to help citizens gain access to services. However, we know little about how frontline workers cope in these challenging circumstances. This article fills this gap by examining frontline workers implementing the Patient Protection and Affordable Care Act. Based on a qualitative analysis, the authors find that frontline workers “move toward clients” when coping with stress: they bend the rules, work overtime, and collaborate in order to help clients. They are less inclined to “move away” or “move against” clients, for instance, through rigid rule following and rationing. In other words, frontline workers try to serve clients, even “when the server crashes.” Frontline workers, then, can play a vital role in the successful implementation of e‐government policies.
Origins of Yersinia pestis Sensitivity to the Arylomycin Antibiotics and the Inhibition of Type I Signal Peptidase
Authors: Steed Danielle B. , Liu Jian , Wasbrough Elizabeth , Miller Lynda , Halasohoris Stephanie , Miller Jeremy , Somerville Brandon , Hershfield Jeremy R. , Romesberg Floyd E. 
Published: April 2015

ABSTRACT

Yersinia pestis
is the etiologic agent of the plague. Reports of
Y. pestis
strains that are resistant to each of the currently approved first-line and prophylactic treatments point to the urgent need to develop novel antibiotics with activity against the pathogen. We previously reported that
Y. pestis
strain KIM6+, unlike most
Enterobacteriaceae
, is susceptible to the arylomycins, a novel class of natural-product lipopeptide antibiotics that inhibit signal peptidase I (SPase). In this study, we show that the arylomycin activity is conserved against a broad range of
Y. pestis
strains and confirm that it results from the inhibition of SPase. We next investigated the origins of this unique arylomycin sensitivity and found that it does not result from an increased affinity of the
Y. pestis
SPase for the antibiotic and that alterations to each component of the
Y. pestis
lipopolysaccharide—O antigen, core, and lipid A—make at most only a small contribution. Instead, the origins of the sensitivity can be traced to an increased dependence on SPase activity that results from high levels of protein secretion under physiological conditions. These results highlight the potential of targeting protein secretion in cases where there is a heavy reliance on this process and also have implications for the development of the arylomycins as an antibiotic with activity against
Y. pestis
and potentially other Gram-negative pathogens.
Validation and Pharmacokinetic Application of a High-Performance Liquid Chromatographic Technique for Determining the Concentrations of Amodiaquine and Its Metabolite in Plasma of Patients Treated with Oral Fixed-Dose Amodiaquine-Artesunate Combination in Areas of Malaria Endemicity
Authors: Adedeji Olumuyiwa N. , Bolaji Oluseye O. , Falade Catherine O. , Osonuga Odusoga A. , Ademowo Olusegun G. 
Published: April 2015

ABSTRACT

Artemisinin-based combination therapies (ACTs) have been adopted by most African countries, including Nigeria, as first-line treatments for uncomplicated falciparum malaria. Fixed-dose combinations of these ACTs, amodiaquine-artesunate (FDC AQAS) and artemether-lumefantrine (AL), were introduced in Nigeria to improve compliance and achieve positive outcomes of malaria treatment. In order to achieve clinical success with AQAS, we developed and validated a simple and sensitive high-performance liquid chromatography (HPLC) method with UV detection for determination of amodiaquine (AQ) and desethylamodiaquine (DAQ) in plasma using liquid-liquid extraction of the drugs with diethyl ether following protein precipitation with acetonitrile. Chromatographic separation was achieved using an Agilent Zorbax C
18
column and a mobile phase consisting of distilled water-methanol (80:20 [vol/vol]) with 2% (vol/vol) triethylamine, pH 2.2, at a flow rate of 1 ml/min. Calibration curves in spiked plasma were linear from 100 to 1,000 ng/ml (
r
> 0.99) for both AQ and DAQ. The limit of detection was 1 ng (sample size, 20 μl). The intra- and interday coefficients of variation at 150, 300, and 900 ng/ml ranged from 1.3 to 4.8%, and the biases were between 6.4 and 9.5%. The mean extraction recoveries of AQ and DAQ were 80.0% and 68.9%, respectively. The results for the pharmacokinetic parameters of DAQ following oral administration of FDC AQAS (612/200 mg) for 3 days in female and male patients with uncomplicated falciparum malaria showed that the maximum plasma concentrations (
C
max
) (740 ± 197 versus 767 ± 185 ng/ml), areas under the plasma concentration-time curve (AUC) (185,080 ± 20,813 versus 184,940 ± 16,370 h · ng/ml), and elimination half-life values (
T
1/2
) (212 ± 1.14 versus 214 ± 0.84 h) were similar (
P
> 0.05).
Autophagy Inhibitors as a Potential Antiamoebic Treatment for Acanthamoeba Keratitis
Authors: Moon Eun-Kyung , Kim So-Hee , Hong Yeonchul , Chung Dong-Il , Goo Youn-Kyoung , Kong Hyun-Hee 
Published: April 2015

ABSTRACT

Acanthamoeba
cysts are resistant to extreme physical and chemical conditions. Autophagy is an essential pathway for encystation of
Acanthamoeba
cells. To evaluate the possibility of an autophagic
Acanthamoeba
encystation mechanism, we evaluated autophagy inhibitors, such as 3-methyladenine (3MA), LY294002, wortmannin, bafilomycin A, and chloroquine. Among these autophagy inhibitors, the use of 3MA and chloroquine showed a significant reduction in the encystation ratio in
Acanthamoeba
cells. Wortmannin also inhibited the formation of mature cysts, while LY294002 and bafilomycin A did not affect the encystation of
Acanthamoeba
cells. Transmission electron microscopy revealed that 3MA and wortmannin inhibited autophagy formation and that chloroquine interfered with the formation of autolysosomes. Inhibition of autophagy or autolysosome formation resulted in a significant block in the encystation in
Acanthamoeba
cells. Clinical treatment with 0.02% polyhexamethylene biguanide (PHMB) showed high cytopathic effects on
Acanthamoeba
trophozoites and cysts; however, it also revealed high cytopathic effects on human corneal epithelial cells. In this study, we investigated effects of the combination of a low (0.00125%) concentration of PHMB with each of the autophagy inhibitors 3MA, wortmannin, and chloroquine on
Acanthamoeba
and human corneal epithelial cells. These new combination treatments showed low cytopathic effects on human corneal cells and high cytopathic effects on
Acanthamoeba
cells. Taken together, these results provide fundamental information for optimizing the treatment of
Acanthamoeba
keratitis.
An Invertron-Like Linear Plasmid Mediates Intracellular Survival and Virulence in Bovine Isolates of Rhodococcus equi
Authors: Valero-Rello Ana , Hapeshi Alexia , Anastasi Elisa , Alvarez Sonsiray , Scortti Mariela , Meijer Wim G. , MacArthur Iain , Vázquez-Boland José A. 
Published: April 2015

ABSTRACT

We report a novel host-associated virulence plasmid in
Rhodococcus equi
, pVAPN, carried by bovine isolates of this facultative intracellular pathogenic actinomycete. Surprisingly, pVAPN is a 120-kb invertron-like linear replicon unrelated to the circular virulence plasmids associated with equine (pVAPA) and porcine (pVAPB variant)
R. equi
isolates. pVAPN is similar to the linear plasmid pNSL1 from
Rhodococcus
sp. NS1 and harbors six new
vap
multigene family members (
vapN
to
vapS
) in a
vap
pathogenicity locus presumably acquired via
en bloc
mobilization from a direct predecessor of equine pVAPA. Loss of pVAPN rendered
R. equi
avirulent in macrophages and mice. Mating experiments using an
in vivo
transconjugant selection strategy demonstrated that pVAPN transfer is sufficient to confer virulence to a plasmid-cured
R. equi
recipient. Phylogenetic analyses assigned the
vap
multigene family complement from pVAPN, pVAPA, and pVAPB to seven monophyletic clades, each containing plasmid type-specific allelic variants of a precursor
vap
gene carried by the nearest
vap
island ancestor. Deletion of
vapN
, the predicted “bovine-type” allelic counterpart of
vapA
, essential for virulence in pVAPA, abrogated pVAPN-mediated intramacrophage proliferation and virulence in mice. Our findings support a model in which
R. equi
virulence is conferred by host-adapted plasmids. Their central role is mediating intracellular proliferation in macrophages, promoted by a key
vap
determinant present in the common ancestor of the plasmid-specific
vap
islands, with host tropism as a secondary trait selected during coevolution with specific animal species.
A Heterologous Reporter Defines the Role of the Tetanus Toxin Interchain Disulfide in Light-Chain Translocation
Authors: Zuverink Madison , Chen Chen , Przedpelski Amanda , Blum Faith C. , Barbieri Joseph T. 
Published: April 2015

ABSTRACT

Botulinum neurotoxins (BoNTs) and tetanus toxin (TeNT) are the most potent toxins for humans and elicit unique pathologies due to their ability to traffic within motor neurons. BoNTs act locally within motor neurons to elicit flaccid paralysis, while retrograde TeNT traffics to inhibitory neurons within the central nervous system (CNS) to elicit spastic paralysis. BoNT and TeNT are dichain proteins linked by an interchain disulfide bond comprised of an N-terminal catalytic light chain (LC) and a C-terminal heavy chain (HC) that encodes an LC translocation domain (HCT) and a receptor-binding domain (HCR). LC translocation is the least understood property of toxin action, but it involves low pH, proteolysis, and an intact interchain disulfide bridge. Recently, Pirazzini et al. (FEBS Lett 587:150–155, 2013,
http://dx.doi.org/10.1016/j.febslet.2012.11.007
) observed that inhibitors of thioredoxin reductase (TrxR) blocked TeNT and BoNT action in cerebellar granular neurons. In the current study, an atoxic TeNT LC translocation reporter was engineered by fusing β-lactamase to the N terminus of TeNT [βlac-TeNT(RY)] to investigate LC translocation in primary cortical neurons and Neuro-2a cells. βlac-TeNT(RY) retained the interchain disulfide bond, showed ganglioside-dependent binding to neurons, required acidification to promote βlac translocation, and was sensitive to auranofin, an inhibitor of thioredoxin reductase. Mutation of βlac-TeNT(RY) at C439S and C467S eliminated the interchain disulfide bond and inhibited βlac translocation. These data support the requirement of an intact interchain disulfide for LC translocation and imply that disulfide reduction is a prerequisite for LC delivery into the host cytosol. The data also support a model that LC translocation proceeds from the C to the N terminus. βlac-TeNT(RY) is the first reporter system to measure translocation by an AB single-chain toxin in intact cells.