bluuebunny/crossref_metadata_2025_split huggingface dataset:
Standardization of skin cleansing in vivo: part II. Validation of a newly developed Automated Cleansing Device (ACiD)
Authors: Sonsmann F. K. , Strunk M. , Gediga K. , Schliemann S. , Seyfarth F. , Elsner P. , Diepgen T. L. , Kutz G. , John S. M. 
Published: September 2013

BackgroundSkin cleansers for occupational use are manufactured for different types and degrees of soiling without common, legally binding requirements for product testing. This leads to different, manufacturer‐specific test methods and a lack of comparable information on skin cleansing products.ObjectivesThe aim of this investigation was to validate a newly developed standardized automated cleansing device (ACiD) for in vivo evaluation of industrial skin cleansers.MethodsTwo ACiD were tested regarding the intra‐ and inter‐device specific reproducibility of test results.ResultsSkin cleansing process carried out by the three independent washing modules which constitute an ACiD‐unit and two separate ACiD‐units led to highly comparable results. There was no significant difference between the washing modules or between the two separate ACiD‐units detected. Only different parameter settings resulted in significantly different detergency.ConclusionsIntra‐ and inter‐device specific test results of an in vivo model of skin cleansing using the automated cleansing device (ACiD) were reproducible. The long‐term aim is a standardized classification of occupational skin cleansing products comparing their skin cleansing effectiveness in relation to their skin irritancy. This might then provide the basis for a rational specific product selection by consumers and may be used as a tool for future product development by manufacturers.
The Arabidopsis calmodulin‐like protein, CML39, functions during early seedling establishment
Authors: Bender Kyle W. , Rosenbaum Daniel M. , Vanderbeld Barbara , Ubaid Midhat , Snedden Wayne A. 
Published: September 2013

SummaryDuring Ca2+ signal transduction, Ca2+‐binding proteins known as Ca2+ sensors function to decode stimulus‐specific Ca2+ signals into downstream responses. Plants possess extended families of unique Ca2+ sensors termed calmodulin‐like proteins (CMLs) whose cellular roles are not well understood. CML39 encodes a predicted Ca2+ sensor whose expression is strongly increased in response to diverse external stimuli. In the present study, we explored the biochemical properties of recombinant CML39, and used a reverse genetics approach to investigate its physiological role. Our data indicate that Ca2+ binding by CML39 induces a conformational change in the protein that results in an increase in exposed‐surface hydrophobicity, a property that is consistent with its predicted function as a Ca2+ sensor. Loss‐of‐function cml39 mutants resemble wild‐type plants under normal growth conditions but exhibit persistent arrest at the seedling stage if grown in the absence of sucrose or other metabolizable carbon sources. Under short‐day conditions, cml39 mutants display increased sucrose‐induced hypocotyl elongation. When grown in the dark, cml39 mutants show impaired hypocotyl elongation in the absence of sucrose. Promoter–reporter data indicate that CML39 expression is prominent in the apical hook in dark‐grown seedlings. Collectively, our data suggest that CML39 functions in Arabidopsis as a Ca2+ sensor that plays an important role in the transduction of light signals that promote seedling establishment.
Impact of Bolus Dosing versus Continuous Infusion of Piperacillin and Tazobactam on the Development of Antimicrobial Resistance in Pseudomonas aeruginosa
Authors: Felton T. W. , Goodwin J. , O'Connor L. , Sharp A. , Gregson L. , Livermore J. , Howard S. J. , Neely M. N. , Hope W. W. 
Published: September 2013

ABSTRACT

Management of nosocomial pneumonia is frequently complicated by bacterial resistance. Extended infusions of beta-lactams are increasingly being used to improve clinical outcomes. However, the impact of this strategy on the emergence of antimicrobial resistance is not known. A hollow-fiber infection model with
Pseudomonas aeruginosa
(PAO1) was used. Pharmacokinetic (PK) profiles of piperacillin-tazobactam similar to those in humans were simulated over 5 days. Three dosages of piperacillin-tazobactam were administered over 0.5 h or 4 h, with redosing every 8 h. Two initial bacterial densities were investigated (∼10
4
CFU/ml and ∼10
7
CFU/ml). The time courses of the total bacterial population and the resistant subpopulation were determined. All data were described using a mathematical model, which was then used to define the relationship between drug concentrations, bacterial killing, and emergence of piperacillin resistance. There was logarithmic growth in controls in the initial 24 h, reaching a plateau of ∼9 log
10
CFU/ml. Bacterial killing following administration of piperacillin via bolus dosing and that after extended infusions were similar. For the lower initial bacterial density, trough total plasma piperacillin concentration/MIC ratios of 3.4 and 10.4 for bolus and extended-infusion regimens, respectively, were able to suppress the emergence of piperacillin resistance. For the higher initial bacterial density, all regimens were associated with progressive growth of a resistant subpopulation. A stratified approach, according to bacterial density, is required to treat patients with nosocomial pneumonia. Antimicrobial monotherapy may be sufficient for some patients. However, for patients with a high bacterial burden, alternative therapeutic strategies are required to maximize bacterial killing and prevent antimicrobial resistance.
Novel Organization of the Arginine Catabolic Mobile Element and Staphylococcal Cassette Chromosome
mec
Composite Island and Its Horizontal Transfer between Distinct Staphylococcus aureus Genotypes
Authors: Sabat Artur J. , Köck Robin , Akkerboom Viktoria , Hendrix Ron , Skov Robert L. , Becker Karsten , Friedrich Alexander W. 
Published: September 2013

ABSTRACT

In this study, 425 methicillin-resistant
Staphylococcus aureus
(MRSA) isolates recovered in the Dutch-German Euregio were investigated for the presence of the arginine catabolic mobile element (ACME). Sequence analysis by whole-genome sequencing revealed an entirely new organization of the ACME-staphylococcal cassette chromosome
mec
composite island (SCC
mec
-CI), with truncated ACME type II located downstream of SCC
mec
. An identical nucleotide sequence of ACME-SCC
mec
-CI was found in two distinct MRSA lineages (t064-ST8 and t002-ST5), which has not been reported previously in
S. aureus
.
Role of the K101E Substitution in HIV-1 Reverse Transcriptase in Resistance to Rilpivirine and Other Nonnucleoside Reverse Transcriptase Inhibitors
Authors: Xu Hong-Tao , Colby-Germinario Susan P. , Huang Wei , Oliveira Maureen , Han Yingshan , Quan Yudong , Petropoulos Christos J. , Wainberg Mark A. 
Published: September 2013

ABSTRACTResistance to the recently approved nonnucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine (RPV) commonly involves substitutions at positions E138K and K101E in HIV-1 reverse transcriptase (RT), together with an M184I substitution that is associated with resistance to coutilized emtricitabine (FTC). Previous biochemical and virological studies have shown that compensatory interactions between substitutions E138K and M184I can restore enzyme processivity and the viral replication capacity. Structural modeling studies have also shown that disruption of the salt bridge between K101 and E138 can affect RPV binding. The current study was designed to investigate the impact of K101E, alone or in combination with E138K and/or M184I, on drug susceptibility, viral replication capacity, and enzyme function. We show here that K101E can be selected in cell culture by the NNRTIs etravirine (ETR), efavirenz (EFV), and dapivirine (DPV) as well as by RPV. Recombinant RT enzymes and viruses containing K101E, but not E138K, were highly resistant to nevirapine (NVP) and delavirdine (DLV) as well as ETR and RPV, but not EFV. The addition of K101E to E138K slightly enhanced ETR and RPV resistance compared to that obtained with E138K alone but restored susceptibility to NVP and DLV. The K101E substitution can compensate for deficits in viral replication capacity and enzyme processivity associated with M184I, while M184I can compensate for the diminished efficiency of DNA polymerization associated with K101E. The coexistence of K101E and E138K does not impair either viral replication or enzyme fitness. We conclude that K101E can play a significant role in resistance to RPV.
Shedding of Tumor Necrosis Factor Receptor 1 Induced by Protein A Decreases Tumor Necrosis Factor Alpha Availability and Inflammation during Systemic Staphylococcus aureus Infection
Authors: Giai Constanza , Gonzalez Cintia , Ledo Camila , Garofalo Ailin , Di Genaro María Silvia , Sordelli Daniel O. , Gomez Marisa I. 
Published: September 2013

ABSTRACTStaphylococcus aureusinfections are an important public health concern due to their increasing incidence and high rates of mortality. The success ofS. aureusas a pathogen is highly related to its enormous capacity to evade the host immune response. The critical role of tumor necrosis factor alpha (TNF-α) in the initial host defense against systemic staphylococcal infection has been demonstrated in experimental models and may partially explain the lack of significant benefits observed in clinical trials attempting to neutralize this cytokine in septic patients.S. aureusprotein A plays a key role in regulating inflammation through its ability to bind and signal through the TNF-α receptor 1 (TNFR1). In this study, we demonstrate thatS. aureus, via protein A-mediated signaling, induces early shedding of TNFR1, which precedes the secretion of TNF-αin vitroandin vivo. The results obtained using a protein A-deficient mutant andtnfr1−/−mice strongly suggest that the increased levels of soluble TNFR1 present during experimentalS. aureusinfection may neutralize circulating TNF-α and impair the host inflammatory response. Early shedding of TNFR1 induced by protein A may constitute a novel mechanism by whichS. aureussubverts the host immune response.
A Regulatory Checkpoint during Flagellar Biogenesis in Campylobacter jejuni Initiates Signal Transduction To Activate Transcription of Flagellar Genes
Authors: Boll Joseph M. , Hendrixson David R. 
Published: September 2013

ABSTRACT

Many polarly flagellated bacteria require similar two-component regulatory systems (TCSs) and σ
54
to activate transcription of genes essential for flagellar motility. Herein, we discovered that in addition to the flagellar type III secretion system (T3SS), the
Campylobacter jejuni
flagellar MS ring and rotor are required to activate the FlgSR TCS. Mutants lacking the FliF MS ring and FliG C ring rotor proteins were as defective as T3SS mutants in FlgSR- and σ
54
-dependent flagellar gene expression. Also, FliF and FliG required each other for stability, which is mediated by atypical extensions to the proteins. A FliF mutant that presumably does not interact with the T3SS protein FlhA did not support flagellar gene transcription, suggesting that FliF-T3SS interactions are essential to generate a signal sensed by the cytoplasmic FlgS histidine kinase. Furthermore, the flagellar T3SS was required for FlgS to immunoprecipitate with FliF and FliG. We propose a model whereby the flagellar T3SS facilitates FliF and FliG multimerization into the MS ring and rotor. As a result, these flagellar structures form a cytoplasmic complex that interacts with and is sensed by FlgS. The synthesis of these structures appears to be a regulatory checkpoint in flagellar biogenesis that the FlgS kinase monitors to initiate signal transduction that activates σ
54
and expression of genes required for the next stage of flagellation. Given that other polar flagellates have flagellar transcriptional hierarchies that are organized similarly as in
C. jejuni
, this regulatory checkpoint may exist in a broad range of bacteria to influence similar TCSs and flagellar gene transcription.

IMPORTANCE
Despite the presence of numerous two-component regulatory systems (TCSs) in bacteria, direct signals sensed by TCSs to activate signal transduction are known for only a minority. Polar flagellates, including
Pseudomonas
,
Vibrio
,
Helicobacter
, and
Campylobacter
species, require a similar TCS and σ
54
for flagellar gene transcription, but the activating signals for these TCSs are unknown. We explored signals that activate the
Campylobacter jejuni
FlgSR TCS to initiate σ
54
-dependent flagellar gene transcription. Our discoveries suggest that the FlgS histidine kinase monitors the formation of the flagellar type III secretion system and the surrounding MS and C rings. The synthesis of these structures creates a regulatory checkpoint in flagellar biogenesis that is sensed by FlgS to ensure proper transcription of the next set of genes for subsequent steps in flagellation. Given the conservation of flagellar-associated TCSs and transcriptional cascades in polar flagellates, this regulatory checkpoint in flagellar biogenesis likely impacts flagellation in a broad range of bacteria.
What a Difference a Dalton Makes: Bacterial Virulence Factors Modulate Eukaryotic Host Cell Signaling Systems via Deamidation
Authors: Washington Erica J. , Banfield Mark J. , Dangl Jeffery L. 
Published: September 2013

SUMMARY
Pathogenic bacteria commonly deploy enzymes to promote virulence. These enzymes can modulate the functions of host cell targets. While the actions of some enzymes can be very obvious (e.g., digesting plant cell walls), others have more subtle activities. Depending on the lifestyle of the bacteria, these subtle modifications can be crucially important for pathogenesis. In particular, if bacteria rely on a living host, subtle mechanisms to alter host cellular function are likely to dominate. Several bacterial virulence factors have evolved to use enzymatic deamidation as a subtle posttranslational mechanism to modify the functions of host protein targets. Deamidation is the irreversible conversion of the amino acids glutamine and asparagine to glutamic acid and aspartic acid, respectively. Interestingly, all currently characterized bacterial deamidases affect the function of the target protein by modifying a single glutamine residue in the sequence. Deamidation of target host proteins can disrupt host signaling and downstream processes by either activating or inactivating the target. Despite the subtlety of this modification, it has been shown to cause dramatic, context-dependent effects on host cells. Several crystal structures of bacterial deamidases have been solved. All are members of the papain-like superfamily and display a cysteine-based catalytic triad. However, these proteins form distinct structural subfamilies and feature combinations of modular domains of various functions. Based on the diverse pathogens that use deamidation as a mechanism to promote virulence and the recent identification of multiple deamidases, it is clear that this enzymatic activity is emerging as an important and widespread feature in bacterial pathogenesis.
150 minutes of vigorous physical activity per week predicts survival and successful ageing: a population-based 11-year longitudinal study of 12 201 older Australian men
Authors: Almeida Osvaldo P , Khan Karim M , Hankey Graeme J , Yeap Bu B , Golledge Jonathan , Flicker Leon 
Published: September 2013

BackgroundPhysical activity has been associated with improved survival, but it is unclear whether this increase in longevity is accompanied by preserved mental and physical functioning, also known as healthy ageing. We designed this study to determine whether physical activity is associated with healthy ageing in later life.MethodsWe recruited a community-representative sample of 12 201 men aged 65–83 years and followed them for 10–13 years. We assessed physical activity at the beginning and the end of the follow-up period. Participants who reported 150 min or more of vigorous physical activity per week were considered physically active. We monitored survival during the follow-up period and, at study exit, assessed the mood, cognition and functional status of survivors. Healthy ageing was defined as being alive at the end of follow-up and having a Patient Health Questionnaire score <10, Telephone Interview for Cognitive Status score >27, and no major difficulty in any instrumental or basic activity of daily living. Cox regression and general linear models were used to estimate HR of death and risk ratio (RR) of healthy ageing. Analyses were adjusted for age, education, marital status, smoking, body mass index and history of hypertension, diabetes, coronary heart disease and stroke.ResultsTwo thousand and fifty-eight (16.9%) participants were physically active at study entry. Active men had lower HR of death over 10–13 years than physically inactive men (HR=0.74, 95% CI=0.68 to 0.81). Among survivors, completion of the follow-up assessment was higher in the physically active than inactive group (risk ratio, RR=1.18, 95% CI=1.08 to 1.30). Physically active men had greater chance of fulfilling criteria for healthy ageing than inactive men (RR=1.35, 95% CI=1.19 to 1.53). Men who were physically active at the baseline and follow-up assessments had the highest chance of healthy ageing compared with inactive men (RR=1.59, 95% CI=1.36 to 1.86).ConclusionsSustained physical activity is associated with improved survival and healthy ageing in older men. Vigorous physical activity seems to promote healthy ageing and should be encouraged when safe and feasible.
Elevated plasma GLP-1 levels and enhanced expression of cardiac GLP-1 receptors as markers of left ventricular systolic dysfunction: a cross-sectional study
Authors: Hattori Arihiro , Kawamura Itta , Yamada Yoshihisa , Kanamori Hiromitsu , Aoyama Takuma , Ushikoshi Hiroaki , Kawasaki Masanori , Nishigaki Kazuhiko , Tamemura Genzou , Minatoguchi Shinya 
Published: September 2013

ObjectiveWe aimed to elucidate usefulness of plasma glucagon-like peptide-1 (GLP-1) levels for the assessment of left ventricular (LV) dysfunction by examining the relationship among plasma GLP-1 levels, expression of cardiac GLP-1 receptors and LV function in patients with impaired and preserved LV function.DesignProspective study.SettingNumber of participating center: 1, Gifu, Japan.ParticipantsNumber of patients enrolled: 102 patients who underwent elective cardiac catheterisation for coronary artery disease, cardiomyopathy and valvular heart disease, and 6 patients who underwent cardiac biopsy.ResultsThe plasma GLP-1 level was significantly increased in patients with impaired LV function (5.7±1.9 pmol/L) as compared with those with preserved LV function (2.7±1.6 pmol/L). Plasma GLP-1 and plasma brain natriuretic peptide (BNP) levels were inversely correlated with the LV ejection fraction(EF), respectively. Plasma GLP-1 level positively correlated with plasma BNP level. Multivariate logistic regression analysis revealed that plasma GLP-1 level was an independent determinant of the impaired LV function, whereas plasma BNP level was not. Intensity of immunostaining for GLP-1 receptor protein was significantly enhanced in patients with impaired LV function compared with those with preserved LV function.ConclusionsThe plasma GLP-1 level was increased in patients with impaired systolic LV function and inversely correlated with the LVEF. The expressions of GLP-1 receptors were enhanced in hearts with impaired LV function. These may suggest that endogenous GLP-1-GLP-1 receptor system serves as a compensatory mechanism for systolic LV dysfunction.Trial registrationUMIN-CTR, ID=UMIN000009361, registration number: R000011000.
Building a safer foundation: the Lessons Learnt patient safety training programme
Authors: Ahmed Maria , Arora Sonal , Tiew Stephenie , Hayden Jacky , Sevdalis Nick , Vincent Charles , Baker Paul 
Published: September 2013

ObjectivesTo develop, implement and evaluate a novel patient safety training programme for junior doctors across a Foundation School—‘Lessons Learnt: Building a Safer Foundation’.Design, setting and participantsProspective preintervention /postintervention study across 16 Foundation Programmes in North West England, UK. 1169 participants including all Foundation Programme Directors, Administrators, Foundation trainees and senior faculty.InterventionsHalf-day stakeholder engagement event and faculty development through recruitment and training of local senior doctors. Foundation trainee-led monthly 60-min sessions integrated into compulsory Foundation teaching from January to July 2011 comprising case-based discussion and analysis of patient safety incidents encountered in practice, facilitated by trained faculty.Main outcome measuresParticipants’ satisfaction and Foundation trainees’ patient safety knowledge, skills, attitudes and behavioural change.ResultsParticipants reported high levels of satisfaction with ‘Lessons Learnt’. There was a significant improvement in trainees’ objective patient safety knowledge scores (Meanpreintervention=51.1%, SD=17.3%; Meanpostintervention=57.6%, SD=20.1%, p<0.001); subjective knowledge ratings and patient safety skills. Trainees’ perceived control and behavioural intentions regarding safety improved significantly postintervention. Feelings and personal beliefs about safety did not shift significantly. Trainees reported significantly more patient safety incidents in the 6 months following introduction of ‘Lessons Learnt’ (Meanpreintervention=0.67, SD=1.11; Meanpostintervention=1.18, SD=1.46, p<0.001). 32 quality improvement projects were initiated by trainees, spanning the development of novel clinical protocols; implementation of user-informed teaching and improved rota designConclusionsPatient safety training can be implemented and sustained to deliver significant improvements in patient safety knowledge, skills and behaviours of junior doctors—with potential for wider positive organisational impact. Medical education commissioners and providers could adopt and build upon the ‘Lessons Learnt’ approach as a springboard to promote medical engagement in quality and safety improvement.