bluuebunny/crossref_metadata_2025_split huggingface dataset:
Melatonin reverses tunicamycin‐induced endoplasmic reticulum stress in human hepatocellular carcinoma cells and improves cytotoxic response to doxorubicin by increasing CHOP and decreasing Survivin
Authors: Fan Lulu , Sun Guoping , Ma Tai , Zhong Fei , Lei Yu , Li Xiaoqiu , Wei Wei 
Published: April 2013

AbstractChemoresistance in hepatocellular carcinoma (HCC) is associated with multiple cellular responses to environmental stresses, such as nutrient deprivation and hypoxia. Nevertheless, whether ER stress resulting from nutrient deprivation and tumor hypoxia contributes to drug resistance remains unclear. Melatonin increased the efficacy of chemotherapeutic drugs in hepatocellular carcinoma in our previous studies. However, the effects of melatonin on endoplasmic reticulum (ER) stress‐induced resistance to chemotherapeutic agents in HCC have not been tested. The effect of the endoplasmic reticulum (ER) stress response during resistance of human hepatocellular carcinoma cells against doxorubicin was investigated in this study. Pretreatment of HepG2 and SMMC‐7721 cells (two human hepatocellular carcinoma cell lines) with tunicamycin, an ER stress inducer, drastically decreased the rate of apoptosis generated by doxorubicin. Interestingly, co‐pretreatment with tunicamycin and melatonin significantly increased apoptosis induced by doxorubicin. Simultaneously, the expression of phosphorylated AKT (p‐AKT) was elevated in HepG2 and SMMC‐7721 cells given tunicamycin but reduced in the presence of melatonin. Furthermore, consistent with inhibition of AKT activation by using the PI3K inhibitor LY294002, melatonin elevated the levels of CHOP (C/EBP‐homologous protein) and reduced the levels of Survivin (a member of the inhibitor of apoptosis protein family)suggesting that inhibition of the PI3K/AKT pathway by melatonin‐reversed ER stress‐induced resistance to doxorubicin in human hepatocellular carcinoma cells. These results demonstrate that melatonin attenuates ER stress‐induced resistance to doxorubicin in human hepatocellular carcinoma cells by down‐regulating the PI3K/AKT pathway, increasing the levels of CHOP and decreasing the levels of Survivin.
Working with Transcripts: An Abridged Review of Issues in Transcription
Authors: Jenks Christopher Joseph 
Published: April 2013

AbstractThis paper provides an abbreviated review of the theories and practices that are related to transcribing spoken discourse. The review identifies four keys areas of transcription, discusses why they are important to all investigations of spoken discourse analysis, and considers the practical implications of carrying out transcript‐based research. The four areas of transcription discussed in this review are organized into the following sections: theoretical issues, representation, transcription software, and transcription ethics. The aim in providing this review is to argue that while there is no monolithic way of transcribing spoken discourse, the theories and practices that underpin and shape transcription work are highly complex, inherently problematic, and therefore should not be taken for granted.
South African critical care nurses' views on end‐of‐life decision‐making and practices
Authors: Langley Gayle , Schmollgruber Shelley , Fulbrook Paul , Albarran John W , Latour Jos M 
Published: April 2013

ABSTRACTBackgroundCare of patients at the end‐of‐life (EOL) may be influenced by the experiences, attitudes and beliefs of nurses involved in their direct care.AimTo investigate South African critical care nurses' experiences and perceptions of EOL care.DesignCross‐sectional survey.MethodsSouth African critical care nurses completed a modified version of the ‘VENICE’ survey tool. Data were collected concerning: attitudes towards EOL care; involvement in EOL decision‐making; and beliefs about EOL practices.ResultsOf 149 surveys distributed, 100 were returned (response rate 67%). Seventy‐six percent stated that they had had direct involvement in EOL care of patients, but a minority (29%) had participated in EOL decision‐making processes. Whilst most nurses (86%) were committed to family involvement in EOL decisions, less than two thirds (62%) reported this as routine practice. When withdrawing treatment, around half (54%) of the respondents indicated they would decrease the inspired oxygen level to room air, and the majority (84%) recommended giving effective pain relief. Continued nutritional support (84%) and hydration (85%) were advocated, with most nurses (62%) indicating that they were against keeping patients deeply sedated. Most respondents (68%) felt patients should remain in intensive care at the end of life, with the majority (72%) supporting open‐visiting, no restriction on number of family members visiting (70%), and the practising of religious or traditional cultural EOL rituals (93%).ConclusionsThe involvement of Johannesburg critical nurses in EOL care discussions and decisions is infrequent despite their participation in care delivery and definite views about the process.Relevance to clinical practiceUse of formal guidelines and education is recommended to increase the nurses' involvement in and their confidence in participating in EOL decisions. Educators, managers, senior nurses and other members of the multi‐disciplinary team should collaborate to enable critical care nurses to become more involved in EOL care.
Links between obesity, diabetes and ethnic disparities in breast cancer among Hispanic populations
Authors: Lopez R. , Agullo P. , Lakshmanaswamy R. 
Published: April 2013

SummaryBreast cancer is the most prevalent malignancy in women worldwide and is a growing concern due to rising incidence and ongoing ethnic disparities in both incidence and mortality. A number of factors likely contribute to these trends including rising rates of obesity and diabetes across the globe and differences in genetic predisposition. Here, we emphasize Hispanic populations and summarize what is currently known about obesity, diabetes and individual genetic predisposition as they relate to ethnic disparities in breast cancer incidence and mortality. In addition, we discuss potential contributions to breast cancer aetiology from molecular mechanisms associated with obesity and diabetes including dyslipidemia, hyperglycaemia, hyperinsulinaemia, endocrine dysfunction and inflammation. We propose that unique differences in diet and lifestyle coupled with individual genetic predisposition and endocrine/immune dysfunction explain most of the ethnic disparities seen in breast cancer incidence and mortality.
Clinical Identifiers for Detecting Underlying Closed Cervical Fractures
Authors: Cook Chad E. , Sizer Phillip S. , Isaacs Robert E. , Wright Alexis 
Published: April 2013

AbstractBackgroundAlthough uncommon, closed cervical fractures (CCFs) may present in orthopedic clinical settings despite previous workup. The objective of this study was to describe the characteristics associated with missed CCF.MethodsThe study was a retrospective database exploration of a cohort of subjects within a department of surgery with cervical pain. The sample consisted of 162 patients seen for a surgical consult for a number of cervical conditions. The examination time frame represented a clinical examination and imaging confirmation of diagnosis after an original initial visit by another provider. Descriptive and diagnostic accuracy values including sensitivity/specificity and positive/negative likelihood ratios (LR+/LR−) were calculated for each targeted variable. Clustered analyses were calculated using the patient history and situational characteristics.ResultsEleven patients in the sample were diagnosed with CCF (6.7%). Six variables were significantly associated with a missed CCF. Using these six variables, it was found that failure to exhibit a condition of 2 of the 6 variables (1 or fewer) was the strongest in ruling out the condition (LR− = 0.0; post‐test probability with a negative finding = 0%), whereas a finding of 4 of 6 was the most diagnostic for ruling in the condition (LR+ = 32; post‐test probability with a positive finding = 70%).ConclusionsThe findings in this sample suggest that select patient history or situational factors are still useful even after initial examination and clinicians must stay vigilant because CCFs may be missed during emergent care screens.
The functional MICA‐129 polymorphism is associated with skin but not joint manifestations of psoriatic disease independently of HLA‐B and HLA‐C
Authors: Pollock R. A. , Chandran V. , Pellett F. J. , Thavaneswaran A. , Eder L. , Barrett J. , Rahman P. , Farewell V. , Gladman D. D. 
Published: April 2013

AbstractA methionine/valine polymorphism at amino acid 129 of the major histocompatibility complex class I chain‐related gene A (MICA‐129) categorizes alleles into strong and weak binders of the natural killer (NK) and T‐cell receptor NKG2D. We investigated whether MICA‐129 is differentially associated with skin and joint manifestations of psoriatic disease (PsD) independently of human leukocyte antigen (HLA)‐C and HLA‐B in patients and controls from Toronto and St. John's. The MICA‐129 methionine (Met) allele, particularly Met/Met homozygosity, was strongly associated with both cutaneous psoriasis (PsC) and psoriatic arthritis (PsA) independently of HLA‐B and HLA‐C in Toronto patients, and was also associated with PsA in St. John's patients, but with no additional effect of Met/Met homozygosity. No association remained after adjustment for HLA alleles in St. John's patients. MICA‐129 was not associated with PsA when compared with PsC. We conclude that MICA‐129 is a marker of skin manifestations of PsD that is independent of HLA class I in Toronto patients.
Calcium channels in rat horizontal cells regulate feedback inhibition of photoreceptors through an unconventional GABA‐ and pH‐sensitive mechanism
Authors: Liu Xue , Hirano Arlene A. , Sun Xiaoping , Brecha Nicholas C. , Barnes Steven 
Published: April 2013

Key points
Inhibitory feedback from horizontal cells to photoreceptors regulates synaptic gain and contributes to centre–surround receptive field formation via mechanisms that are not fully understood.
We show that horizontal cell calcium channels and ionotropic GABA receptors mediate the inhibitory feedback, and that the results of their actions are blocked by strong pH buffering with Hepes.
GABA appears to act not upon the photoreceptor but instead upon the horizontal cell itself. The horizontal cell GABA receptors are permeable to chloride and bicarbonate, meaning their activation can produce changes in synaptic cleft pH.
These results suggest that activation of calcium channels in a depolarized horizontal cell releases GABA, which acts in an autaptic manner to increase bicarbonate permeability. The resulting influx of bicarbonate contributes to acidification of the synaptic cleft, inhibiting photoreceptor calcium channels, the hallmark of inhibitory feedback at this synapse.
Abstract  Horizontal cells send inhibitory feedback to photoreceptors, helping form antagonistic receptive fields in the retina, but the neurotransmitter and the mechanisms underlying this signalling are not known. Since the proteins responsible for conventional Ca2+‐dependent release of GABAergic synaptic vesicles are present in mammalian horizontal cells, we investigated this conventional mechanism as the means by which horizontal cells inhibit photoreceptors. Using Ca2+ imaging in rat retinal slices, we confirm that horizontal cell depolarization with kainate inhibits and horizontal cell hyperpolarization with NBQX disinhibits the Ca2+ signals produced by pH‐sensitive activation of voltage‐gated calcium channels (Ca channels) in photoreceptors. We show that while 100 μm Co2+ reduces photoreceptor Ca2+ signals, it disinhibits them at 10 μm, an effect reminiscent of earlier studies where low [Co2+] eliminated feedback. The low [Co2+] disinhibition is pH sensitive. We localized L‐, N‐ and P/Q‐type Ca channels in rat horizontal cells, and showed that both the N‐type Ca channel blocker ω‐conotoxin GVIA and the P/Q‐type Ca channel blocker ω‐agatoxin IVA increased Ca2+ signals in photoreceptors in a pH‐sensitive manner. Pronounced actions of GABAergic agents on feedback signals to photoreceptors were observed, and are pH sensitive, but are inconsistent with direct inhibition by GABA of photoreceptor [Ca2+]. Patch‐clamp studies revealed that GABA activates a conductance having high bicarbonate permeability in isolated horizontal cells, suggesting that the commonality of pH sensitivity throughout the results could arise from a GABA autofeedback action in horizontal cells. This could change cleft pH with concomitant inhibitory influences on photoreceptor Ca channels.
The kinetic properties of the α3 rat glycine receptor make it suitable for mediating fast synaptic inhibition
Authors: Marabelli Alessandro , Moroni Mirko , Lape Remigijus , Sivilotti Lucia G. 
Published: April 2013

Key points
In the adult, most inhibitory transmission mediated by glycine uses channels containing α1 subunits, but both α1 and the related α3 subunit are present in spinal areas that process pain.
We recorded the effect of a range of fixed glycine concentrations on the activity of individual glycine channels expressed in vitro to contain only α3 subunits.
Glycine is very effective in opening α3 channels. At full activation, both α1 and α3 channels are open nearly 100% of the time, but α3 channels need all, or almost all, of the five glycine binding sites to be occupied, whereas α1 channels need only three.
When channels were activated in synaptic‐like conditions (fast, 1 ms, 10 mm glycine pulses), α3 responses decayed more slowly than α1 responses.
This difference is likely to be too small to allow α1‐ and α3‐mediated synaptic responses to be distinguishable on the basis of time course alone.
Abstract  Glycine receptors mediate fast synaptic inhibition in spinal cord and brainstem. Two α subunits are present in adult neurones, α1, which forms most of the synaptic glycine receptors, and α3. The physiological role of α3 is not known, despite the fact that α3 expression is concentrated in areas involved in nociceptive processing, such as the superficial dorsal horn. In the present study, we characterized the kinetic properties of rat homomeric α3 glycine receptors heterologously expressed in HEK293 cells. We analysed steady state single channel activity at a range of different glycine concentrations by fitting kinetic schemes and found that α3 channels resemble α1 receptors in their high maximum open probability (99.1% cf. 98% for α1), but differ in that maximum open probability is reached when all five binding sites are occupied by glycine (cf. three out of five sites for α1). α3 activation was best described by kinetic schemes that allow the channel to open also when partially liganded and that contain more than the minimum number of shut states, either as desensitized distal states (Jones and Westbrook scheme) or as pre‐open gating intermediates (flip scheme). We recorded also synaptic‐like α3 currents elicited by the rapid application of 1 ms pulses of high concentration glycine to outside‐out patches. These currents had fast deactivation, with a time constant of decay of 9 ms. Thus, if native synaptic currents can be mediated by α3 glycine receptors, they are likely to be very close in their kinetics to α1‐mediated synaptic events.
Partial Disruption of Translational and Posttranslational Machinery Reshapes Growth Rates of Bartonella birtlesii
Authors: Rolain Jean Marc , Vayssier-Taussat Muriel , Saisongkorh Watcharee , Merhej Vicky , Gimenez Gregory , Robert Catherine , Le Rhun Danielle , Dehio Christoph , Raoult Didier 
Published: April 2013

ABSTRACT

Specialization of bacteria in a new niche is associated with genome repertoire changes, and speciation in bacterial specialists is associated with genome reduction. Here, we tested a signature-tagged mutant library of 3,456
Bartonella birtlesii
clones to detect mutants that could grow rapidly
in vitro
. Overall, we found 124 mutants that grew faster than the parental wild-type strain
in vitro
. We sequenced the genomes of the four mutants with the most rapid growth (formed visible colonies in only 1 to 2 days compared with 5 days for the wild type) and compared them to the parental isolate genome. We found that the number of disrupted genes associated with translation in the 124 rapid-growth clones was significantly higher than the number of genes involved in translation in the full genome (
P
< 10
−6
). Analysis of transposon integration in the genome of the four most rapidly growing clones revealed that one clone lacked one of the two wild-type RNA ribosomal operons. Finally, one of the four clones did not induce bacteremia in our mouse model, whereas infection with the other three resulted in a significantly lower bacterial count in blood than that with the wild-type strain.

IMPORTANCE
Here, we show that specialization in a specific niche could be caused by the disruption of critical genes. Most of these genes were involved in translation, and we show that evolution of obligate parasitism bacteria was specifically associated with disruption of translation system-encoding genes.
Divergent Protein Motifs Direct Elongation Factor P-Mediated Translational Regulation in Salmonella enterica and Escherichia coli
Authors: Hersch Steven J. , Wang Mengchi , Zou S. Betty , Moon Kyung-Mee , Foster Leonard J. , Ibba Michael , Navarre William Wiley 
Published: April 2013

ABSTRACT

Elongation factor P (EF-P) is a universally conserved bacterial translation factor homologous to eukaryotic/archaeal initiation factor 5A. In
Salmonella
, deletion of the
efp
gene results in pleiotropic phenotypes, including increased susceptibility to numerous cellular stressors. Only a limited number of proteins are affected by the loss of EF-P, and it has recently been determined that EF-P plays a critical role in rescuing ribosomes stalled at PPP and PPG peptide sequences. Here we present an unbiased
in vivo
investigation of the specific targets of EF-P by employing stable isotope labeling of amino acids in cell culture (SILAC) to compare the proteomes of wild-type and
efp
mutant
Salmonella
. We found that metabolic and motility genes are prominent among the subset of proteins with decreased production in the
Δefp
mutant. Furthermore, particular tripeptide motifs are statistically overrepresented among the proteins downregulated in
efp
mutant strains. These include both PPP and PPG but also additional motifs, such as APP and YIRYIR, which were confirmed to induce EF-P dependence by a translational fusion assay. Notably, we found that many proteins containing polyproline motifs are not misregulated in an EF-P-deficient background, suggesting that the factors that govern EF-P-mediated regulation are complex. Finally, we analyzed the specific region of the PoxB protein that is modulated by EF-P and found that mutation of any residue within a specific GSCGPG sequence eliminates the requirement for EF-P. This work expands the known repertoire of EF-P target motifs and implicates factors beyond polyproline motifs that are required for EF-P-mediated regulation.

IMPORTANCE
Bacterial cells regulate gene expression at several points during and after transcription. During protein synthesis, for example, factors can interact with the ribosome to influence the production of specific proteins. Bacterial elongation factor P (EF-P) is a protein that facilitates the synthesis of proteins that contain polyproline motifs by preventing the ribosome from stalling. Bacterial cells that lack EF-P are viable but are sensitive to a large number of stress conditions. In this study, a global analysis of protein synthesis revealed that EF-P regulates many more proteins in the cell than predicted based solely on the prevalence of polyproline motifs. Several new EF-P-regulated motifs were uncovered, thereby providing a more complete picture of how this critical factor influences the cell’s response to stress at the level of protein synthesis.
Which patients with chronic obstructive pulmonary disease benefit from the addition of an inhaled corticosteroid to their bronchodilator? A cluster analysis
Authors: DiSantostefano Rachael L , Li Hao , Rubin David B , Stempel David A 
Published: April 2013

ObjectiveTo identify subsets of chronic obstructive pulmonary disease (COPD) patients who are more protected from exacerbations with the use of an inhaled corticosteroid/long-acting β2agonist (ICS/LABA) combination, compared with the use of LABA monotherapy.DesignPost hoc cluster analysis of patients from two randomised clinical trials of salmeterol/fluticasone propionate (SFC) and salmeterol (SAL) that had primary endpoints of moderate/severe exacerbation rates.SettingCentres in North America.Participants1543 COPD patients were studied.InterventionsSFC 50/250 µg or SAL 50 µg, twice daily.Primary and secondary outcome measuresThe analysis identified clusters of COPD patients more responsive to SFC versus SAL with respect to the annual rate of moderate/severe exacerbations and compared their baseline clinical characteristics.ResultsOverall, SFC significantly reduced the annual rate of moderate/severe exacerbations as compared with SAL alone (rate ratio (RR)=0.701, p<0.001). Three-patient clusters were identified: COPD patients receiving diuretics (RR=0.56, p<0.001); patients not receiving diuretics but with forced expiratory volume in 1 s (FEV1) reversibility ≥12% (RR=0.67, p<0.001) exhibited a substantial reduction in the annual rate of moderate/severe exacerbations relative to SAL. A third cluster, consisting of patients not receiving diuretics and without FEV1reversibility, demonstrated no difference for SFC versus SAL. Patients receiving diuretics had a significantly higher prevalence of comorbid cardiovascular disease.ConclusionsCOPD patients receiving diuretics and those not receiving diuretics but with FEV1reversibility >12% at baseline were significantly more likely to experience a reduction in COPD-associated exacerbations with SFC versus SAL alone.Trial registrationNCT00115492,NCT00144911
Centor criteria in children in a paediatric emergency department: for what it is worth
Authors: Roggen Inge , van Berlaer Gerlant , Gordts Frans , Pierard Denis , Hubloue Ives 
Published: April 2013

IntroductionCentor criteria (fever >38.5°C, swollen, tender anterior cervical lymph nodes, tonsillar exudate and absence of cough) are an algorithm to assess the probability of group A β haemolyticStreptococcus(GABHS) as the origin of sore throat, developed for adults. We wanted to evaluate the correlation between Centor criteria and presence of GABHS in children with sore throat admitted to our paediatric emergency department (PED).DesignRetrospective cohort study.SettingThe emergency department of a large tertiary university hospital in Brussels, with over 20 000 yearly visits for children below age 16.ParticipantsAll medical records (from 2008 to 2010) of children between ages 2 and 16, who were diagnosed with pharyngitis, tonsillitis or sore throat and having a throat swab culture for GABHS. Children with underlying chronic respiratory, cardiac, haematological or immunological diseases and children who had already received antibiotics (AB) prior to the PED consult were excluded. Only records with a full disease history were selected. Out of a total 2118 visits for sore throats, 441 met our criteria. The children were divided into two age groups, 2–5 and 5–16 years.ResultsThe prevalence of GABHS was higher in the older children compared to the preschoolers (38.7 vs 27.6; p=0.01), and the overall prevalence was 32%. There was no significant difference in the prevalence of GABHS for all different Centor scores within an age group. Likelihood ratios (LR) demonstrate that none of the individual symptoms or a Centor score of ≥3 seems to be effective in ruling in or ruling out GABHS. Pooled LR (CI) for Centor ≥3 was 0.67 (CI 0.50 to 0.90) for the preschoolers and 1.37 (CI 1.04 to 1.79) for the older children.ConclusionsOur results confirm the ineffectiveness of Centor criteria as a predicting factor for finding GABHS in a throat swab culture in children.