bluuebunny/crossref_metadata_2025 huggingface dataset:
Radiofrequency and Cryo‐Ablation Effect on Transvenous Pacing and Defibrillatory Lead Integrity: An In Vitro Study
Authors: DARRAT YOUSEF H. , AGARWAL ANUJ , MORALES GUSTAVO X. , THOMPSON JOSEPH , ABDEL‐LATIF AHMED , WAESPE KELLY , DI BIASE LUIGI , NATALE ANDREA , PATWARDAN ABHIJIT , ELAYI CLAUDE‐SAMY
Published: May 2016

Effects of Catheter Ablation on Transvenous Leads

Intorduction

Medical societies and cardiac implantable electronic device (CIED) manufacturers recommend avoiding close or direct contact between the body of transvenous leads and ablation catheters used to treat cardiac arrhythmias. These recommendations are made despite the lack of clinical studies. However, the target myocardium for successful ablation can be contiguous to CIED leads.

Methods and Results

We examine in vitro the effects of direct application of radiofrequency (RF) and cryo‐ablation energy on the integrity and functionality of CIED leads (excluding the pacing electrodes and defibrillation coils). A saline bath was created to mimic the body milieu. CIED leads, including all commercially available lead insulation materials, were connected to a CIED pulse generator and placed in direct contact with an ablation catheter in the tissue bath. RF and cryo‐ablation energy were delivered under various conditions, including maximal ablation power, temperature, and impedance via the RF generator. CIED lead functionality, reflective of conductor integrity, was evaluated through lead impedance monitoring during ablation. CIED leads were then visually inspected, and examined with optic and electron microscopy as per protocol. A total of 42 leads were studied. All leads showed the absence of insulation damage at the site of ablation visually and with microscopy. Lead functionality was also preserved in all leads.

Conclusion

Catheter ablation in contact with CIED leads using radiofrequency or cryo‐ablation in vitro did not affect lead body integrity and function despite aggressive ablation settings. It may be reasonable to perform ablation in contact with the body of CIED leads when clinically necessary.
Using prognostic factors from case series and cohort studies to identify individuals with poor long‐term outcomes during periodontal maintenance
Authors: Fardal Øystein , Grytten Jostein , Martin John , Houlihan Ciara , Heasman Peter
Published: May 2016

Background

The accuracy of applying prognostic factors to individual patients is uncertain.

Aim/Method

The aim was to apply prognostic factors from several outcome studies (case series and cohort) to identify: (1) patients who lost a tooth/teeth during periodontal maintenance; (2) patients who were non‐responding to treatment; (3) patients needing re‐treatment during periodontal maintenance. In addition, tooth loss was related to initial prognosis and it was determined which of the prognostic factors were also risk factors. Chi squared analysis was carried out for the outcomes of patients with‐, and without prognostic factors. Significance level was set at p ≤ 0.05. Sensitivity and specificity was calculated for patients with and without prognostic factors.

Results

The prognostic factors only identified a small proportion of patients who lost teeth (34–38%). Combining the prognostic factors resulted in a lower accuracy. A higher proportion of patients with no prognostic factors lost teeth (53.8–96.2%). The chance of identifying a non‐responding patient based on family history was 5.9%, for stress 32.4%, and for heavy smoking 8.7%. Significantly more patients (29/40 , χ² = 16.2 p < 0.05) with initial uncertain/poor prognosis and significantly fewer patients (11/40, χ² = 16.2, p < 0.05) with erratic/no compliance needing re‐treatment were identified. 21 of 40 patients (52.5%) (p = 0.655) with family history needing retreatment were identified. Combining the prognostic factors identified 5–22% out of a total of 40% of patients needing re‐treatment. six out of nine (67%) teeth with an initial hopeless prognosis were lost, 10/109 (9%) teeth with a poor prognosis were lost, 11/346 (3%) teeth with a moderate prognosis were lost and 9/1972 (0.46%) of teeth with a good prognosis were lost. None of the prognostic factors was found also to be a risk factor for developing periodontal diseases.

Conclusion

Applying prognostic factors to identify individual patients with poor long‐term outcomes is associated with low accuracy.
A Delphi Approach to Understanding Varying Expert Viewpoints in Sustainability Communication: The Case of Water Footprints of Bio‐Based Fiber Resources
Authors: Sutterlüty Andrea , Hesser Franziska , Schwarzbauer Peter , Schuster Kurt Christian , Windsperger Andreas , Stern Tobias
Published: May 2016

In recent years, the concepts of accounting for water use and assessing its impact, also known as the water footprint (WF), have evolved. The cultivation of wood and cotton are two important bio‐based fiber resources that can use, consume, and pollute huge amounts of water. The purpose of this study is to identify the methodological options on an inventory level asociated with a WF assessment for bio‐based fiber resources. Using a three‐step Argument Delphi approach with international experts, important, but controversial, aspects of water footprinting are elaborated. During the different rounds of the Delphi procedure, the interlacement of the crucial topics became apparent, including the net green water or the total volume of green water, trade‐offs between water use and land‐use impacts, allocation of the green WF on ecosystem services, and nomination of a reference situation (e.g., potential natural vegetation). Further, this study evaluates whether the experts allowed generalizations about these methodological options. Finally, the agreement of experts on some generalized statements showed that such statements can be used legitimately as long as knowledge of the inventory methods and knowledge of production characteristics are carefully combined.
Epithelial expression of cytokeratins 15 and 19 in vitiligo
Authors: Saleh Fatma Y , Awad Sherif S , Nasif Ghada A , Halim Christein
Published: May 2016

Background

Cytokeratins (CK) belong to the family of intermediate filament proteins, and among them specific epithelial keratins are considered markers for stem cells activation.

Objectives

This study aims to investigate the expression of CK15 and CK19 as possible stem cell markers in vitiligo during phototherapy.

Methods

The study was conducted on vitiligo patients receiving narrow‐band ultraviolet therapy. Immunohistochemical staining for CK15 and CK19 was carried out, and clinical follow‐up continued for 4 weeks.

Results

Of 28 patients, CK15 expression was demonstrated in 17 cases (61%) while CK19 expression was demonstrated in 11 cases (39%). Cells expressing positive staining were demonstrated in follicular and interfollicular epithelium. Expression was clearly demonstrated in patients younger than 20 years old, with shorter disease duration, with disease stability, and with normally pigmented hairs. Expression of cytokeratins was significantly correlated to improvement of vitiligo lesions.

Conclusion

CK15 and CK19 are expressed in vitiligo during UV repigmentation in the follicular and interfollicular epithelium. This expression of cytokeratins was significantly correlated to improvement and can be considered valuable tool to monitor stem cells stimulation for the sake of the repigmentation process in vitiligo.
Mental health nurses’ attitudes, behaviour, experience and knowledge regarding adults with a diagnosis of borderline personality disorder: systematic, integrative literature review
Authors: Dickens Geoffrey L , Lamont Emma , Gray Sarah
Published: May 2016

Aims and objectives

To establish whether mental health nurses responses to people with borderline personality disorder are problematic and, if so, to inform solutions to support change.

Background

There is some evidence that people diagnosed with borderline personality disorder are unpopular among mental health nurses who respond to them in ways which could be counter‐therapeutic. Interventions to improve nurses’ attitudes have had limited success.

Design

Systematic, integrative literature review.

Methods

Computerised databases were searched from inception to April 2015 for papers describing primary research focused on mental health nurses’ attitudes, behaviour, experience, and knowledge regarding adults diagnosed with borderline personality disorder. Analysis of qualitative studies employed metasynthesis; analysis of quantitative studies was informed by the theory of planned behaviour.

Results

Forty studies were included. Only one used direct observation of clinical practice. Nurses’ knowledge and experiences vary widely. They find the group very challenging to work with, report having many training needs, and, objectively, their attitudes are poorer than other professionals’ and poorer than towards other diagnostic groups. Nurses say they need a coherent therapeutic framework to guide their practice, and their experience of caregiving seems improved where this exists.

Conclusions

Mental health nurses’ responses to people with borderline personality disorder are sometimes counter‐therapeutic. As interventions to change them have had limited success there is a need for fresh thinking. Observational research to better understand the link between attitudes and clinical practice is required. Evidence‐based education about borderline personality disorder is necessary, but developing nurses to lead in the design, implementation and teaching of coherent therapeutic frameworks may have greater benefits.

Relevance to clinical practice

There should be greater focus on development and implementation of a team‐wide approach, with nurses as equal partners, when working with patients with borderline personality disorder.
Direct estimation of the permeation of topical excipients through artificial membranes and human skin with non-invasive Terahertz time-domain techniques
Authors: Lopez-Dominguez Victor , Boix-Montañes Antoni , Redo-Sanchez Albert , Tejada-Palacios Javier
Published: May 2016

Background

Drug permeation through skin, or a synthetic membrane, from locally acting pharmaceutical products can be influenced by the permeation behaviour of pharmaceutical excipients.

Objective

Terahertz time-domain technology is investigated as a non-invasive method for a direct and accurate measurement of excipients permeation through synthetic membranes or human skin.

Methods

A series of in-vitro release and skin permeation experiments of liquid excipients (e.g. propylene glycol and polyethylene glycol 400) has been conducted with vertical diffusion cells. The permeation profiles of excipients through different synthetic membranes or skin were obtained using Terahertz pulses providing a direct measurement. Corresponding permeation flux and permeability coefficient values were calculated based on temporal changes of the terahertz pulses.

Results

The influence of different experimental conditions, such as the polarity of the membrane and the viscosity of the permeant, was assessed in release experiments. Specific transmembrane flux values of those excipients were directly calculated with statistical differences between cases. Finally, an attempt to estimate the skin permeation of propylene glycol with this technique was also achieved. All these permeation results were likely comparable to those obtained by other authors with usual analytical techniques.

Conclusion

Terahertz time-domain technology is shown to be a suitable technique for an accurate and non-destructive measurement of the permeation of liquid substances through different synthetic membranes or even human skin.
Preliminary evaluation of prostate-targeted radiotherapy using 131I-MIP-1095 in combination with radiosensitising chemotherapeutic drugs
Authors: Tesson Mathias , Rae Colin , Nixon Colin , Babich John W , Mairs Robert J
Published: May 2016

Objectives

Despite recent advances in the treatment of metastatic prostate cancer, survival rates are low and treatment options are limited to chemotherapy and hormonal therapy. 131I-MIP-1095 is a recently developed prostate-specific membrane antigen (PSMA)-targeting, small molecular weight radiopharmaceutical which has anti-tumour activity as a single agent. Our purpose was to determine in vitro the potential benefit to be gained by combining 131I-MIP-1095 with cytotoxic drug treatments.

Methods

Various cytotoxic agents were evaluated in combination with 131I-MIP-1095 for their capacity to delay the growth of LNCaP cells cultured as multicellular tumour spheroids. Two end-points were used to assess treatment efficacy: (i) the time required for doubling of spheroid volume and (ii) the area under the volume–time growth curves.

Key findings

The PARP-1 inhibitor olaparib, the topoisomerase I inhibitor topotecan, the proteasome inhibitor bortezomib, the inhibitor of the P53–MDM2 interaction nutlin-3 and the copper-chelated form of the oxidising agent disulfiram (DSF:Cu) all significantly enhanced the inhibition of the growth of spheroids induced by 131I-MIP-1095. However, the Chk1 inhibitor AZD7762 failed to potentiate the effect of 131I-MIP-1095.

Conclusions

These results indicate that targeted radiotherapy of prostate cancer may be optimised by combining its administration with chemotherapy.
Sodium transport through the cerebral sodium–glucose transporter exacerbates neuron damage during cerebral ischaemia
Authors: Yamazaki Yui , Harada Shinichi , Wada Tetsuyuki , Yoshida Shigeru , Tokuyama Shogo
Published: May 2016

Objectives

We recently demonstrated that the cerebral sodium-glucose transporter (SGLT) is involved in postischaemic hyperglycaemia-induced exacerbation of cerebral ischaemia. However, the associated SGLT-mediated mechanisms remain unclear. Thus, we examined the involvement of cerebral SGLT-induced excessive sodium ion influx in the development of cerebral ischaemic neuronal damage.

Methods

[Na+]i was estimated according to sodium-binding benzofuran isophthalate fluorescence. In the in vitro study, primary cortical neurons were prepared from fetuses of ddY mice. Primary cortical neurons were cultured for 5 days before each treatment with reagents, and these survival rates were assessed using biochemical assays. In in vivo study, a mouse model of focal ischaemia was generated using middle cerebral artery occlusion (MCAO).

Key findings

In these experiments, treatment with high concentrations of glucose induced increment in [Na+]i, and this phenomenon was suppressed by the SGLT-specific inhibitor phlorizin. SGLT-specific sodium ion influx was induced using a-methyl-D-glucopyranoside (a-MG) treatments, which led to significant concentration-dependent declines in neuronal survival rates and exacerbated hydrogen peroxide-induced neuronal cell death. Moreover, phlorizin ameliorated these effects. Finally, intracerebroventricular administration of a-MG exacerbated the development of neuronal damage induced by MCAO, and these effects were ameliorated by the administration of phlorizin.

Conclusions

Hence, excessive influx of sodium ions into neuronal cells through cerebral SGLT may exacerbate the development of cerebral ischaemic neuronal damage.
Clinical response of masitinib mesylate in the treatment of canine macroscopic mast cell tumours
Authors: Grant J. , North S. , Lanore D.
Published: May 2016

OBJECTIVES

To retrospectively evaluate the clinical response and toxicity associated with masitinib mesylate (Masivet®) treatment of macroscopic mast cell tumours in the dog.

METHODS

Retrospective review of medical records of 39 dogs that had undergone treatment with masitinib for macroscopic mast cell tumours. Patient signalment, tumour location, tumour grade, tumour stage, previous treatments, concurrent medications, dose of masitinib, side effects, response, time to tumour progression, survival time and cause of death were documented. Response was assessed according to RECIST criteria.

RESULTS

Clinical response was observed in 32 (82·1%) dogs receiving masitinib, with 15 dogs (38·5%) exhibiting a complete response and 17 dogs (43·6%) achieving a partial response. The median time to progression was 79 days (range: 14 to 667 days). Adverse effects were seen in 25 dogs (64·1%) with serum alanine aminotransferase elevation (n=9; 23·1%) and vomiting (n=6; 15·4%) being most common. Median survival time following initiation of masitinib was 159 days (range: 14 to 1339).

CLINICAL SIGNIFICANCE

Masitinib appears to be a well‐tolerated and effective drug against macroscopic mast cell tumours.
Sleep fragmentation alters brain energy metabolism without modifying hippocampal electrophysiological response to novelty exposure
Authors: Baud Maxime O. , Parafita Julia , Nguyen Audrey , Magistretti Pierre J. , Petit Jean‐Marie
Published: May 2016

Sleep is viewed as a fundamental restorative function of the brain, but its specific role in neural energy budget remains poorly understood. Sleep deprivation dampens brain energy metabolism and impairs cognitive functions. Intriguingly, sleep fragmentation, despite normal total sleep duration, has a similar cognitive impact, and in this paper we ask the question of whether it may also impair brain energy metabolism. To this end, we used a recently developed mouse model of 2 weeks of sleep fragmentation and measured 2‐deoxy‐glucose uptake and glycogen, glucose and lactate concentration in different brain regions. In order to homogenize mice behaviour during metabolic measurements, we exposed them to a novel environment for 1 h. Using an intra‐hippocampal electrode, we first showed that hippocampal electroencephalograph (EEG) response to exploration was unaltered by 1 or 14 days of sleep fragmentation. However, after 14 days, sleep fragmented mice exhibited a lower uptake of 2‐deoxy‐glucose in cortex and hippocampus and lower cortical lactate levels than control mice. Our results suggest that long‐term sleep fragmentation impaired brain metabolism to a similar extent as total sleep deprivation without affecting the neuronal responsiveness of hippocampus to a novel environment.
Thinking Is Modulated by Recent Linguistic Experience: Second Language Priming Affects Perceived Event Similarity
Authors: Montero‐Melis Guillermo , Jaeger T. Florian , Bylund Emanuel
Published: May 2016

Can recent second language (L2) exposure affect what we judge to be similar events? Using a priming paradigm, we manipulated whether native Swedish adult learners of L2 Spanish were primed to use path or manner during L2 descriptions of scenes depicting caused motion events (encoding phase). Subsequently, participants engaged in a nonverbal task, arranging events on the screen according to similarity (test phase). Path versus manner priming affected how participants judged event similarity during the test phase. The effects we find support the hypotheses that (a) speakers create or select ad hoc conceptual categories that are based on linguistic knowledge to carry out nonverbal tasks, and that (b) short‐term, recent L2 experience can affect this ad hoc process. These findings further suggest that cognition can flexibly draw on linguistic categories that have been implicitly highlighted during recent exposure.

Open Practices

This article has been awarded an Open Data badge. All data are publicly accessible via the Harvard Dataverse athttp://dx.doi.org/10.7910/DVN/QOD8ZU. Learn more about the Open Practices badges from the Center for Open Science:https://osf.io/tvyxz/wiki.
When rumination counts: Perceived social support and heart rate variability in daily life
Authors: Gerteis Ann Kathrin S. , Schwerdtfeger Andreas R.
Published: May 2016

Rumination and social support could modulate cardiac activity. Although both variables are somehow interrelated, they are often studied independently, and their interplay is seldom considered. We aimed to analyze the interaction of rumination and perceived social support on vagally mediated heart rate variability (HRV) in daily life. The sample consisted of 117 healthy participants (57% female, mean age = 27.9, SD = 5.5 years). Ambulatory HRV (root mean squared successive differences), respiration, body position, and body movements were recorded continuously on three consecutive weekdays. Momentary social, situational, and cognitive‐affective variables (affect, ruminative thoughts, perceived social support) were assessed using a computerized diary. There was a significant interaction between momentary rumination and perceived social support on ambulatory HRV: When participants were involved in social interactions with low social support, concurrent rumination was associated with attenuated HRV. However, when rumination was accompanied by a strong sense of support, HRV significantly increased. The quality of social interactions and rumination seem to interact in daily life to predict cardiac autonomic control. The results stress the necessity to consider the interplay of psychological and social factors in order to evaluate beneficial or adverse effects on cardiac health.
Tax Revenue Effects of Sectoral Growth and Public Expenditure in Uganda
Authors: Mawejje Joseph , Francis Munyambonera Ezra
Published: May 2016

This paper contributes to a growing strand of literature on the determinants of tax revenue performance in developing countries, particularly in Sub‐Saharan Africa. More specifically we estimate the tax elasticities of sectoral output growth and public expenditure. The unique features of this paper are twofold: First, we develop a simple analytical model for tax revenue performance taking into account some structural features pervasive in most developing countries with large informal sectors. Second, we test the model predictions on Ugandan time series data using ARDL bounds testing techniques. Results indicate that dominance of the agricultural and informal sectors pose the largest impediments to tax revenue performance. In addition development expenditures, trade openness, and industrial sector growth are positively associated with tax revenue performance. We propose policies to support the development of value added linkages between agricultural and industrial sectors while emphasizing the need to unlock the potentially large contributions of the informal sector with a view of widening the tax base.
Genetic variants associated with physical and mental characteristics of the elite athletes in the Polish population
Authors: Peplonska B. , Adamczyk J. G. , Siewierski M. , Safranow K. , Maruszak A. , Sozanski H. , Gajewski A. K. , Zekanowski C.
Published: May 2016

The aim of the study was to assess whether selected genetic variants are associated with elite athlete performance in a group of 413 elite athletes and 451 sedentary controls. Polymorphisms in ACE, ACTN3, AGT, NRF‐2, PGC1A, PPARG, and TFAM implicated in physical performance traits were analyzed. Additionally, polymorphisms in CHRNB3 and FAAH coding for proteins modulating activity of brain's emotion centers were included. The results of univariate analyses indicated that the elite athletic performance is associated with four polymorphisms: ACE (rs4341, P = 0.0095), NRF‐2 (rs12594956, P = 0.011), TFAM (rs2306604, P = 0.049), and FAAH (rs324420, P = 0.0041). The multivariate analysis adjusted for age and gender confirmed this association. The higher number of ACE D alleles (P = 0.0021) and the presence of NRF‐2 rs12594956 A allele (P = 0.0067) are positive predictors, whereas TFAM rs2306604 GG genotype (P = 0.031) and FAAH rs324420 AA genotype (P = 0.0084) negatively affect the elite athletic performance. The CHRNB3 variant (rs4950, G allele) is significantly more frequent in the endurance athletes compared with the power ones (P = 0.025). Multivariate analysis demonstrated that the presence of rs4950 G allele contributes to endurance performance (P = 0.0047). Our results suggest that genetic inheritance of psychological traits should be taken into consideration while trying to decipher a genetic profile of top athletic performance.
Immortalization and characterization of a new canine mammary tumour cell line FR37‐CMT
Authors: Raposo L. R. , Roma‐Rodrigues C. , Faísca P. , Alves M. , Henriques J. , Carvalheiro M. C. , Corvo M. L. , Baptista P. V. , Pombeiro A. J. , Fernandes A. R.
Published: May 2016

Here we describe the establishment of a new canine mammary tumour (CMT) cell line, FR37‐CMT that does not show dependence on female hormonal signaling to induce tumour xenografts in NOD‐SCID mice. FR37‐CMT cell line has a stellate or fusiform shape, displays the ability to reorganize the collagen matrix, expresses vimentin, CD44 and shows the loss of E‐cadherin which is considered a fundamental event in epithelial to mesenchymal transition (EMT). The up‐regulation of ZEB1, the detection of phosphorylated ERK1/2 and the downregulation of DICER1 and miR‐200c are also in accordance with the mesenchymal characteristics of FR37‐CMT cell line. FR37‐CMT shows a higher resistance to cisplatin (IC50>50 µM) and to doxorubicin (IC50>5.3 µM) compared with other CMT cell lines. These results support the use of FR37‐CMT as a new CMT model that may assist the understanding of the molecular mechanisms underlying EMT, CMT drug resistance, fostering the development of novel therapies targeting CMT.
Contextualising a pedagogical model for English‐language education in Hong Kong
Authors: CHAN JIM Y. H.
Published: May 2016

A major controversy in the fields of World Englishes (WE) and English as a lingua franca (ELF) has been the application of exonormative Inner Circle norms to ELT classrooms in diverse multilingual societies. This article seeks to examine the suitability of adopting a WE and/or an ELF‐oriented pedagogical model, as well as the corresponding research findings, in Hong Kong's ELT classroom. More specifically, the study investigated the use of English by the local professionals and, furthermore, evaluated the comparability of Hong Kong's sociolinguistic reality to typical WE and ELF contexts via a structured questionnaire survey and semi‐structured interviews.
Investigation of Workpiece Distortion During the Photopolymerization of a PAAW Joint
Authors: Doll Kristopher R. , De Meter Edward C.
Published: May 2016

As a workpiece is bonded to a photo-activated adhesive workholding (PAAW) fixture, the adhesive shrinks during photopolymerization. This leads to the buildup of residual stresses that may distort the workpiece or reduce the external load capacity of the adhesive joints. This research quantifies the impact of adhesive shrinkage on fractional thickness reduction and residual tensile force for a commercially available adhesive and gripper. These variables are quantified for typical ranges of adhesive joint thickness and workpiece interface stiffness. Empirical models are presented for relating these variables. This research reveals that once photopolymerization ceases, workpiece distortion and residual stresses are permanent, and are not diminished by adhesive stress relaxation. It also reveals that the fractional thickness reduction of a PAAW joint can range from close to zero to a value equivalent to the fractional volumetric shrinkage of the adhesive. Furthermore, it decreases with increasing workpiece interface stiffness and increasing adhesive joint thickness following a power law relationship. It is believed that necking within the adhesive joint has a significant influence on this relationship. For stiff workpiece interfaces, residual tensile forces can grow larger than 25% of the tensile break strength of an adhesive joint formed without restraint.
Auditory localization by subjects with unilateral tinnitus
Authors: Hyvärinen Petteri , Mendonça Catarina , Santala Olli , Pulkki Ville , Aarnisalo Antti A.
Published: May 2016

Tinnitus is associated with changes in neural activity. How such alterations impact the localization ability of subjects with tinnitus remains largely unexplored. In this study, subjects with self-reported unilateral tinnitus were compared to subjects with matching hearing loss at high frequencies and to normal-hearing subjects in horizontal and vertical plane localization tasks. Subjects were asked to localize a pink noise source either alone or over background noise. Results showed some degree of difference between subjects with tinnitus and subjects with normal hearing in horizontal plane localization, which was exacerbated by background noise. However, this difference could be explained by different hearing sensitivities between groups. In vertical plane localization there was no difference between groups in the binaural listening condition, but in monaural listening the tinnitus group localized significantly worse with the tinnitus ear. This effect remained when accounting for differences in hearing sensitivity. It is concluded that tinnitus may degrade auditory localization ability, but this effect is for the most part due to the associated levels of hearing loss. More detailed studies are needed to fully disentangle the effects of hearing loss and tinnitus.
Effects of complex tonal stimuli on latency and amplitude of a late auditory evoked potential
Authors: Marx Charles G. , Goshorn Edward L.
Published: May 2016

An optimum stimulus for evoking late auditory potentials is not well established. A typical stimulus for clinical purposes is either a brief speech signal or a brief single-frequency tone. Based on previous research, it is reasonable to assume that a complex stimulus may enhance waveform morphology relative to a single-frequency stimulus. The current project investigated the effects on P1 latency and P1/N1 amplitude of a two-frequency complex stimulus with the second frequency having either a dissonant or harmonic relationship to a single-frequency reference stimulus. An 80 ms 1000 Hz tone with 10 ms rise/fall times served as the reference stimulus. The two-frequency complex stimuli consisted of the reference (1000 Hz) frequency mixed with a second frequency of equal duration and amplitude at 1100, 1250, 1500, 2000, or 4000 Hz, resulting in three dissonant and two harmonic stimuli. One dissonant stimulus (1000 + 1100 Hz) was designed to fall within the critical band of the reference stimulus. Stimuli were presented in a counterbalanced order to 20 normal hearing adult subjects. Two replicate runs were obtained for each stimulus condition. Results showed that the complex stimuli had no significant effect on P1 latency relative to the reference stimulus, but produced a significant increase in P1/N1 amplitude for the harmonic stimuli.
Multi-tone suppression of distortion-product otoacoustic emissions in humans
Authors: Sieck Nicole E. , Rasetshwane Daniel M. , Kopun Judy G. , Jesteadt Walt , Gorga Michael P. , Neely Stephen T.
Published: May 2016

The purpose of this study was to investigate the combined effect of multiple suppressors. Distortion-product otoacoustic emission (DPOAE) measurements were made in normal-hearing participants. Primary tones had fixed frequencies (f2 = 4000 Hz; f1 / f2 = 1.22) and a range of levels. Suppressor tones were at three frequencies (fs = 2828, 4100, 4300 Hz) and range of levels. Decrement was defined as the attenuation in DPOAE level due to the presence of a suppressor. A measure of suppression called suppressive intensity was calculated by an equation previously shown to fit DPOAE suppression data. Suppressor pairs, which were the combination of two different frequencies, were presented at levels selected to have equal single-suppressor decrements. A hybrid model that represents a continuum between additive intensity and additive attenuation best described the results. The suppressor pair with the smallest frequency ratio produced decrements that were more consistent with additive intensity. The suppressor pair with the largest frequency ratio produced decrements at the highest level that were consistent with additive attenuation. Other suppressor-pair conditions produced decrements that were intermediate between these two alternative models. The hybrid model provides a useful framework for representing the observed range of interaction when two suppressors are combined.
Multifractal analysis of visualized room impulse response for detecting early reflections
Authors: Pavlović Milan , Ristić Dragan M. , Reljin Irini , Mijić Miomir
Published: May 2016

This paper describes an improved method for detecting early reflections in the initial part of the room impulse response using multifractals. The proposed method uses the two-dimensional multifractal analysis. The room impulse response is visualized as a spectrogram image which is then subjected to the multifractal analysis. The algorithm is based on describing local regularity in the image using distribution of Hölder exponents. The time positions of the selected Hölder exponents in the image are utilized in detecting early reflections. The obtained results show better efficiency of the proposed algorithm compared to the previous one-dimensional multifractal analysis based algorithm.
Transforming growth factor–β and Notch ligands act as opposing environmental cues in regulating the plasticity of type 3 innate lymphoid cells
Authors: Viant Charlotte , Rankin Lucille C. , Girard-Madoux Mathilde J. H. , Seillet Cyril , Shi Wei , Smyth Mark J. , Bartholin Laurent , Walzer Thierry , Huntington Nicholas D. , Vivier Eric , Belz Gabrielle T.
Published: May 2016

Opposing signals in the tissue microenvironment balance the number of intestinal group 3 innate lymphoid cells.
Science Signaling
Podcast for 3 May 2016: Innate lymphoid cell plasticity
Authors: Vivier Eric , Golub Rachel , VanHook Annalisa M.
Published: May 2016

Notch and TGF-β signaling control the plasticity of group 3 innate lymphoid cells.
A Multinational, Preregistered Cohort Study of β-Lactam/β-Lactamase Inhibitor Combinations for Treatment of Bloodstream Infections Due to Extended-Spectrum-β-Lactamase-Producing Enterobacteriaceae
Authors: Gutiérrez-Gutiérrez Belén , Pérez-Galera Salvador , Salamanca Elena , de Cueto Marina , Calbo Esther , Almirante Benito , Viale Pierluigi , Oliver Antonio , Pintado Vicente , Gasch Oriol , Martínez-Martínez Luis , Pitout Johann , Akova Murat , Peña Carmen , Molina José , Hernández Alicia , Venditti Mario , Prim Nuria , Origüen Julia , Bou German , Tacconelli Evelina , Tumbarello Mario , Hamprecht Axel , Giamarellou Helen , Almela Manel , Pérez Federico , Schwaber Mitchell J. , Bermejo Joaquín , Lowman Warren , Hsueh Po-Ren , Mora-Rillo Marta , Natera Clara , Souli Maria , Bonomo Robert A. , Carmeli Yehuda , Paterson David L. , Pascual Alvaro , Rodríguez-Baño Jesús
Published: May 2016

The spread of extended-spectrum-β-lactamase (ESBL)-producing
Enterobacteriaceae
(ESBL-E) is leading to increased carbapenem consumption. Alternatives to carbapenems need to be investigated. We investigated whether β-lactam/β-lactamase inhibitor (BLBLI) combinations are as effective as carbapenems in the treatment of bloodstream infections (BSI) due to ESBL-E. A multinational, retrospective cohort study was performed. Patients with monomicrobial BSI due to ESBL-E were studied; specific criteria were applied for inclusion of patients in the empirical-therapy (ET) cohort (ETC; 365 patients), targeted-therapy (TT) cohort (TTC; 601 patients), and global cohort (GC; 627 patients). The main outcome variables were cure/improvement rate at day 14 and all-cause 30-day mortality. Multivariate analysis, propensity scores (PS), and sensitivity analyses were used to control for confounding. The cure/improvement rates with BLBLIs and carbapenems were 80.0% and 78.9% in the ETC and 90.2% and 85.5% in the TTC, respectively. The 30-day mortality rates were 17.6% and 20% in the ETC and 9.8% and 13.9% in the TTC, respectively. The adjusted odds ratio (OR) (95% confidence interval [CI]) values for cure/improvement rate with ET with BLBLIs were 1.37 (0.69 to 2.76); for TT, they were 1.61 (0.58 to 4.86). Regarding 30-day mortality, the adjusted OR (95% CI) values were 0.55 (0.25 to 1.18) for ET and 0.59 (0.19 to 1.71) for TT. The results were consistent in all subgroups studied, in a stratified analysis according to quartiles of PS, in PS-matched cases, and in the GC. BLBLIs, if active
in vitro
, appear to be as effective as carbapenems for ET and TT of BSI due to ESLB-E regardless of the source and specific species. These data may help to avoid the overuse of carbapenems. (This study has been registered at ClinicalTrials.gov under registration no. NCT01764490.)
Characteristics and Outcomes of Complicated Intra-abdominal Infections Involving Pseudomonas aeruginosa from a Randomized, Double-Blind, Phase 3 Ceftolozane-Tazobactam Study
Authors: Miller Benjamin , Popejoy Myra W. , Hershberger Ellie , Steenbergen Judith N. , Alverdy John
Published: May 2016

Ceftolozane-tazobactam is active against Gram-negative pathogens, including multidrug-resistant
Pseudomonas aeruginosa
. In a subgroup analysis of patients with complicated intra-abdominal infections (cIAIs) involving
P. aeruginosa
from a phase 3 program, ceftolozane-tazobactam demonstrated potent
in vitro
activity against
P. aeruginosa
. Clinical cure in the microbiologically evaluable population was 100% (26/26) for ceftolozane-tazobactam plus metronidazole and 93.1% (27/29) for meropenem. These findings support the use of ceftolozane-tazobactam in the management of cIAI when
P. aeruginosa
is suspected or confirmed. (This study has been registered at ClinicalTrials.gov under registration no. NCT01445665 and NCT01445678.)
Antifungal Mechanism of Action of Lactoferrin: Identification of H
+
-ATPase (P
3A
-Type) as a New Apoptotic-Cell Membrane Receptor
Authors: Andrés María T. , Acosta-Zaldívar Maikel , Fierro José F.
Published: May 2016

Human lactoferrin (hLf) is a protein of the innate immune system which induces an apoptotic-like process in yeast. Determination of the susceptibility to lactoferrin of several yeast species under different metabolic conditions, respiratory activity, cytoplasmic ATP levels, and external medium acidification mediated by glucose assays suggested plasma membrane Pma1p (P
3A
-type ATPase) as the hLf molecular target. The inhibition of plasma membrane ATPase activity by hLf and the identification of Pma1p as the hLf-binding membrane protein confirmed the previous physiological evidence. Consistent with this, cytoplasmic ATP levels progressively increased in hLf-treated
Candida albicans
cells. However, oligomycin, a specific inhibitor of the mitochondrial F-type ATPase proton pump (mtATPase), abrogated the antifungal activity of hLf, indicating a crucial role for mtATPase in the apoptotic process. We suggest that lactoferrin targeted plasma membrane Pma1p H
+
-ATPase, perturbing the cytoplasmic ion homeostasis (i.e., cytoplasmic H
+
accumulation and subsequent K
+
efflux) and inducing a lethal mitochondrial dysfunction. This initial event involved a normal mitochondrial ATP synthase activity responsible for both the ATP increment and subsequent hypothetical mitochondrial proton flooding process. We conclude that human lactoferrin inhibited Pma1p H
+
-ATPase, inducing an apoptotic-like process in metabolically active yeast. Involvement of mitochondrial H
+
-ATPase (nonreverted) was essential for the progress of this programmed cell death in which the ionic homeostasis perturbation seems to precede classical nonionic apoptotic events.
Identification, Characterization, and Application of the Replicon Region of the Halophilic Temperate Sphaerolipovirus SNJ1
Authors: Wang Yuchen , Sima Linshan , Lv Jie , Huang Suiyuan , Liu Ying , Wang Jiao , Krupovic Mart , Chen Xiangdong
Published: May 2016

The temperate haloarchaeal virus SNJ1 displays lytic and lysogenic life cycles. During the lysogenic cycle, the virus resides in its host,
Natrinema
sp. strain J7-1, in the form of an extrachromosomal circular plasmid, pHH205. In this study, a 3.9-kb region containing seven predicted genes organized in two operons was identified as the minimal replicon of SNJ1. Only RepA, encoded by open reading frame 11-12 (ORF11-12), was found to be essential for replication, and its expression increased during the lytic cycle. Sequence analysis suggested that RepA is a distant homolog of HUH endonucleases, a superfamily that includes rolling-circle replication initiation proteins from various viruses and plasmids. In addition to RepA, two genetic elements located within both termini of the 3.9-kb replicon were also required for SNJ1 replication. SNJ1 genome and SNJ1 replicon-based shuttle vectors were present at 1 to 3 copies per chromosome. However, the deletion of ORF4 significantly increased the SNJ1 copy number, suggesting that the product of ORF4 is a negative regulator of SNJ1 abundance. Shuttle vectors based on the SNJ1 replicon were constructed and validated for stable expression of heterologous proteins, both in J7 derivatives and in
Natrinema
pallidum
JCM 8980
T
, suggesting their broad applicability as genetic tools for
Natrinema
species.

IMPORTANCE
Archaeal viruses exhibit striking morphological diversity and unique gene content. In this study, the minimal replicon of the temperate haloarchaeal virus SNJ1 was identified. A number of ORFs and genetic elements controlling virus genome replication, maintenance, and copy number were characterized. In addition, based on the replicon, a novel expression shuttle vector has been constructed and validated for protein expression and purification in
Natrinema
sp. CJ7 and
Natrinema pallidum
JCM 8980
T
. This study not only provided mechanistic and functional insights into SNJ1 replication but also led to the development of useful genetic tools to investigate SNJ1 and other viruses infecting
Natrinema
species as well as their hosts.
Biosynthetic Genes for the Tetrodecamycin Antibiotics
Authors: Gverzdys Tomas , Nodwell Justin R.
Published: May 2016

We recently described 13-deoxytetrodecamycin, a new member of the tetrodecamycin family of antibiotics. A defining feature of these molecules is the presence of a five-membered lactone called a tetronate ring. By sequencing the genome of a producer strain,
Streptomyces
sp. strain WAC04657, and searching for a gene previously implicated in tetronate ring formation, we identified the biosynthetic genes responsible for producing 13-deoxytetrodecamycin (the
ted
genes). Using the
ted
cluster in WAC04657 as a reference, we found related clusters in three other organisms:
Streptomyces atroolivaceus
ATCC 19725,
Streptomyces globisporus
NRRL B-2293, and
Streptomyces
sp. strain LaPpAH-202. Comparing the four clusters allowed us to identify the cluster boundaries. Genetic manipulation of the cluster confirmed the involvement of the
ted
genes in 13-deoxytetrodecamycin biosynthesis and revealed several additional molecules produced through the
ted
biosynthetic pathway, including tetrodecamycin, dihydrotetrodecamycin, and another, W5.9, a novel molecule. Comparison of the bioactivities of these four molecules suggests that they may act through the covalent modification of their target(s).

IMPORTANCE
The tetrodecamycins are a distinct subgroup of the tetronate family of secondary metabolites. Little is known about their biosynthesis or mechanisms of action, making them an attractive subject for investigation. In this paper we present the biosynthetic gene cluster for 13-deoxytetrodecamycin in
Streptomyces
sp. strain WAC04657. We identify related clusters in several other organisms and show that they produce related molecules.
Efficient Sulfide Assimilation in Methanosarcina acetivorans Is Mediated by the MA1715 Protein
Authors: Rauch Benjamin Julius , Perona John J.
Published: May 2016

Conserved genes essential to sulfur assimilation and trafficking in aerobic organisms are missing in many methanogens, most of which inhabit highly sulfidic, anaerobic environmental niches. This suggests that methanogens possess distinct pathways for the synthesis of key metabolites and intermediates, including cysteine, homocysteine, and protein persulfide groups. Prior work identified a novel tRNA-dependent two-step pathway for cysteine biosynthesis and a new metabolic transformation by which sulfur is inserted into aspartate semialdehyde to produce homocysteine. Homocysteine biosynthesis requires two of the three proteins previously identified in our laboratory by a comprehensive bioinformatics approach. Here, we show that the third protein identified
in silico
, the ApbE-like protein COG2122, facilitates sulfide assimilation in
Methanosarcina acetivorans
. Knockout strains lacking the gene encoding COG2122 are severely impaired for growth when sulfide is provided as the sole sulfur source. However, rapid growth is recovered upon supplementation with cysteine, homocysteine, or cystathionine, suggesting that COG2122 is required for efficient biosynthesis of both cysteine and homocysteine. Deletion of the gene encoding COG2122 does not influence the extent of sulfur modifications in tRNA or the prevalence of iron-sulfur clusters, indicating that the function of COG2122 could be limited to sulfide assimilation for cysteine and homocysteine biosynthesis alone.

IMPORTANCE
We have found that the conserved
M. acetivorans
ma1715
gene, which encodes an ApbE-like protein, is required for optimal growth with sulfide as the sole sulfur source and supports both cysteine and homocysteine biosynthesis
in vivo
. Together with related functional-genomics studies in methanogens, these findings make a key contribution to elucidating the novel pathways of sulfide assimilation and sulfur trafficking in anaerobic microorganisms that existed before the advent of oxygenic photosynthesis. The data suggest that the MA1715 protein is particularly important to sustaining robust physiological function when ambient sulfide concentrations are low. Phylogenetic analysis shows that MA1715 and other recently discovered methanogen sulfur-trafficking proteins share an evolutionary history with enzymes in the methanogenesis pathway. The newly characterized genes thus likely formed an essential part of the core metabolic machinery of the ancestral euryarchaeote.
Coexpression of Escherichia coli obgE, Encoding the Evolutionarily Conserved Obg GTPase, with Ribosomal Proteins L21 and L27
Authors: Maouche Rim , Burgos Hector L. , My Laetitia , Viala Julie P. , Gourse Richard L. , Bouveret Emmanuelle
Published: May 2016

Multiple essential small GTPases are involved in the assembly of the ribosome or in the control of its activity. Among them, ObgE (CgtA) has been shown recently to act as a ribosome antiassociation factor that binds to ppGpp, a regulator whose best-known target is RNA polymerase. The present study was aimed at elucidating the expression of
obgE
in
Escherichia coli
. We show that
obgE
is cotranscribed with ribosomal protein genes
rplU
and
rpmA
and with a gene of unknown function,
yhbE
. We show here that about 75% of the transcripts terminate before
obgE
, because there is a transcriptional terminator between
rpmA
and
yhbE
. As expected for ribosomal protein operons, expression was highest during exponential growth, decreased during entry into stationary phase, and became almost undetectable thereafter. Expression of the operon was derepressed in mutants lacking ppGpp or DksA. However, regulation by these factors appears to occur post-transcription initiation, since no effects of ppGpp and DksA on
rplU
promoter activity were observed
in vitro
.

IMPORTANCE
The conserved and essential ObgE GTPase binds to the ribosome and affects its assembly. ObgE has also been reported to impact chromosome segregation, cell division, resistance to DNA damage, and, perhaps most interestingly, persister formation and antibiotic tolerance. However, it is unclear whether these effects are related to its role in ribosome formation. Despite its importance, no studies on ObgE expression have been reported. We demonstrate here that
obgE
is expressed from an operon encoding two ribosomal proteins, that the operon's expression varies with the growth phase, and that it is dependent on the transcription regulators ppGpp and DksA. Our results thus demonstrate that
obgE
expression is coupled to ribosomal gene expression.