bluuebunny/crossref_metadata_2025 huggingface dataset:
The State of the Art in Vortex Extraction
Authors: Günther Tobias , Theisel Holger
Published: January 2018

Vortices are commonly understood as rotating motions in fluid flows. The analysis of vortices plays an important role in numerous scientific applications, such as in engineering, meteorology, oceanology, medicine and many more. The successful analysis consists of three steps: vortex definition, extraction and visualization. All three have a long history, and the early themes and topics from the 1970s survived to this day, namely, the identification of vortex cores, their extent and the choice of suitable reference frames. This paper provides an overview over the advances that have been made in the last 40 years. We provide sufficient background on differential vector field calculus, extraction techniques like critical point search and the parallel vectors operator, and we introduce the notion of reference frame invariance. We explain the most important region‐based and line‐based methods, integration‐based and geometry‐based approaches, recent objective techniques, the selection of reference frames by means of flow decompositions, as well as a recent local optimization‐based technique. We point out relationships between the various approaches, classify the literature and identify open problems and challenges for future work.
Heidelberg interaction training for language promotion in early childhood settings (HIT)
Authors: Buschmann Anke , Sachse Steffi
Published: January 2018

Beside parents, teachers in early childhood education and care have the greatest potential to foster language acquisition in children. This is especially important for children with language delays, language disorders or bi‐/multilingual children. However, they present teachers with a particular challenge in language support. Therefore, integrated language facilitation programmes are needed to promote language acquisition in the daily routine of daycare facilities and kindergartens. In this article, the Heidelberg Interaction Training for Language Promotion in Early Childhood Settings (HIT) is presented as a systematic approach to improve daily interactions between preschool teachers and children. This group training comprises six half‐day sessions over a period of six months. The objective is to expand teachers’ knowledge about language development in general and more specifically regarding children with language problems or bi‐/multilingual children. Furthermore, teachers learn a responsive interaction style and various strategies of language modelling by means of video supervision and feedback. Teachers’ satisfaction with the training has been evaluated and its efficacy in terms of changes in their behaviour and children's language performance has been proven in several intervention studies and meta‐analytic reviews. Lastly, implementation considerations for lasting effects following the HIT are discussed.
Toward a Resource‐Based View of City Quality: A New Framework
Authors: Carvalho João M. S. , Costa Ricardo V. , Marnoto Sandra , Sousa Célio A. A. , Vieira José Carvalho
Published: January 2018

Based on an extensive literature review on intelligent cities, smart cities, and happy cities, and on their conceptual connections with citizens' well‐being, quality of life, and happiness, we developed a resource‐based view on City Quality: the PESNAT (political, economic, social, natural, artificial, and technological) framework. The concept of City Quality rests on the idea of cities interconnected sub‐habitats—PESNAT—which are powerful analytical categories needed for understanding cities as complex and intricate loci. This framework eventually aims at assessing the cities' power to attract businesses and people, to contribute to a sustainable development of the city and an increased quality of life. Furthermore, two hypotheses are outlined regarding the level of importance of each sub‐habitat in relation to happiness, and the level of controversy of each one for citizens, city planners, and decision makers.
Long‐term outcome of stereotactic body radiotherapy for patients with small hepatocellular carcinoma
Authors: Kubo Katsumaro , Kimura Tomoki , Aikata Hiroshi , Takahashi Shigeo , Takeuchi Yuki , Takahashi Ippei , Nishibuchi Ikuno , Murakami Yuji , Chayama Kazuaki , Nagata Yasushi
Published: January 2018

Aim

To evaluate the long‐term outcome of stereotactic body radiotherapy in patients with small hepatocellular carcinoma who were ineligible for resection or ablation therapies.

Methods

A total of 65 patients with 74 hepatocellular carcinomas (median tumor size 16 mm) were enrolled in the present study. They were treated with the prescribed dose of 48 Gy in four fractions at the isocenter. We extended the observation period and analyzed long‐term outcomes, including overall survival, progression‐free survival, local control, and various prognostic factors, in these patients.

Results

The median follow‐up period was 41 months for all patients and 62 months for surviving patients. The 3‐ and 5‐year overall survival rates were 56.3% (95% confidence interval, 44.1–68.5%) and 41.4% (95% confidence interval, 28.7–54.1%), respectively. The 3‐ and 5‐year progression‐free survival rates were 25.4% (95% confidence interval, 14.0–36.8%) and 10.6% (95% confidence interval, 1.5–19.8%), respectively. The 3‐ and 5‐year local control rates were both 100% (95% confidence interval 100%). Liver toxicities exceeding grade 3 were observed in 15 patients (23.1%). The proportion of patients who had grade ≥3 toxicities did not increase. Adverse effects (grade ≤2) presented as significant prognostic factors of overall survival, while TNM stage (T1N0M0) was a significant prognostic factor of progression‐free survival after multivariate analysis.

Conclusions

Stereotactic body radiotherapy was effective for patients with small hepatocellular carcinomas who were ineligible for resection or ablation therapies. The incidence of grade ≥3 adverse effects did not increase, even after longer follow‐up times.
Mandatory audit firm rotation and prohibition of audit firm‐provided tax services: Evidence from investment consultants’ perceptions
Authors: Aschauer Ewald , Quick Reiner
Published: January 2018

The European Union has discussed and recently implemented both audit‐firm instead of audit‐partner rotation and a restriction against audit‐firm‐provided tax services in order to improve auditor independence and audit quality. This study provides experimental evidence of the effects of the rotation system, the impact of audit‐firm‐provided tax services, and, for the first time, the interplay between both regulatory measures. Based on the assessments of 140 professional investment consultants from credit institutions, the results show that an audit‐partner rotation regime which allows audit‐firm‐provided tax services generates the lowest assessments of auditor independence and audit quality. While investment consultants view both audit‐firm rotation and a prohibition against audit‐firm‐provided tax services as beneficial, the joint implementation of a prohibition against audit‐firm‐provided tax services and audit‐firm rotation leads to no additional benefits in either the appearance of independence or the perceived audit quality. Besides the theoretical contribution, we discuss the practical implications of our findings, in particular that more regulation does not automatically lead to higher audit quality.
The plutocratic bias in the Indian consumer price index
Authors: NACHANE Dilip M. , CHAUBAL Aditi
Published: January 2018

Studies have found a plutocratic bias in the traditional Laspeyres‐type consumer price index (CPI), attaching greater importance to expenditure by rich households compared to the poor, while the democratic CPI attaches equal weight to all. The authors calculate the democratic index and estimate the plutocratic bias for the new Indian CPI (launched in 2012), the rural and urban CPIs, and the CPIs of three Indian states from 2012 to 2015. They further develop democratic indices for commodity groups and separate indices for three expenditure brackets. The biases found against less developed states and the poorer sections of the population have important implications for monetary policy and indexation of transfer payments.
The effect of 22.5 kHz low‐frequency contact ultrasound debridement (LFCUD) on lower extremity wound healing for a vascular surgery population: A randomised controlled trial
Authors: Murphy Christine Anne , Houghton Pamela , Brandys Tim , Rose Gregory , Bryant Dianne
Published: January 2018

The aim of this study was to compare changes in wound size and appearance and health complication rates in patients with vasculopathy and lower‐extremity wounds treated with or without low‐frequency contact ultrasound debridement (LFCUD) This study was a randomised controlled trial. The study was conducted in a vascular surgery service, including outpatient wound clinic and inpatient ward, in a tertiary care academic centre. In total, 70 patients with vasculopathy and lower‐extremity wounds of mixed aetiology were enrolled in the trial; 68 completed the study. Patients were randomised to receive LFCUD plus usual care (n= 33) or usual care (n= 37) at 4 weekly visits, and were followed thereafter for up to 12 wk. The main outcome measures included closed wounds, change in wound surface area (WSA), and wound appearance by the revised Photographic Wound Assessment Tool (revPWAT). After 4 weekly LFCUD treatments, patients in the LFCUD group had significantly better wound appearance (total revPWAT score) compared with the control group treated only with usual care (P= <0.05). LFCUD‐treated wounds also had a significant reduction in WSA over 4 wk that was not found in the UC group. LFCUD treatment was also associated with a greater number of healed wounds, odds ratio 5.00 (95% CI 1.24‐20.25), and fewer instances of wound deterioration. Weekly LFCUD applications to patients with significant vasculopathy resulted in superior healing outcomes when compared with current usual wound care practice.
A Rawlsian Case for Economic Nationalism: Globalisation and Distributional Autonomy in the Law of Peoples
Authors: Schrepfer Matthew
Published: January 2018

John Rawls’ resistance to any kind of global egalitarian principle has seemed strange and unconvincing to many commentators, including those generally supportive of Rawls’ project. His rejection of a global egalitarian principle seems to rely on an assumption that states are economically bounded and separate from one another, which is not an accurate portrayal of economic relations among states in our globalised world. In this article, I examine the implications of the domestic theory of justice as fairness to argue that Rawls has good reason to insist on economically bounded states. I argue that certain central features of the contemporary global economy, particularly the free movement of capital across borders, undermine the distributional autonomy required for states to realise Rawls’ principles of justice, and the domestic theory thus requires a certain degree of economic separation among states prior to the convening of the international original position. Given this, I defend Rawls’ reluctance to endorse a global egalitarian principle and defend a policy regime of international capital controls, to restore distributional autonomy and make the realisation of the principles of justice as fairness possible.
Optimal Culture Temperature for Larval and Juvenile Pigfish, Orthopristis chrysoptera
Authors: Faulk Cynthia K. , Oberg Erik W. , Thompson Kathryn L. , Fuiman Lee A.
Published: January 2018

Pigfish, Orthopristis chrysoptera, is a candidate for aquaculture because it is a regionally popular marine baitfish and commercial production could increase its supply and reduce fishing pressure on wild populations. Identifying optimal conditions for pigfish growout is needed for efficient production. We investigated the effects of temperature on growth and survival from hatching to market size at five constant temperatures, ranging from 22 to 30 C. Larval survival was greatest at 22 C, but growth was slowest. Complete mortality of larvae at 30 C occurred by 6 d after hatch, suggesting an upper thermal limit between 28 and 30 C. For juveniles, growth in length and weight was greatest at 28 and 30 C, but there were no differences in survival among temperatures. The predicted upper thermal limit for juveniles is 35 C. Results indicate that maximum growth and survival would be achieved by rearing larvae at 24 C and juveniles at 28 C. Under this temperature schedule, pigfish would reach preferred market sizes of 7.6 cm (for bay fishing) and 15 cm (for offshore fishing) after 2.5 and 4 mo of culture, respectively.
A noble gas data collection of lunar meteorites
Authors: Mészáros Marianna , Hofmann Beda A. , Leya Ingo
Published: January 2018

We collected the published noble gas data of altogether 35 lunar meteorites. This compilation includes the stable isotopes of He, Ne, Ar, Kr, and Xe. We also give a summary of cosmogenic, trapped, and radiogenic noble gas components of lunar meteorites for which data are available in the literature.
Shapes of chondrules determined from the petrofabric of the CR2 chondrite NWA 801
Authors: Charles Christopher R. J. , Robin Pierre‐Yves F. , Davis Donald W. , McCausland Phil J. A.
Published: January 2018

The approximately spherical shapes of chondrules has long been attributed to surface tension acting on ~1 mm melt droplets that formed and cooled in the microgravity field of the solar nebula. However, chondrule shapes commonly depart significantly from spherical. In this study, 109 chondrules in a sample of CR2 chondrite NWA 801 were imaged by X‐ray computed tomography and best‐fitted to ellipsoids. The analysis confirms that many chondrules are indeed not spherical, and also that the chondrules’ collective shape fabric records a definite 13% compaction in the host meteorite. Dehydration of phyllosilicates within chondrules may account for that strain. However, retro‐deforming all chondrules shows that a large majority were already far from spherical prior to accretion. Possible models for these initial shapes include prior deformation of individual chondrules in earlier hosts, and, as suggested by previous authors, rotation of chondrules as they were solidifying, and/or “streaming” of molten chondrules by their differential velocities with their gaseous hosts after melting. More in situ 3‐D work such as this study on a variety of unequilibrated chondrites, combined with detailed structural petrography, should help further constrain these models and refine our understanding of chondrite formation.
Unearthing belowground bud banks in fire‐prone ecosystems
Authors: Pausas Juli G. , Lamont Byron B. , Paula Susana , Appezzato‐da‐Glória Beatriz , Fidelis Alessandra
Published: January 2018

Despite long‐time awareness of the importance of the location of buds in plant biology, research on belowground bud banks has been scant. Terms such as lignotuber, xylopodium and sobole, all referring to belowground bud‐bearing structures, are used inconsistently in the literature. Because soil efficiently insulates meristems from the heat of fire, concealing buds below ground provides fitness benefits in fire‐prone ecosystems. Thus, in these ecosystems, there is a remarkable diversity of bud‐bearing structures. There are at least six locations where belowground buds are stored: roots, root crown, rhizomes, woody burls, fleshy swellings and belowground caudexes. These support many morphologically distinct organs. Given their history and function, these organs may be divided into three groups: those that originated in the early history of plants and that currently are widespread (bud‐bearing roots and root crowns); those that also originated early and have spread mainly among ferns and monocots (nonwoody rhizomes and a wide range of fleshy underground swellings); and those that originated later in history and are strictly tied to fire‐prone ecosystems (woody rhizomes, lignotubers and xylopodia). Recognizing the diversity of belowground bud banks is the starting point for understanding the many evolutionary pathways available for responding to severe recurrent disturbances.
Knowledge and community resilience in rangelands recovery: the case of Wadi Allaqi Biosphere Reserve, South Eastern Desert, Egypt
Authors: Yacoub Hoda
Published: January 2018

Many ecosystems are actually social–ecological systems (SESs) consisting of mutually interacting natural and social subsystems. Resilience, the capacity to absorb or withstand perturbations while maintaining structure and functions, is an important feature of these systems. Indigenous or traditional knowledge is considered to be an important factor in being able to absorb change and maintain structure in the context of ecosystem dynamics. In this article, I use the framework of resilience to analyze how the Bedouin communities in Wadi Allaqi, Egypt, experienced and responded to the disturbing impact of Lake Nasser's formation in the mid‐1960s. Prior to that disturbance, the Bedouin lifestyle was characterized by traditional pastoral life based on rotational grazing by their herds. Afterward, the Bedouins permanently settled along the shores to make use of the new abundant water resource. This resulted in overgrazing of the rangelands along the lakeside and the disappearance of the traditional pastoral lifestyle. However, the Bedouins later learned to use the Najas species in the lake, ushering in a new SES. This new system is based on tactical grazing along the shores, giving the rangelands the opportunity to recover from the temporary grazing pressure. I argue that because many degraded ecosystems are actually SESs, ecological restoration should also focus on societal‐level measures.
Acute renal replacement therapy during hospitalization: Is training adequate?
Authors: Palevsky Paul M.
Published: January 2018

Acute renal replacement therapy is one of the most common interventions provided by nephrologists, however, data on the quality of training provided to nephrology fellows is limited. Extensive curricula for acute renal replacement therapy and the management of poisonings and intoxications have been published, but personal experience suggests that there are significant opportunities to improve training. Particular areas to be considered include the use of novel technologies for assessment of volume status, greater emphasis on the dosing of medications during acute renal replacement therapy, greater training in assessing and tailoring treatment to the goals of care of the individual patient, incorporation of continuous quality improvement tools into the management of acute renal replacement therapy programs and development of robust simulation training to augment training.
Simulating urban growth in a megalopolitan area using a patch‐based cellular automata
Authors: Alaei Moghadam Sanaz , Karimi Mohammad , Habibi Kyoumars
Published: January 2018

Although traditional cellular automata (CA)‐based models can effectively simulate urban land‐use changes, they typically ignore the spatial evolution of urban patches, due to their use of cell‐based simulation strategies. This research proposes a new patch‐based CA model to incorporate a spatial constraint based on the growth patterns of urban patches into the conventional CA model for reducing the uncertainty of the distribution of simulated new urban patches. In this model, the growth pattern of urban patches is first estimated using a developed indicator that is based on the local variations in existing urban patches. The urban growth is then simulated by integrating the estimated growth pattern and land suitability using a pattern‐calibrated method. In this method, the pattern of new urban patches is gradually calibrated toward the dominant growth pattern through the steps of the CA model. The proposed model is applied to simulate urban growth in the Tehran megalopolitan area during 2000–2006–2012. The results from this model were compared with two common models: cell‐based CA and logistic‐patch CA. The proposed model yields a degree of patch‐level agreement that is 23.4 and 7.5% higher than those of these pre‐existing models, respectively. This reveals that the patch‐based CA model simulates actual development patterns much better than the two other models.
A multi‐objective framework for analysis of road network vulnerability for relief facility location during flood hazards: A case study of relief location analysis in Bankura District, India
Authors: Chakraborty Omprakash , Das Arup , Dasgupta Arindam , Mitra Pabitra , Ghosh Soumya K. , Mazumder Taraknath
Published: January 2018

The location of disaster management facilities is a challenging and multifaceted problem. The road networks, population distribution along the road networks, and disaster risk maps are the major components for management of this problem. This article aims to decide on the location of such facilities for flood hazards in a region. The methodology is based on a multi‐objective framework. Objective functions include edge importance indices under fair weather and elevation parameters of the edges. Multiple scenarios are simulated for varying levels of hazard, and the outputs are analyzed. Analyses are carried out for the individual percentage loss of road links. A case study has been presented for the Bankura District in West Bengal, India. The inferences drawn from the results identify the critical links over the road networks of the region. The study also indicates locations in the region for relief facility setups to enable best‐serving capabilities and provide safe shelters, even in the most adverse flood conditions. The article depicts the vulnerability status of the road networks of the region. Further, it identifies the locations for relief facility provisioning that bring out the best road utilization and the best‐serving capabilities within the flood‐affected area under different flood levels.
The use of amorphous silica-alumina-based additive in the adhesive dry mixes of building materials
Authors: V. I. Loganina , Ch.V. Zhegera
Published: January 2018

Proved the possibility of using amorphous aluminosilicate as a modifying agent for the adhesive dry mixes. Are given the data on the microstructure and chemical composition of the amorphous aluminosilicates. Installed , that the microstructure of the synthetic additives is characterized by particles of round shape, dimensions 5,208-5,704 μm, Also there are particles of elongated shape in size 7.13-8.56 μm. Predominate chemical elements O, Si, Na, S, and Al in quantity 60.69%, 31.26%, 24.23%, 18.69% and 8.29% respectively. Described the character changes in the rheological properties of cement-sand mortar, depending on the percentage of additives. Determined, that the introduction in the cement-sand mortar the additive based on amorphous aluminosilicate leads to higher values of plastic strength. Are given the model of cement stone strength using synthetic additives in the formulation. The results of the evaluation of the frost resistance of cement-based tile adhesives with the use of amorphous aluminosilicates as a modifying additive are presented. In the article is determined the mark on frost resistance of tile glue and frost resistance of the contact zone of tile glue. The evaluation of the performance properties of the layer of tile adhesive on the basis of cement, dry mixes. The calculation of the value of displacement of the adhesive layer made on the basis of the developed recipes cement dry mixes applied to a vertical surface. Experimental data obtained values of displacement tiles relative to the substrate. Described the results of physical and mechanical properties of tile adhesive made on the basis of the developed adhesive dry mix formulations.
Evaluating Neighborhoods Livability in Nigeria: A Structural Equation Modelling (SEM) Approach
Authors: Iyanda Sule Abass , Ismail Ojetunde , Fabunmi Foluke Olanike , Adeogun Adekunle Sunday , Mohit Mohammad Abdul
Published: January 2018

There is a growing concern about city livability around the world and of particular concern is the aspects of the person-environment relationship which encompasses many characteristics suffice to make a place livable. Extant literature provides livability dimensions such as housing unit characteristics, neighborhood facilities, economic vitality and safety environment. These livability dimensions as well as their attributes found in the extant literature have been reported to have high reliability measurement level. Although, various methods have been applied to examine relationships among the variables however structural equation modeling (SEM) has been found more holistic as a modeling technique to understand and explain the relationships that may exist among variable measurements. Structural equation modeling simultaneously performs multivariate analysis including multiple regression, path and factor analysis in the cause-effect relationships between latent constructs. Therefore, this study investigates the key factors of livability of planned residential neighborhoods in Minna, Nigeria with the research objectives of – (a) to study the livability level of the selected residential neighborhoods, (b) to determine the dimensions and indicators which most influence the level of livability in the selected residential neighborhoods, and (c) to reliably test the efficacy of structural equation modeling (SEM) in the assessment of livability. The methodology adopted in this study includes- Data collection with the aid of structured questionnaire survey administered to the residents of the study area based on stratified random sampling. The data collected was analyzed with the aid of the Statistical Package for Social Sciences (SPSS) 22.0 and AMOS 22.0 software for structural equation modeling (a second-order factor). The study revealed that livability as a second-order factor is indicated by economic vitality, safety environment, neighborhood facilities and housing unit characteristics first-order factors. The result shows that economic vitality (income, mobility and mobility cost) most significantly measures neighborhood livability. Also, results of the model achieved good fit indices such as CFI of 0.907 and the RMSEA value of 0.096. Thus, SEM analyses in this study offer a methodological guide on the efficacy of CFA second-order factor.
Elevated sympathetic vasomotor outflow in response to increased inspiratory muscle activity during exercise is less in young women compared with men
Authors: Katayama Keisho , Smith Joshua R. , Goto Kanako , Shimizu Kaori , Saito Mitsuru , Ishida Koji , Koike Teruhiko , Iwase Satoshi , Harms Craig A.
Published: January 2018

New Findings

What is the central question of this study?

Premenopausal women have an attenuated inspiratory muscle metaboreflex‐induced increase in arterial blood pressure compared with men. It is unclear whether sympathetic vasomotor outflow during dynamic exercise with increased inspiratory muscle activation is less in young women than in men.

What is the main finding and its importance?

The magnitude of increased sympathetic vasomotor outflow during leg cycling with inspiratory resistance was smaller in women than in men. Less sympathetic vasomotor outflow with inspiratory muscle metaboreflex activation could be one of the mechanisms for the attenuated inspiratory muscle‐induced metaboreflex during exercise in young women.

We compared changes in muscle sympathetic nerve activity (MSNA) and cardiovascular variables during leg cycle exercise with increased inspiratory muscle resistance in men and women. We hypothesized that sympathetic vasomotor outflow during exercise with increased inspiratory resistance would be attenuated in young women compared with age‐matched men. Eight women and seven men completed the study. The subjects performed two 10 min exercise bouts at 40% peak oxygen uptake using a cycle ergometer in a semirecumbent position [spontaneous breathing for 5 min and voluntary hyperventilation with or without inspiratory resistive breathing for 5 min (breathing frequency 50 breaths min−1 with a 50% duty cycle; inspiratory resistance 30% of maximal inspiratory pressure)]. Mean arterial blood pressure (MAP) was acquired using finger photoplethysmography. The MSNA was recorded via microneurography of the right median nerve at the cubital fossa. During leg cycle exercise with inspiratory resistive breathing, MSNA burst frequency was increased, accompanied by an increase in MAP in both men and women. Women, compared with men, had less of an increase in MAP (women +22.8 ± 12.3 mmHg versus men +32.2 ± 5.4 mmHg; P < 0.05) and MSNA burst frequency (women +9.6 ± 2.9 bursts min−1 versus men +14.6 ± 6.4 bursts min−1; P < 0.05). These results suggest that the attenuated inspiratory muscle‐induced metaboreflex during exercise in young women is attributable, in part, to a lesser sympathetic vasomotor outflow compared with men.
Ether‐à‐go‐go K+ channels: effective modulators of neuronal excitability
Authors: Bauer Christiane K. , Schwarz Jürgen R.
Published: January 2018

Mammalian ether‐à‐go‐go (EAG) channels are voltage‐gated K+ channels. They are encoded by the KCNH gene family and divided into three subfamilies, eag (Kv10), erg (eag‐related gene; Kv11) and elk (eag‐like; Kv12). All EAG channel subtypes are expressed in the brain where they effectively modulate neuronal excitability. This Topical Review describes the biophysical properties of each of the EAG channel subtypes, their function in neurons and the neurological diseases induced by EAG channel mutations. In contrast to the function of erg currents in the heart, where they contribute to repolarization of the cardiac action potential, erg currents in neurons are involved in the maintenance of the resting potential, setting of action potential threshold and frequency accommodation. They can even support high frequency firing by preventing a depolarization‐induced Na+ channel block. EAG channels are modulated differentially, e.g. eag channels by intracellular Ca2+, erg channels by extracellular K+ and GPCRs, and elk channels by changes in pH. So far, only currents mediated by erg channels have been recorded in neurons with the help of selective blockers. Neuronal eag and elk currents have not been isolated due to the lack of suitable channel blockers. However, findings in KO mice indicate a physiological role of eag1 currents in synaptic transmission and an involvement of elk2 currents in cognitive performance. Human eag1 and eag2 gain‐of‐function mutations underlie syndromes associated with epileptic seizures.

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Clinical and Pathophysiological Overview of Acinetobacter Infections: a Century of Challenges
Authors: Wong Darren , Nielsen Travis B. , Bonomo Robert A. , Pantapalangkoor Paul , Luna Brian , Spellberg Brad
Published: January 2018

Acinetobacter
is a complex genus, and historically, there has been confusion about the existence of multiple species. The species commonly cause nosocomial infections, predominantly aspiration pneumonia and catheter-associated bacteremia, but can also cause soft tissue and urinary tract infections. Community-acquired infections by
Acinetobacter
spp. are increasingly reported. Transmission of
Acinetobacter
and subsequent disease is facilitated by the organism's environmental tenacity, resistance to desiccation, and evasion of host immunity. The virulence properties demonstrated by
Acinetobacter
spp. primarily stem from evasion of rapid clearance by the innate immune system, effectively enabling high bacterial density that triggers lipopolysaccharide (LPS)–Toll-like receptor 4 (TLR4)-mediated sepsis. Capsular polysaccharide is a critical virulence factor that enables immune evasion, while LPS triggers septic shock. However, the primary driver of clinical outcome is antibiotic resistance. Administration of initially effective therapy is key to improving survival, reducing 30-day mortality threefold. Regrettably, due to the high frequency of this organism having an extreme drug resistance (XDR) phenotype, early initiation of effective therapy is a major clinical challenge. Given its high rate of antibiotic resistance and abysmal outcomes (up to 70% mortality rate from infections caused by XDR strains in some case series), new preventative and therapeutic options for
Acinetobacter
spp. are desperately needed.
Cell Cycle Arrest and Apoptosis Induced by Porphyromonas gingivalis Require Jun N-Terminal Protein Kinase- and p53-Mediated p38 Activation in Human Trophoblasts
Authors: Inaba Hiroaki , Amano Atsuo , Lamont Richard J. , Murakami Yukitaka , Matsumoto-Nakano Michiyo
Published: January 2018

Porphyromonas gingivalis
, a periodontal pathogen, has been implicated as a causative agent of preterm delivery of low-birth-weight infants. We previously reported that
P. gingivalis
activated cellular DNA damage signaling pathways and ERK1/2 that lead to G
1
arrest and apoptosis in extravillous trophoblast cells (HTR-8 cells) derived from the human placenta. In the present study, we further examined alternative signaling pathways mediating cellular damage caused by
P. gingivalis. P. gingivalis
infection of HTR-8 cells induced phosphorylation of p38 and Jun N-terminal protein kinase (JNK), while their inhibitors diminished both G
1
arrest and apoptosis. In addition, heat shock protein 27 (HSP27) was phosphorylated through both p38 and JNK, and knockdown of HSP27 with small interfering RNA (siRNA) prevented both G
1
arrest and apoptosis. Furthermore, regulation of G
1
arrest and apoptosis was associated with p21 expression. HTR-8 cells infected with
P. gingivalis
exhibited upregulation of p21, which was regulated by p53 and HSP27. These results suggest that
P. gingivalis
induces G
1
arrest and apoptosis via novel molecular pathways that involve p38 and JNK with its downstream effectors in human trophoblasts.
Genome-Wide Identification by Transposon Insertion Sequencing of Escherichia coli K1 Genes Essential for
In Vitro
Growth, Gastrointestinal Colonizing Capacity, and Survival in Serum
Authors: McCarthy Alex J. , Stabler Richard A. , Taylor Peter W.
Published: January 2018

Escherichia coli
K1 strains are major causative agents of invasive disease of newborn infants. The age dependency of infection can be reproduced in neonatal rats. Colonization of the small intestine following oral administration of K1 bacteria leads rapidly to invasion of the blood circulation; bacteria that avoid capture by the mesenteric lymphatic system and evade antibacterial mechanisms in the blood may disseminate to cause organ-specific infections such as meningitis. Some
E. coli
K1 surface constituents, in particular the polysialic acid capsule, are known to contribute to invasive potential, but a comprehensive picture of the factors that determine the fully virulent phenotype has not emerged so far. We constructed a library and constituent sublibraries of ∼775,000 Tn
5
transposon mutants of
E. coli
K1 strain A192PP and employed transposon-directed insertion site sequencing (TraDIS) to identify genes required for fitness for infection of 2-day-old rats. Transposon insertions were lacking in 357 genes following recovery on selective agar; these genes were considered essential for growth in nutrient-replete medium. Colonization of the midsection of the small intestine was facilitated by 167
E. coli
K1 gene products. Restricted bacterial translocation across epithelial barriers precluded TraDIS analysis of gut-to-blood and blood-to-brain transits; 97 genes were required for survival in human serum. This study revealed that a large number of bacterial genes, many of which were not previously associated with systemic
E. coli
K1 infection, are required to realize full invasive potential.

IMPORTANCE
Escherichia coli
K1 strains cause life-threatening infections in newborn infants. They are acquired from the mother at birth and colonize the small intestine, from where they invade the blood and central nervous system. It is difficult to obtain information from acutely ill patients that sheds light on physiological and bacterial factors determining invasive disease. Key aspects of naturally occurring age-dependent human infection can be reproduced in neonatal rats. Here, we employ transposon-directed insertion site sequencing to identify genes essential for the
in vitro
growth of
E. coli
K1 and genes that contribute to the colonization of susceptible rats. The presence of bottlenecks to invasion of the blood and cerebrospinal compartments precluded insertion site sequencing analysis, but we identified genes for survival in serum.
Gammaherpesvirus Colonization of the Spleen Requires Lytic Replication in B Cells
Authors: Lawler Clara , de Miranda Marta Pires , May Janet , Wyer Orry , Simas J. Pedro , Stevenson Philip G.
Published: January 2018

Gammaherpesviruses infect lymphocytes and cause lymphocytic cancers. Murid herpesvirus-4 (MuHV-4), Epstein-Barr virus, and Kaposi's sarcoma-associated herpesvirus all infect B cells. Latent infection can spread by B cell recirculation and proliferation, but whether this alone achieves systemic infection is unclear. To test the need of MuHV-4 for lytic infection in B cells, we flanked its essential ORF50 lytic transactivator with
loxP
sites and then infected mice expressing B cell-specific Cre (CD19-Cre). The floxed virus replicated normally in Cre
−
mice. In CD19-Cre mice, nasal and lymph node infections were maintained; but there was little splenomegaly, and splenic virus loads remained low. Cre-mediated removal of other essential lytic genes gave a similar phenotype. CD19-Cre spleen infection by intraperitoneal virus was also impaired. Therefore, MuHV-4 had to emerge lytically from B cells to colonize the spleen. An important role for B cell lytic infection in host colonization is consistent with the large CD8
+
T cell responses made to gammaherpesvirus lytic antigens during infectious mononucleosis and suggests that vaccine-induced immunity capable of suppressing B cell lytic infection might reduce long-term virus loads.

IMPORTANCE
Gammaherpesviruses cause B cell cancers. Most models of host colonization derive from cell cultures with continuous, virus-driven B cell proliferation. However, vaccines based on these models have worked poorly. To test whether proliferating B cells suffice for host colonization, we inactivated the capacity of MuHV-4, a gammaherpesvirus of mice, to reemerge from B cells. The modified virus was able to colonize a first wave of B cells in lymph nodes but spread poorly to B cells in secondary sites such as the spleen. Consequently, viral loads remained low. These results were consistent with virus-driven B cell proliferation exploiting normal host pathways and thus having to transfer lytically to new B cells for new proliferation. We conclude that viral lytic infection is a potential target to reduce B cell proliferation.
Gut Microbial Glycerol Metabolism as an Endogenous Acrolein Source
Authors: Zhang Jianbo , Sturla Shana , Lacroix Christophe , Schwab Clarissa
Published: January 2018

Acrolein is a highly reactive electrophile causing toxic effects, such as DNA and protein adduction, oxidative stress, endoplasmic reticulum stress, immune dysfunction, and membrane damage. This Opinion/Hypothesis provides an overview of endogenous and exogenous acrolein sources, acrolein’s mode of action, and its metabolic fate. Recent reports underpin the finding that gut microbial glycerol metabolism leading to the formation of reuterin is an additional source of endogenous acrolein. Reuterin is an antimicrobial multicomponent system consisting of 3-hydroxypropionaldehyde, its dimer and hydrate, and also acrolein. The major conclusion is that gut microbes can metabolize glycerol to reuterin and that this transformation occurs
in vivo
. Given the known toxicity of acrolein, the observation that acrolein is formed in the gut necessitates further investigations on functional relevance for gut microbiota and the host.
Pandemic Paradox: Early Life H2N2 Pandemic Influenza Infection Enhanced Susceptibility to Death during the 2009 H1N1 Pandemic
Authors: Gagnon Alain , Acosta Enrique , Hallman Stacey , Bourbeau Robert , Dillon Lisa Y. , Ouellette Nadine , Earn David J. D. , Herring D. Ann , Inwood Kris , Madrenas Joaquin , Miller Matthew S.
Published: January 2018

Recent outbreaks of H5, H7, and H9 influenza A viruses in humans have served as a vivid reminder of the potentially devastating effects that a novel pandemic could exert on the modern world. Those who have survived infections with influenza viruses in the past have been protected from subsequent antigenically similar pandemics through adaptive immunity. For example, during the 2009 H1N1 “swine flu” pandemic, those exposed to H1N1 viruses that circulated between 1918 and the 1940s were at a decreased risk for mortality as a result of their previous immunity. It is also generally thought that past exposures to antigenically dissimilar strains of influenza virus may also be beneficial due to cross-reactive cellular immunity. However, cohorts born during prior heterosubtypic pandemics have previously experienced elevated risk of death relative to surrounding cohorts of the same population. Indeed, individuals born during the 1890 H3Nx pandemic experienced the highest levels of excess mortality during the 1918 “Spanish flu.” Applying Serfling models to monthly mortality and influenza circulation data between October 1997 and July 2014 in the United States and Mexico, we show corresponding peaks in excess mortality during the 2009 H1N1 “swine flu” pandemic and during the resurgent 2013–2014 H1N1 outbreak for those born at the time of the 1957 H2N2 “Asian flu” pandemic. We suggest that the phenomenon observed in 1918 is not unique and points to exposure to pandemic influenza early in life as a risk factor for mortality during subsequent heterosubtypic pandemics.

IMPORTANCE
The relatively low mortality experienced by older individuals during the 2009 H1N1 influenza virus pandemic has been well documented. However, reported situations in which previous influenza virus exposures have enhanced susceptibility are rare and poorly understood. One such instance occurred in 1918—when those born during the heterosubtypic 1890 H3Nx influenza virus pandemic experienced the highest levels of excess mortality. Here, we demonstrate that this phenomenon was not unique to the 1918 H1N1 pandemic but that it also occurred during the contemporary 2009 H1N1 pandemic and 2013–2014 H1N1-dominated season for those born during the heterosubtypic 1957 H2N2 “Asian flu” pandemic. These data highlight the heretofore underappreciated phenomenon that, in certain instances, prior exposure to pandemic influenza virus strains can enhance susceptibility during subsequent pandemics. These results have important implications for pandemic risk assessment and should inform laboratory studies aimed at uncovering the mechanism responsible for this effect.
Magic Pools: Parallel Assessment of Transposon Delivery Vectors in Bacteria
Authors: Liu Hualan , Price Morgan N. , Waters Robert Jordan , Ray Jayashree , Carlson Hans K. , Lamson Jacob S. , Chakraborty Romy , Arkin Adam P. , Deutschbauer Adam M.
Published: January 2018

Molecular genetics is indispensable for interrogating the physiology of bacteria. However, the development of a functional genetic system for any given bacterium can be time-consuming. Here, we present a streamlined approach for identifying an effective transposon mutagenesis system for a new bacterium. Our strategy first involves the construction of hundreds of different transposon vector variants, which we term a “magic pool.” The efficacy of each vector in a magic pool is monitored in parallel using a unique DNA barcode that is introduced into each vector design. Using archived DNA “parts,” we next reassemble an effective vector for making a whole-genome transposon mutant library that is suitable for large-scale interrogation of gene function using competitive growth assays. Here, we demonstrate the utility of the magic pool system to make mutant libraries in five genera of bacteria.
Examining patterns of multimorbidity, polypharmacy and risk of adverse drug reactions in chronic obstructive pulmonary disease: a cross-sectional UK Biobank study
Authors: Hanlon Peter , Nicholl Barbara I , Jani Bhautesh Dinesh , McQueenie Ross , Lee Duncan , Gallacher Katie I , Mair Frances S
Published: January 2018

Objective

This study aims: (1) to describe the pattern and extent of multimorbidity and polypharmacy in UK Biobank participants with chronic obstructive pulmonary disease (COPD) and (2) to identify which comorbidities are associated with increased risk of adverse drug reactions (ADRs) resulting from polypharmacy.

Design

Cross-sectional.

Setting

Community cohort.

Participants

UK Biobank participants comparing self-reported COPD (n=8317) with no COPD (n=494 323).

Outcomes

Multimorbidity (≥4 conditions) and polypharmacy (≥5 medications) in participants with COPD versus those without. Risk of ADRs (taking ≥3 medications associated with falls, constipation, urinary retention, central nervous system (CNS) depression, bleeding or renal injury) in relation to the presence of COPD and individual comorbidities.

Results

Multimorbidity was more common in participants with COPD than those without (17% vs 4%). Polypharmacy was highly prevalent (52% with COPD taking ≥5 medications vs 18% in those without COPD). Adjusting for age, sex and socioeconomic status, those with COPD were significantly more likely than those without to be prescribed ≥3 medications contributing to falls (OR 2.27, 95% CI 2.13 to 2.42), constipation (OR 3.42, 95% CI 3.10 to 3.77), urinary retention (OR 3.38, 95% CI 2.94 to 3.87), CNS depression (OR 3.75, 95% CI 3.31 to 4.25), bleeding (OR 4.61, 95% CI 3.35 to 6.19) and renal injury (OR 2.22, 95% CI 1.86 to 2.62). Concomitant cardiovascular disease was associated with the greatest risk of taking ≥3 medications associated with falls/renal injury. Concomitant mental health conditions were most strongly associated with medications linked with CNS depression/urinary retention/bleeding.

Conclusions

Multimorbidity is common in COPD and associated with high levels of polypharmacy. Co-prescription of drugs with various ADRs is common. Future research should examine the effects on healthcare outcomes of co-prescribing multiple drugs with similar potential ADRs. Clinical guidelines should emphasise assessment of multimorbidity and ADR risk.
Reduced miR-144-3p expression in serum and bone mediates osteoporosis pathogenesis by targeting RANK
Authors: Wang Chunqing , He Hanliang , Wang Liang , Jiang Yu , Xu Youjia
Published: January 2018

Osteoblasts and osteoclasts are responsible for the formation and resorption of bone, respectively. An imbalance between these two processes results in a disease called osteoporosis, in which a decreased level of bone strength increases the risk of a bone fracture. MicroRNAs (miRNAs) are small non-coding RNA molecules of 18–25 nucleotides that have been previously shown to control bone metabolism by regulating osteoblast and osteoclast differentiation. In this study, we detected the expression pattern of 10 miRNAs in serum samples from patients with osteoporosis, and identified the altered expression of 6 miRNAs by comparison with patients without osteoporosis. We selected miR-144-3p for further investigation, and showed that it regulates osteoclastogenesis by targeting RANK, and that it is conserved amongst vertebrates. Disrupted expression of miR-144-3p in CD14+ peripheral blood mononuclear cells changed TRAP activity and the osteoclast-specific genes TRAP, cathepsin K (CTSK), and NFATC. TRAP staining, CCK-8, and flow cytometry analyses revealed that miR-144-3p also affects osteoclast formation, proliferation, and apoptosis. Together, these results indicate that miR-144-3p critically mediates bone homeostasis, and thus, represents a promising novel therapeutic candidate for the treatment of this disease.