bluuebunny/crossref_metadata_2025 huggingface dataset:
Brexit and Tariff Rate Quotas on EU Imports: A Complex Problem
Authors: Revell Brian J.
Published: August 2017

Tariff rate quotas (TRQs) are a means by which non‐EU suppliers of agri‐food products can be given preferential access to EU markets within a regulated framework of quotas at tariff rates below the Most Favoured Nation rates bound in the GATT. TRQs are common in governing trade in the meat and dairy sectors of the EU, although they apply to a wide range of other agricultural commodity and processed agri‐food products. Brexit poses a complex set of problems regarding TRQs in terms of how the respective parties should divide up jointly undertaken commitments within the WTO, since TRQs have been negotiated by the Commission on behalf of all EU Member States. Whilst individual quota allocations can be allocated to specific third country suppliers, individual Member States receive no specific allocation of the global product TRQ either in total, or from any named preferential supplier. The article outlines the nature of TRQs in the meat and dairy sectors of the EU, and how a simple partitioning of existing quotas between the EU‐27 and the UK is unlikely to resolve the complex issue of access rights of third countries to both markets. Possible solutions are explored, including the potential need for reciprocal EU‐27–UK TRQs post Brexit.
IDW‐Plus: An ArcGIS Toolset for Calculating Spatially Explicit Watershed Attributes for Survey Sites
Authors: Peterson Erin E. , Pearse Alan R.
Published: August 2017

Watershed characteristics such as land‐use and land‐cover affect stream condition at multiple scales, but it is widely accepted that conditions in close proximity to the stream or survey site tend to have a stronger influence. Although spatially weighted watershed metrics have existed for years, nonspatial lumped landscape metrics (i.e., areal mean or percentage) are still widely used because relatively few technical skills are needed to implement them. The Inverse Distance Weighted Percent Land Use for Streams (IDW‐Plus) custom ArcGIS toolset provides the functionality to efficiently calculate six spatially explicit watershed metrics which account for the Euclidean or flow length distance to the stream or outlet, as well as the probability for overland runoff. These include four distance‐weighted metrics, those being inverse Euclidean distance to the stream or outlet, and the inverse flow length to the stream or outlet. Two tools are also included to generate hydrologically active (i.e., runoff potential), inverse flow length to the stream or outlet metrics. We demonstrate the tools using real data from Southeast Queensland, Australia. We also provide detailed instructions, so readers can recreate the examples themselves before applying the tools to their own data.
Hospital systems and bargaining power: evidence from out‐of‐market acquisitions
Authors: Lewis Matthew S. , Pflum Kevin E.
Published: August 2017

Analyses of hospital mergers typically focus on acquisitions that alter local market concentration. However, as prices are negotiated between hospital systems and insurers, this focus may overlook the impact of cross‐market interdependence in the bargaining outcome. Using data on out‐of‐market acquisitions occurring across the United States from 2000–2010, we investigate the impact of cross‐market dependencies on negotiated prices. We find that prices at hospitals acquired by out‐of‐market systems increase by about 17% more than unacquired, stand‐alone hospitals and confirm that out‐of‐market mergers result in a relaxation of competition, the prices of nearby competitors to acquired hospitals increase by around 8%.
Advertising, consumer awareness, and choice: evidence from the U.S. banking industry
Authors: Honka Elisabeth , Hortaçsu Ali , Vitorino Maria Ana
Published: August 2017

How does advertising influence consumer decisions and market outcomes? We utilize detailed data on consumer shopping behavior and choices over bank accounts to investigate the effects of advertising on the different stages of the shopping process: awareness, consideration, and choice. We formulate a structural model with costly search and endogenous consideration sets, and show that advertising in the U.S. banking industry is primarily a shifter of awareness as opposed to consideration or choice. Advertising makes consumers aware of more options, search more, and find better alternatives. This increases the market share of smaller banks and makes the industry more competitive.
Auctions versus negotiations: the effects of inefficient renegotiation
Authors: Herweg Fabian , Schmidt Klaus M.
Published: August 2017

For the procurement of complex goods, the early exchange of information is important to avoid costly renegotiation. If the buyer can specify the main characteristics of possible design improvements in a complete contingent contract, scoring auctions implement the efficient allocation. If this is not feasible, the buyer must choose between a price‐only auction (discouraging early information exchange) and bilateral negotiations with a preselected seller (reducing competition). Bilateral negotiations are superior if potential design improvements are important, if renegotiation is very costly, and if the buyer's bargaining position is strong. Moreover, negotiations provide stronger incentives for sellers to investigate design improvements.
Demand for nondurable goods: a shortcut to estimating long‐run price elasticities
Authors: Perrone Helena
Published: August 2017

When consumers stockpile, static demand models overestimate long‐term price responses. This article presents a dynamic model of demand with consumer inventories and proposes a shortcut to estimate the long‐run price elasticities without having to solve the dynamic program. Using French data on food purchases, I find elasticities consistent with those that result from the full‐blown estimations found in the literature.
Microvascular and lymphovascular tumour invasion are associated with poor prognosis and metastatic spread in renal cell carcinoma: a validation study in clinical practice
Authors: Bedke Jens , Heide Johannes , Ribback Silvia , Rausch Steffen , de Martino Michela , Scharpf Marcus , Haitel Andrea , Zimmermann Uwe , Pechoel Maik , Alkhayyat Hussam , Shariat Shahrokh F. , Dombrowski Frank , Stenzl Arnulf , Burchardt Martin , Klatte Tobias , Kroeger Nils
Published: August 2017

Objective

To validate microvascular (MVI) and lymphovascular (LVI) invasion as prognostic factors in patients with renal cell carcinoma (RCC).

Patients and Methods

Data of patients with RCC who underwent radical or nephron‐sparing surgery were prospectively collected from three academic centres. The occurrence of MVI and LVI was determined with standard staining protocols by experienced pathologists at the time of diagnosis. The association of MVI and LVI with clinicopathological data, metastatic spread, and cancer‐specific survival (CSS) were evaluated with Fisher's exact tests, binary logistic regression analyses, and univariable and multivariable Cox proportional hazard regression models.

Results

MVI was present in 201 of 747 patients (26.9%) and was associated with advanced Tumour‐Node‐Metastasis (TNM) stages, high Fuhrman grades, and sarcomatoid features (all P < 0.001). MVI was associated with a higher rate of metastatic spread. LVI was present in 32 of 573 patients (5.5%) and was associated with advanced TNM stages, high Fuhrman grade, and sarcomatoid features (all P < 0.001). Two‐thirds of LVI‐positive patients died (P < 0.001). Both LVI and MVI were significantly associated with CSS in all patients, clear cell RCC (ccRCC), and localised RCC in univariable analysis (all P < 0.001). On multivariable analysis, presence of MVI was identified as an independent prognostic factor (hazard ratio 2.09; P = 0.001). Moreover, MVI [odds ratio (OR) 2.7; P = 0.001] and not macrovascular invasion (P = 0.895) was an independent predictor of sychronuous metastatic spread. LVI was the strongest factor associated with sychronous metastatic spread (OR 4.73, 95% confidence interval 1.84–12.14; P = 0.001) in all patients and in the subgroup of patients with ccRCC (P = 0.001).

Conclusions

The present study validated LVI and MVI as prognostic factors for poor outcome in RCC. These findings endorse an evaluation of both variables in the clinical routine setting to facilitate survival prognostication in follow‐up protocols and for assignment to adjuvant treatment trials.
Understanding frames: A UK survey of parents and professionals regarding the use of standing frames for children with cerebral palsy
Authors: Goodwin J. , Colver A. , Basu A. , Crombie S. , Howel D. , Parr J. R. , McColl E. , Kolehmainen N. , Roberts A. , Lecouturier J. , Smith J. , Miller K. , Cadwgan J.
Published: August 2017

Background

Standing frames are used for children with cerebral palsy (CP). They may improve body structure and function (e.g., reducing risk of hip subluxation, and improving bladder and bowel function), improving activity (e.g., motor abilities) and participation (e.g., interaction with peers), but there is little evidence that they do. We aimed to identify current UK standing frame practice for children with CP and to understand stakeholder views regarding their clinical benefits and challenges to use.

Method

Three populations were sampled: clinicians prescribing standing frames for children with CP (n = 305), professionals (health and education) working with children with CP who use standing frames (n = 155), and parents of children with CP who have used standing frames (n = 91). Questionnaires were developed by the co‐applicant group and piloted with other professionals and parents of children with CP. They were distributed online via clinical and parent networks across the UK.

Results

Prescribing practice was consistent, but achieving the prescribed use was not always possible. Respondents in all groups reported the perceived benefits of frames, which include many domains of the International Classification of Functioning Disability and Health for Children and Youth. Challenges of use are related to physical space and child‐reported pain.

Conclusions

These survey findings provide information from key stakeholders regarding current UK standing frame practice.
Can incomplete knowledge of species’ physiology facilitate ecological niche modelling? A case study with virtual species
Authors: Feng Xiao , Papeş Monica
Published: August 2017

Aim

Ecological niche modelling (ENM) is widely used in biogeography and conservation studies. The performance ofENMis influenced by the quality of species’ presence and absence datasets. Presences may include marginal localities, and absences are usually difficult to collect. We evaluated the use of species’ physiological limits to improve selection of presences and absences forENMin a virtual species framework with defined response functions as surrogates for physiological knowledge.

Location

The lower 48 states inUSA.

Methods

We generated physiologically informed absences based on either complete or incomplete knowledge of species’ physiology. With the same physiological knowledge, we reduced noise (incorrect or marginal locations) from presence datasets, completely or incompletely. We compared (i) models based on physiologically informed absences and random background points, (ii) models based on presences with and without noise and (iii) models obtained with and without incorporating physiological knowledge in absence and presence datasets.

Results

Only absences based on complete physiological information produced better performing models than random background points. Model improvement was positively correlated with the percentage of noise being removed from the presence data, and best‐performing models were obtained with true presences (all noise removed). Manipulating both absences and presences led to better models than manipulating only presences when all or majority of physiological limits were known.

Main conclusions

The benefit of incorporating physiological information intoENMdatasets largely depends on completeness of physiological knowledge, but in reality incomplete understanding of species’ physiology is the norm. We found that applying incomplete physiological knowledge to absences may biasENM, and thus, use of random background points is recommended; on the other hand, removing noise from species’ presence datasets based on incomplete physiological limits increases model performance, thus this approach could potentially improve the effectiveness ofENMapplications in conservation planning and invasive species management.
Prediction of esophageal stricture in patients given locoregional triamcinolone injections immediately after endoscopic submucosal dissection
Authors: Nagami Yasuaki , Ominami Masaki , Shiba Masatsugu , Sakai Taishi , Fukunaga Shusei , Sugimori Satoshi , Otani Koji , Hosomi Shuhei , Tanaka Fumio , Taira Koichi , Kamata Noriko , Yamagami Hirokazu , Tanigawa Tetsuya , Watanabe Toshio , Ishihara Takuma , Yamamoto Kouji , Fujiwara Yasuhiro
Published: August 2017

Background and Aim

Esophageal endoscopic submucosal dissection (ESD) to resect widespread lesions has increased the incidence of strictures, and some patients develop strictures despite receiving prophylactic locoregional triamcinolone injections. The present study evaluated the predictive factors for esophageal stricture formation in patients given prophylactic triamcinolone injections after ESD.

Methods

This was a retrospective observational study. Of 552 consecutive patients who underwent ESD, those who received prophylactic triamcinolone injections immediately after ESD were enrolled. Primary outcome was predictive factors for esophageal stricture formation in patients given prophylactic triamcinolone injections.

Results

We evaluated 101 en bloc resections involving 144 lesions in 96 patients. Strictures occurred following 17 (16.8%) resections. Wider circumferential mucosal defect (odds ratio [OR] 2.42, 95% confidence interval [CI]: 1.01–5.80; P = 0.048) was an independent predictive factor for stricture development. Cut‐off value associated with stricture formation was five‐sixths of the circumferential mucosal defect. Propensity analysis determined that frequency of esophageal strictures increased in patients with circumferential mucosal defects of more than five‐sixths compared with those less than five‐sixths (OR = 5.70, 95% CI: 1.61–20.18; P = 0.007).

Conclusion

Resections involving circumferential mucosal defects of more than five‐sixths increased the likelihood of stricture formation in patients given prophylactic locoregional triamcinolone injections after esophageal ESD.
Atypical parkinsonian syndromes: a general neurologist's perspective
Authors: Deutschländer A. B. , Ross O. A. , Dickson D. W. , Wszolek Z. K.
Published: August 2017

The differential diagnosis of atypical parkinsonian syndromes is challenging. These severe and often rapidly progressive neurodegenerative disorders are clinically heterogeneous and show significant phenotypic overlap. Here, clinical, imaging, neuropathological and genetic features of multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration and frontotemporal lobar degeneration (FTLD) are reviewed. The terms corticobasal degeneration and FTLD refer to pathologically confirmed cases of corticobasal syndrome and frontotemporal dementia (FTD). Frontotemporal lobar degeneration clinically presents as the behavioral variant FTD, semantic variant primary progressive aphasia (PPA), non‐fluent agrammatic variant PPA, logopenic variant PPA and FTD associated with motor neuron disease. While progressive supranuclear palsy and corticobasal syndrome have been called Parkinson‐plus syndromes in the past, they are now classified as FTD‐related disorders, reflecting that they pathologically differ from α‐synucleinopathies like multiple system atrophy and Parkinson disease. The contribution of genetic factors to atypical parkinsonian syndromes is increasingly recognized. Genes involved in the etiology of FTLD include MAPT, GRN and C9orf72. Novel neuroimaging techniques, including tau positron emission tomography imaging, are being investigated. Multimodal magnetic resonance imaging approaches and automated magnetic resonance imaging volume segmentation techniques are being evaluated for optimized differential diagnosis. Current treatment options are symptomatic, and disease modifying therapies are under active investigation.
Restricted responsiveness to noise interference in two anurans from the southern temperate forest
Authors: Penna Mario , Cisternas Javiera , Toloza Jessica
Published: August 2017

Animals adopt different strategies to communicate by means of sound in noisy environments such that some species increase, while others decrease their vocal activity in the presence of interference. Anuran amphibians from diverse latitudes exhibit both kinds of responses. Recent studies have shown that males of Batrachyla taeniata and Batrachyla antartandica from the temperate austral forest do not call in response to the presentation of advertisement calls of sympatric congeneric species. In contrast, Batrachyla leptopus responds to these signals in a similar way as to conspecific calls. The responsiveness of B. taeniata to natural abiotic interference has also been tested and found that noises of such sources produce strong increases in vocal activity. To assess the diversity in responsiveness to acoustic intrusion in this group, we exposed males of B. leptopus and B. antartandica to prolonged pre‐recorded natural abiotic noises of wind, creek, rain, and to a band‐pass noise centered at 2,000 Hz, at 67 dB Sound Pressure Level (SPL). The subjects did not increase their vocal activity significantly when exposed to these sounds and to band‐pass noise at increasing intensities (55–79 dB SPL). These results contrast with the increase in vocal activity observed previously in B. taeniata to continuous abiotic noise and point to the existence of diverse strategies to confront acoustic intrusion among related species. The lack of vocal activation observed also contrasts with the responsiveness of B. leptopus to heterospecific signals, but parallels the lack of response to such sounds in B. antartandica. Furthermore, the results obtained contrast with the responsiveness of these species to synthetic prolonged sounds observed in previous studies, suggesting that the modes of responses to acoustic intrusion may depend on previous experience, rather than having a species‐specific nature.
Case of possible multiple system atrophy with a characteristic imaging finding of open bladder neck during storage phase as an initial sign
Authors: Zhang Lu , Haga Nobuhiro , Ogawa Soichiro , Matsuoka Kanako , Koguchi Tomoyuki , Akaihata Hidenori , Hata Junya , Kataoka Masao , Ishibashi Kei , Kojima Yoshiyuki
Published: August 2017

Multiple system atrophy is a neurodegenerative disease that affects autonomic and motor systems. Patients with multiple system atrophy usually experience lower urinary tract symptoms, which sometimes appear as an initial symptom before the emergence of the generalized symptoms. An open bladder neck during the filling phase on video urodynamic study is one characteristic imaging finding after the diagnosis of multiple system atrophy, but has not previously been reported at an early phase of the disease. We report a case in which an open bladder neck was observed on several imaging modalities before generalized symptoms emerged. Because occult neurogenic bladder might exist in patients whose lower urinary tract symptoms are resistant to pharmacotherapy, we report this case to raise awareness of the importance of sufficient imaging evaluations. An open bladder neck might be an important imaging finding for diagnosing multiple system atrophy, irrespective of the presence of generalized symptoms. This finding could help avoid false diagnosis and unnecessary treatment.
Anatomical description of the main vessels for venipuncture in the black‐striped capuchin monkey (Sapajus libidinosus, Silva Junior, 2002)
Authors: La Salles Ana Y.F. , Cordeiro Jefferson F. , Santos José R. S. , Carreiro Artur N. , Medeiros Gildenor X. , Menezes Danilo J. A.
Published: August 2017

Background

The scarcity of data on the anatomy of Sapajus libidinosus has impeded the execution for appropriate veterinary treatment. The objective of this study was to describe the main peripheral veins of the capuchin monkey, used in venipuncture and indicate the best access route for venipuncture procedures.

Methods

Ten S. libidinosus corpses were used. The face, neck, chest, and pelvic limb were dissected using surgical instruments to identify and locate surface vessels.

Results

The main superficial veins identified could be used for venipuncture in capuchin monkey where the external jugular, brachial, cephalic, saphenous, and femoral veins. The veins in the pelvic limb were the most suitable for this purpose, with an un anesthetized subject.

Conclusions

The femoral vein was shown to be the most suitable for blood sampling and drug administration and the saphenous vein for serum therapy protocols.
Repeated exposure to two stressors in sequence demonstrates that corticosterone and paraventricular nucleus of the hypothalamus interleukin‐1β responses habituate independently
Authors: Lovelock D. F. , Deak T.
Published: August 2017

A wide range of stress‐related pathologies such as post‐traumatic stress disorder are considered to arise from aberrant or maladaptive forms of stress adaptation. The hypothalamic‐pituitary‐adrenal (HPA) axis readily adapts to repeated stressor exposure, yet little is known about adaptation in neuroimmune responses to repeated or sequential stress challenges. In Experiment 1, rats were exposed to 10 days of restraint alone (60 minutes daily), forced swim alone (30 minutes daily) or daily sequential exposure to restraint (60 minutes) followed immediately by forced swim (30 minutes), termed sequential stress exposure. Habituation of the corticosterone (CORT) response occurred to restraint by 5 days and swim at 10 days, whereas rats exposed to sequential stress exposure failed to display habituation to the combined challenge. Experiment 2 compared 1 or 5 days of forced swim with sequential stress exposure and examined how each affected expression of several neuroimmune and cellular activation genes in the paraventricular nucleus of the hypothalamus (PVN), prefrontal cortex (PFC) and hippocampus (HPC). Sequential exposure to restraint and swim increased interleukin (IL)‐1β in the PVN, an effect that was attenuated after 5 days. Sequential stress exposure also elicited IL‐6 and tumour necrosis factor‐α responses in the HPC and PFC, respectively, which did not habituate after 5 days. Experiment 3 tested whether prior habituation to restraint (5 days) would alter the IL‐1β response evoked by swim exposure imposed immediately after the sixth day of restraint. Surprisingly, a history of repeated exposure to restraint attenuated the PVN IL‐1β response after swim in comparison to acutely‐exposed subjects despite an equivalent CORT response. Overall, these findings suggest that habituation of neuroimmune responses to stress proceeds: (i) independent of HPA axis habituation; (ii) likely requires more daily sessions of stress to develop; and (iii) IL‐1β displays a greater tendency to habituate after repeated stress challenges compared to other stress‐reactive cytokines.
Characterisation, in-vitro and in-vivo evaluation of valproic acid-loaded nanoemulsion for improved brain bioavailability
Authors: Tan Suk Fei , Kirby Brian P , Stanslas Johnson , Basri Hamidon Bin
Published: August 2017

Objective

This study was aimed to investigate the potential of formulated valproic acid-encapsulated nanoemulsion (VANE) to improve the brain bioavailability of valproic acid (VPA).

Methods

Valproic acid-encapsulated nanoemulsions were formulated and physically characterised (osmolarity, viscosity, drug content, drug encapsulation efficiency). Further investigations were also conducted to estimate the drug release, cytotoxic profile, in-vitro blood–brain barrier (BBB) permeability, pharmacokinetic parameter and the concentration of VPA and VANE in blood and brain.

Key findings

Physical characterisation confirmed that VANE was suitable for parenteral administration. Formulating VPA into nanoemulsion significantly reduced the cytotoxicity of VPA. In-vitro drug permeation suggested that VANEs crossed the BBB as freely as VPA. Pharmacokinetic parameters of VANE-treated rats in plasma and brain showed F3 VANE had a remarkable improvement in AUC, prolongation of half-life and reduction in clearance compared to VPA. Given the same extent of in-vitro BBB permeation of VPA and VANE, the higher bioavailability of VANE in brain was believed to have due to higher concentration of VANE in blood. The brain bioavailability of VPA was improved by prolonging the half-life of VPA by encapsulating it within the nanoemulsion-T80.

Conclusions

Nanoemulsion containing VPA has alleviated the cytotoxic effect of VPA and improved the plasma and brain bioavailability for parenteral delivery of VPA.
The contribution of behavioural science to nutrition: Appetite control
Authors: Blundell J. E.
Published: August 2017

Behaviour and nutrition are inextricably linked. The behaviour of eating is the agency through which nutrients enter the body and exert their effects on physiology, metabolism and health. It is therefore inevitable that the study of eating behaviour (or appetite in general) is essential to an understanding of the discipline of nutrition and therefore to describing the ways in which nutrients can begin to exert their effects. The fact that humans are omnivores, with the potential to eat a huge diversity of foods, clearly denotes the importance of behaviour for nutrition. The roles of culture and biology in determining what foods people put into their mouths highlights the centrality of food choice for nutrition. In turn, behavioural science has made a huge contribution to defining the mechanisms responsible for food choice. This scientific approach has also specified the roles of homoeostatic and hedonic principles (and their interactions) in controlling the amount and type of food (nutrition) ingested. A substantial focus has been the investigation of the processes of satiation and satiety, with implications for understanding routes to over‐consumption and obesity. All of these investigations have been incorporated within a generally accepted and well‐described behavioural science methodology that involves the application of objective scientific principles to the study of eating behaviour. This methodology has been heavily implicated in the search for commercially viable functional foods for satiety. In recent years, behavioural science has engaged with the fields of energy balance and physical activity, recognising that nutrient intake is not independent of nutrient utilisation. This approach has been fostered by the pervasive problem of obesity and by its dependence on the interaction between over nutrition and under activity. The diversity of foods in the omnivore's repertoire is matched only by the diversity of humans themselves. This diversity is reality, and a future track for behavioural science seems destined to lead to understanding and managing individual differences.
Nutrition, epigenetics and health through life
Authors: Malcomson F. C. , Mathers J. C.
Published: August 2017

Epigenetics describe heritable changes to the genome without changes to the DNA sequence itself. Epigenetic marks include DNA methylation and histone modifications, and epigenetic molecules include microRNAs. Epigenetic mechanisms modulate gene expression and so regulate many cellular processes such as cell proliferation and cell death. As a consequence, changes to the epigenome may have consequences for the function of cells, tissues and organs and may modify the risk of developing disease. Epigenetic marks and molecules change during development and also during ageing; as we age, global DNA methylation declines whilst some specific genes become hypermethylated. Unlike the genome (DNA sequence), the epigenome is not fixed and the constellation of epigenetic marks and molecules is influenced by environmental exposures, including diet. Therefore, epigenetics provides a mechanism though which nutrition modulates health and wellbeing throughout the life course and, importantly, a plausible mechanism for the long‐term effects of early life nutritional exposures. There is growing evidence of the specific nutrients and other food constituents that influence the epigenome but, to date, the molecular pathways through which nutritional exposures and status are transduced (received and recorded) remain to be elucidated. Epigenetic patterns are promising candidate diet‐related biomarkers of ageing and of disease risk and, therefore, may be useful as surrogate endpoints in nutritional epidemiology and in dietary intervention studies.
Dreamless: the silent epidemic of REM sleep loss
Authors: Naiman Rubin
Published: August 2017

We are at least as dream deprived as we are sleep deprived. Many of the health concerns attributed to sleep loss result from a silent epidemic of REM sleep deprivation. REM/dream loss is an unrecognized public health hazard that silently wreaks havoc with our lives, contributing to illness, depression, and an erosion of consciousness. This paper compiles data about the causes and extent of REM/dream loss associated with commonly used medications, endemic substance use disorders, rampant sleep disorders, and behavioral and lifestyle factors. It examines the consequences of REM/dream loss and concludes with recommendations for restoring healthy REM/dreaming.
Overexpression of DEMETER, a DNA demethylase, promotes early apical bud maturation in poplar
Authors: Conde Daniel , Moreno‐Cortés Alicia , Dervinis Christopher , Ramos‐Sánchez José M. , Kirst Matias , Perales Mariano , González‐Melendi Pablo , Allona Isabel
Published: August 2017

The transition from active growth to dormancy is critical for the survival of perennial plants. We identified a DEMETER‐like (CsDML) cDNA from a winter‐enriched cDNA subtractive library in chestnut (Castanea sativa Mill.), an economically and ecologically important species. Next, we characterized this DNA demethylase and its putative ortholog in the more experimentally tractable hybrid poplar (Populus tremula × alba), under the signals that trigger bud dormancy in trees. We performed phylogenetic and protein sequence analysis, gene expression profiling, and 5‐methyl‐cytosine methylation immunodetection studies to evaluate the role of CsDML and its homolog in poplar, PtaDML6. Transgenic hybrid poplars overexpressing CsDML were produced and analysed. Short days and cold temperatures induced CsDML and PtaDML6. Overexpression of CsDML accelerated short‐day‐induced bud formation, specifically from Stages 1 to 0. Buds acquired a red‐brown coloration earlier than wild‐type plants, alongside with the up‐regulation of flavonoid biosynthesis enzymes and accumulation of flavonoids in the shoot apical meristem and bud scales. Our data show that the CsDML gene induces bud formation needed for the survival of the apical meristem under the harsh conditions of winter.
A Risk Analysis Approach to Prioritizing Epidemics: Ebola Virus Disease in West Africa as a Case Study
Authors: Ajisegiri Whenayon Simeon , Chughtai Abrar Ahmad , MacIntyre C. Raina
Published: August 2017

The 2014 Ebola virus disease (EVD) outbreak affected several countries worldwide, including six West African countries. It was the largest Ebola epidemic in the history and the first to affect multiple countries simultaneously. Significant national and international delay in response to the epidemic resulted in 28,652 cases and 11,325 deaths. The aim of this study was to develop a risk analysis framework to prioritize rapid response for situations of high risk. Based on findings from the literature, sociodemographic features of the affected countries, and documented epidemic data, a risk scoring framework using 18 criteria was developed. The framework includes measures of socioeconomics, health systems, geographical factors, cultural beliefs, and traditional practices. The three worst affected West African countries (Guinea, Sierra Leone, and Liberia) had the highest risk scores. The scores were much lower in developed countries that experienced Ebola compared to West African countries. A more complex risk analysis framework using 18 measures was compared with a simpler one with 10 measures, and both predicted risk equally well. A simple risk scoring system can incorporate measures of hazard and impact that may otherwise be neglected in prioritizing outbreak response. This framework can be used by public health personnel as a tool to prioritize outbreak investigation and flag outbreaks with potentially catastrophic outcomes for urgent response. Such a tool could mitigate costly delays in epidemic response.
Validation of the Resilience Scale for Adolescents in Norwegian adolescents 13–18 years
Authors: Moksnes Unni K. , Haugan Gørill
Published: August 2017

Aim

Resilience is seen as a vital resource for coping and mental health in adolescents. However, there is no universally accepted theory or definition of resilience, leading to considerable challenges regarding how to operationalise and measure this construct. The study aimed at providing further knowledge of the psychometric properties (dimensionality, construct validity and internal consistency) of the 28‐item version of the Resilience Scale for Adolescents (READ) in N = 1183 Norwegian adolescents, 13–18 years old.

Methods

Dimensionality of READ was tested using confirmatory factor analysis (CFA). Convergent validity and reliability were tested using Pearson's correlation analysis, Cronbach's alpha and composite reliability.

Results

The CFA supported a modified, 20‐item, five‐factor structure with high reliability, supporting the dimensionality and internal consistency of the instrument. Convergent validity was confirmed where all factors correlated in expected directions with measures of sense of coherence, self‐esteem, stress and depression.

Conclusion

The psychometric properties of the READ need to be further evaluated in adolescents; however, the results indicate that a modified 20‐item version of READ is adequate for assessing resilience in the present sample of Norwegian adolescents.
Evolution of MNC and lymphocyte collection settings employing different Spectra Optia® Leukapheresis systems
Authors: Punzel M. , Kozlova A. , Quade A. , Schmidt A. H. , Smith R.
Published: August 2017

Background and Objectives

The Spectra Optia® continuous mononuclear cell (CMNC apheresis) system has emerged as the preferred device in peripheral blood stem cell collections over the original two‐step Spectra Optia® mononuclear cell (MNC apheresis) system. Until now, no comparative data were available for non‐stimulated MNC collections that are required for immunotherapy.

Materials and Methods

We compared collection parameters and product composition for Spectra Optia MNC‐ as well as CMNC‐apheresis systems in non‐stimulated MNC collections from 35 registry donors intended for donor lymphocyte infusions. In a subsequent analysis, different centrifugation forces (determined as packing factor or PF) were investigated regarding target cell yield and contamination in 61 collections using the CMNC device only.

Results

Comparable collection efficiencies as well as target cell yields could be achieved with the Spectra Optia MNC‐ versus CMNC program. Similar numbers of MNC, T, B and NK cells could be collected with both devices. This led to a more than twofold lymphocyte recruitment from lymphatic tissue into the blood during apheresis. However, significantly more blood had to be processed with longer procedure time using the MNC program resulting in larger product volumes compared to the CMNC setting. Red blood cell and platelet (PLT) contamination were similar. Lowering the centrifugation force from PF4·5 to PF4·0 significantly reduced PLT contamination without affecting target cell yield in the product.

Conclusion

The Spectra Optia® CMNC device using lower centrifugal force (PF4·0) showed similar target cell yield and composition as well as collection efficiencies with superior performance parameters and lower PLT contamination compared to the MNC setting.
Interleukin-36 cytokines may overcome microbial immune evasion strategies that inhibit interleukin-1 family signaling
Authors: Jensen Liselotte E.
Published: August 2017

Interleukin-36 (IL-36) cytokines may enable mammals to overcome pathogen-induced suppression of IL-1– and IL-18–mediated immunity.
Papers of note in
Nature
548
(7666)
Authors: Ferrarelli Leslie K.
Published: August 2017

This week’s articles describe the consequences of preserving pluripotency in cultured stem cells, how glutamate metabolism in T cells contributes to autoimmune disease, and how inactivating BRAF mutations promote tumor growth.
PBP4 Mediates β-Lactam Resistance by Altered Function
Authors: Chatterjee Som S. , Chen Liang , Gilbert Aubre , da Costa Thaina M. , Nair Vinod , Datta Sandip K. , Kreiswirth Barry N. , Chambers Henry F.
Published: August 2017

Penicillin binding protein 4 (PBP4) can provide high-level β-lactam resistance in
Staphylococcus aureus
. A series of missense and promoter mutations associated with
pbp4
were detected in strains that displayed high-level resistance. We show here that the missense mutations facilitate the β-lactam resistance mediated by PBP4 and the promoter mutations lead to overexpression of
pbp4
. Our results also suggest a cooperative interplay among PBPs for β-lactam resistance.
Development and Use of Personalized Bacteriophage-Based Therapeutic Cocktails To Treat a Patient with a Disseminated Resistant Acinetobacter baumannii Infection
Authors: Schooley Robert T. , Biswas Biswajit , Gill Jason J. , Hernandez-Morales Adriana , Lancaster Jacob , Lessor Lauren , Barr Jeremy J. , Reed Sharon L. , Rohwer Forest , Benler Sean , Segall Anca M. , Taplitz Randy , Smith Davey M. , Kerr Kim , Kumaraswamy Monika , Nizet Victor , Lin Leo , McCauley Melanie D. , Strathdee Steffanie A. , Benson Constance A. , Pope Robert K. , Leroux Brian M. , Picel Andrew C. , Mateczun Alfred J. , Cilwa Katherine E. , Regeimbal James M. , Estrella Luis A. , Wolfe David M. , Henry Matthew S. , Quinones Javier , Salka Scott , Bishop-Lilly Kimberly A. , Young Ry , Hamilton Theron
Published: August 2017

Widespread antibiotic use in clinical medicine and the livestock industry has contributed to the global spread of multidrug-resistant (MDR) bacterial pathogens, includingAcinetobacter baumannii. We report on a method used to produce a personalized bacteriophage-based therapeutic treatment for a 68-year-old diabetic patient with necrotizing pancreatitis complicated by an MDRA. baumanniiinfection. Despite multiple antibiotic courses and efforts at percutaneous drainage of a pancreatic pseudocyst, the patient deteriorated over a 4-month period. In the absence of effective antibiotics, two laboratories identified nine different bacteriophages with lytic activity for anA. baumanniiisolate from the patient. Administration of these bacteriophages intravenously and percutaneously into the abscess cavities was associated with reversal of the patient's downward clinical trajectory, clearance of theA. baumanniiinfection, and a return to health. The outcome of this case suggests that the methods described here for the production of bacteriophage therapeutics could be applied to similar cases and that more concerted efforts to investigate the use of therapeutic bacteriophages for MDR bacterial infections are warranted.
Bedaquiline Inhibits the ATP Synthase in Mycobacterium abscessus and Is Effective in Infected Zebrafish
Authors: Dupont Christian , Viljoen Albertus , Thomas Sangeeta , Roquet-Banères Françoise , Herrmann Jean-Louis , Pethe Kevin , Kremer Laurent
Published: August 2017

Pulmonary infections caused by
Mycobacterium abscessus
are emerging as a global threat, especially in cystic fibrosis patients. Further intensifying the concern of
M. abscessus
infection is the recent evidence of human-to-human transmission of the infection.
M. abscessus
is a naturally multidrug-resistant fast-growing pathogen for which pharmacological options are limited. Repurposing antitubercular drugs represents an attractive option for the development of chemotherapeutic alternatives against
M. abscessus
infections. Bedaquiline (BDQ), an ATP synthase inhibitor, has recently been approved for the treatment of multidrug-resistant tuberculosis. Herein, we show that BDQ has a very low MIC against a vast panel of clinical isolates. Despite being bacteriostatic
in vitro
, BDQ was highly efficacious in a zebrafish model of
M. abscessus
infection. Remarkably, a very short period of treatment was sufficient to protect the infected larvae from
M. abscessus
-induced killing. This was corroborated with reduced numbers of abscesses and cords, considered to be major pathophysiological signs in infected zebrafish. Mode-of-action studies revealed that BDQ triggered a rapid depletion of ATP in
M. abscessus
in vitro
, consistent with the drug targeting the F
o
F
1
ATP synthase. Importantly, despite a failure to select
in vitro
for spontaneous mutants that are highly resistant to BDQ, the transfer of single nucleotide polymorphisms leading to D29V or A64P substitutions in
atpE
conferred high resistance, thus resolving the target of BDQ in
M. abscessus
. Overall, this study indicates that BDQ is active against
M. abscessus
in vitro
and
in vivo
and should be considered for clinical use against the difficult-to-manage
M. abscessus
pulmonary infections.
Listeria monocytogenes and Shigella flexneri Activate the NLRP1B Inflammasome
Authors: Neiman-Zenevich Jana , Stuart Sarah , Abdel-Nour Mena , Girardin Stephen E. , Mogridge Jeremy
Published: August 2017

Activation of the innate immune receptor NLRP1B leads to the formation of an inflammasome, which induces autoproteolytic processing of pro-caspase-1, and ultimately to the release of inflammatory cytokines and to the execution of pyroptosis. One of the signals to which NLRP1B responds is metabolic stress that occurs in cells deprived of glucose or treated with metabolic inhibitors. NLRP1B might therefore sense microbial infection, as intracellular pathogens such as
Listeria monocytogenes
and
Shigella flexneri
cause metabolic stress as a result of nutrient scavenging and host cell damage. Here we addressed whether these pathogens activate the NLRP1B inflammasome. We found that
Listeria
infection activated the NLRP1B inflammasome in a reconstituted fibroblast model. Activation of NLRP1B by
Listeria
was diminished in an NLRP1B mutant shown previously to be defective at detecting energy stress and was dependent on the expression of listeriolysin O (LLO), a protein required for vacuolar escape. Infections of either
Listeria
or
Shigella
activated NLRP1B in the RAW264.7 murine macrophage line, which expresses endogenous NLRP1B. We conclude that NLRP1B senses cellular infection by distinct invasive pathogens.
Incremental Contributions of FbaA and Other Impetigo-Associated Surface Proteins to Fitness and Virulence of a Classical Group A Streptococcal Skin Strain
Authors: Rouchon Candace N. , Ly Anhphan T. , Noto John P. , Luo Feng , Lizano Sergio , Bessen Debra E.
Published: August 2017

Group A streptococci (GAS) are highly prevalent human pathogens whose primary ecological niche is the superficial epithelial layers of the throat and/or skin. Many GAS strains with a strong tendency to cause pharyngitis are distinct from strains that tend to cause impetigo; thus, genetic differences between them may confer host tissue-specific virulence. In this study, the FbaA surface protein gene was found to be present in most skin specialist strains but largely absent from a genetically related subset of pharyngitis isolates. In an Δ
fbaA
mutant constructed in the impetigo strain Alab49, loss of FbaA resulted in a slight but significant decrease in GAS fitness in a humanized mouse model of impetigo; the Δ
fbaA
mutant also exhibited decreased survival in whole human blood due to phagocytosis. In assays with highly sensitive outcome measures, Alab49ΔfbaA was compared to other isogenic mutants lacking virulence genes known to be disproportionately associated with classical skin strains. FbaA and PAM (i.e., the M53 protein) had additive effects in promoting GAS survival in whole blood. The pilus adhesin tip protein Cpa promoted Alab49 survival in whole blood and appears to fully account for the antiphagocytic effect attributable to pili. The finding that numerous skin strain-associated virulence factors make slight but significant contributions to virulence underscores the incremental contributions to fitness of individual surface protein genes and the multifactorial nature of GAS-host interactions.
Defining Electron Bifurcation in the Electron-Transferring Flavoprotein Family
Authors: Garcia Costas Amaya M. , Poudel Saroj , Miller Anne-Frances , Schut Gerrit J. , Ledbetter Rhesa N. , Fixen Kathryn R. , Seefeldt Lance C. , Adams Michael W. W. , Harwood Caroline S. , Boyd Eric S. , Peters John W.
Published: August 2017

Electron bifurcation is the coupling of exergonic and endergonic redox reactions to simultaneously generate (or utilize) low- and high-potential electrons. It is the third recognized form of energy conservation in biology and was recently described for select electron-transferring flavoproteins (Etfs). Etfs are flavin-containing heterodimers best known for donating electrons derived from fatty acid and amino acid oxidation to an electron transfer respiratory chain via Etf-quinone oxidoreductase. Canonical examples contain a flavin adenine dinucleotide (FAD) that is involved in electron transfer, as well as a non-redox-active AMP. However, Etfs demonstrated to bifurcate electrons contain a second FAD in place of the AMP. To expand our understanding of the functional variety and metabolic significance of Etfs and to identify amino acid sequence motifs that potentially enable electron bifurcation, we compiled 1,314 Etf protein sequences from genome sequence databases and subjected them to informatic and structural analyses. Etfs were identified in diverse archaea and bacteria, and they clustered into five distinct well-supported groups, based on their amino acid sequences. Gene neighborhood analyses indicated that these Etf group designations largely correspond to putative differences in functionality. Etfs with the demonstrated ability to bifurcate were found to form one group, suggesting that distinct conserved amino acid sequence motifs enable this capability. Indeed, structural modeling and sequence alignments revealed that identifying residues occur in the NADH- and FAD-binding regions of bifurcating Etfs. Collectively, a new classification scheme for Etf proteins that delineates putative bifurcating versus nonbifurcating members is presented and suggests that Etf-mediated bifurcation is associated with surprisingly diverse enzymes.

IMPORTANCE
Electron bifurcation has recently been recognized as an electron transfer mechanism used by microorganisms to maximize energy conservation. Bifurcating enzymes couple thermodynamically unfavorable reactions with thermodynamically favorable reactions in an overall spontaneous process. Here we show that the electron-transferring flavoprotein (Etf) enzyme family exhibits far greater diversity than previously recognized, and we provide a phylogenetic analysis that clearly delineates bifurcating versus nonbifurcating members of this family. Structural modeling of proteins within these groups reveals key differences between the bifurcating and nonbifurcating Etfs.