bluuebunny/crossref_metadata_2025 huggingface dataset:
Pelagostrobilidium liui n. sp. (Ciliophora, Choreotrichida) from the Coastal Waters of Northeastern Taiwan and an Improved Description of Pelagostrobilidium minutum Liu et al., 2012
Authors: Chen Po‐Cheng , Chiang Kuo‐Ping , Tsai Sheng‐Fang
Published: January 2017

The number of somatic kineties in Pelagostrobilidium ranges from 4 to 6 according to the present state of knowledge. This study investigates Pelagostrobilidium liui n. sp. using live observation, protargol stain, and small subunit rDNA data sequencing. Pelagostrobilidium liui n. sp. is characterized by having a spherical‐shaped body, four somatic kineties, with kinety 2 spiraled around the left side of body, about six elongated external membranelles, and invariably no buccal membranelle. It differs from its most similar congener, Pelagostrobilidium minutum Liu et al., , in (i) cell shape; (ii) macronucleus width; (iii) oral apparatus; (iv) anterior orientation of kinety 2; (v) location where kinety 2 commences; (vi) arrangement of kinety 1; (vii) distance between the anterior cell end and the locations where kineties commence; and (viii) the presence of 12 different bases (including two deletions) in the small subunit rDNA sequences. The diagnosis of P. minutum Liu et al., is also improved to include the following new characteristics: invariably four somatic kineties; kineties 2 and 4 alone commence at the same level; kinety 2 originates from right anterior cell half on ventral side, extends sinistrally posteriorly, over kinety 1, around left posterior region, terminates near posterior cell end on dorsal side; kinety 1 commences below anterior third of kinety 2.
Crosstalk between intestinal epithelial cell and adaptive immune cell in intestinal mucosal immunity
Authors: Lu Jun Tao , Xu An Tao , Shen Jun , Ran Zhi Hua
Published: January 2017

Constantly challenged by luminal bacteria, intestinal epithelium forms both a physical and biochemical defense against pathogens. Besides, intestinal epithelium senses dynamic and continuous changes in luminal environment and transmits signals to subjacent immune cells accordingly. It has been long accepted that adaptive immune cells fulfill their roles partly by modulating function of intestinal epithelial cells. Recent studies have brought up the proposal that intestinal epithelial cells also actively participate in the regulation of adaptive immunity, especially CD4+ adaptive T cells, which indicates that there is reciprocal crosstalk between intestinal epithelial cells and adaptive immune cells, and the crosstalk may play important role in intestinal mucosal immunity. This Review makes a comprehensive summary about crosstalk between intestinal epithelial cells and CD4+ adaptive T cells in intestinal immunity. Special attention would be given to their implications in inflammatory bowel disease pathogenesis and potential therapeutic targets.
Non‐neuronal acetylcholine involved in reproduction in mammals and honeybees
Authors: Wessler Ignaz Karl , Kirkpatrick Charles James
Published: January 2017

Bacteria and archaea synthesize acetylcholine (ACh). Thus, it can be postulated that ACh was created by nature roughly three billion years ago. Therefore, the wide expression of ACh in nature (i.e., in bacteria, archaea, unicellular organisms, plants, fungi, non‐vertebrates and vertebrates and in the abundance of non‐neuronal cells of mammals) is not surprising. The term non‐neuronal ACh and non‐neuronal cholinergic system have been introduced to describe the auto‐ and paracrine, that is, local regulatory actions of ACh in cells not innervated by neuronal cholinergic fibers and to communicate among themselves. In this way non‐neuronal ACh binds to the nicotinic or muscarinic receptors expressed on these local and migrating cells and modulates basic cells functions such as proliferation, differentiation, migration and the transport of ions and water. The present article is focused to the effects of non‐neuronal ACh linked to reproduction; data on the expression and function of the non‐neuronal cholinergic system in the following topics are summarized: (i) Sperm, granulosa cells, oocytes; (ii) Auxiliary systems (ovary, oviduct, placenta); (iii) Embryonic stem cells as first step for reproduction of a new individual after fertilization; (iv) Larval food as an example of reproduction in insects (honeybees) and adverse effects of the neonicotinoids, a class of world‐wide applied insecticides. The review article will show that non‐neuronal ACh is substantially involved in the regulation of reproduction in mammals and also non‐mammals like insects (honeybees). There is a need to learn more about this biological role of ACh. In particular, we have to consider that insecticides like the neonicotinoids, but also carbamates and organophosphorus pesticides, interfere with the non‐neuronal cholinergic system thus compromising for example the breeding of honeybees. But it is possible that other species may also be adversely affected as well, a mechanism which may contribute to the observed decline in biodiversity.

This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms.

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Splicing regulation and dysregulation of cholinergic genes expressed at the neuromuscular junction
Authors: Ohno Kinji , Rahman Mohammad Alinoor , Nazim Mohammad , Nasrin Farhana , Lin Yingni , Takeda Jun‐ichi , Masuda Akio
Published: January 2017

We humans have evolved by acquiring diversity of alternative RNA metabolisms including alternative means of splicing and transcribing non‐coding genes, and not by acquiring new coding genes. Tissue‐specific and developmental stage‐specific alternative RNA splicing is achieved by tightly regulated spatiotemporal regulation of expressions and activations of RNA‐binding proteins that recognize their cognate splicing cis‐elements on nascent RNA transcripts. Genes expressed at the neuromuscular junction are also alternatively spliced. In addition, germline mutations provoke aberrant splicing by compromising binding of RNA‐binding proteins, and cause congenital myasthenic syndromes (CMS). We present physiological splicing mechanisms of genes for agrin (AGRN), acetylcholinesterase (ACHE), MuSK (MUSK), acetylcholine receptor (AChR) α1 subunit (CHRNA1), and collagen Q (COLQ) in human, and their aberration in diseases. Splicing isoforms of AChET, AChEH, and AChER are generated by hnRNP H/F. Skipping of MUSK exon 10 makes a Wnt‐insensitive MuSK isoform, which is unique to human. Skipping of exon 10 is achieved by coordinated binding of hnRNP C, YB‐1, and hnRNP L to exon 10. Exon P3A of CHRNA1 is alternatively included to generate a non‐functional AChR α1 subunit in human. Molecular dissection of splicing mutations in patients with CMS reveals that exon P3A is alternatively skipped by hnRNP H, polypyrimidine tract‐binding protein 1, and hnRNP L. Similarly, analysis of an exonic mutation in COLQ exon 16 in a CMS patient discloses that constitutive splicing of exon 16 requires binding of serine arginine‐rich splicing factor 1. Intronic and exonic splicing mutations in CMS enable us to dissect molecular mechanisms underlying alternative and constitutive splicing of genes expressed at the neuromuscular junction.

This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms.

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Evolutionary aspects of the development of teeth and baleen in the bowhead whale
Authors: Thewissen J. G. M. , Hieronymus Tobin L. , George John C. , Suydam Robert , Stimmelmayr Raphaela , McBurney Denise
Published: January 2017

In utero, baleen whales initiate the development of several dozens of teeth in upper and lower jaws. These tooth germs reach the bell stage and are sometimes mineralized, but toward the end of prenatal life they are resorbed and no trace remains after birth. Around the time that the germs disappear, the keratinous baleen plates start to form in the upper jaw, and these form the food‐collecting mechanism. Baleen whale ancestors had two generations of teeth and never developed baleen, and the prenatal teeth of modern fetuses are usually interpreted as an evolutionary leftover. We investigated the development of teeth and baleen in bowhead whale fetuses using histological and immunohistochemical evidence. We found that upper and lower dentition initially follow similar developmental pathways. As development proceeds, upper and lower tooth germs diverge developmentally. Lower tooth germs differ along the length of the jaw, reminiscent of a heterodont dentition of cetacean ancestors, and lingual processes of the dental lamina represent initiation of tooth bud formation of replacement teeth. Upper tooth germs remain homodont and there is no evidence of a secondary dentition. After these germs disappear, the oral epithelium thickens to form the baleen plates, and the protein FGF‐4 displays a signaling pattern reminiscent of baleen plates. In laboratory mammals, FGF‐4 is not involved in the formation of hair or palatal rugae, but it is involved in tooth development. This leads us to propose that the signaling cascade that forms teeth in most mammals has been exapted to be involved in baleen plate ontogeny in mysticetes.
Dynamic Frailty Count Process in Insurance: A Unified Framework for Estimation, Pricing, and Forecasting
Authors: Lu Yang
Published: January 2017

We study count processes in insurance, in which the underlying risk factor is time varying and unobservable. The factor follows an autoregressive gamma process, and the resulting model generalizes the static Poisson‐Gamma model and allows for closed form expression for the posterior Bayes (linear or nonlinear) premium. Moreover, the estimation and forecasting can be conducted within the same framework in a rather efficient way. An example of automobile insurance pricing illustrates the ability of the model to capture the duration dependent, nonlinear impact of past claims on future ones and the improvement of the Bayes pricing method compared to the linear credibility approach.
The Cross‐Section of Asia‐Pacific Mortality Dynamics: Implications for Longevity Risk Sharing
Authors: Biffis Enrico , Lin Yijia , Milidonis Andreas
Published: January 2017

We study the dynamics of longevity risk across a subset of countries in the Asia‐Pacific (APAC) region. We use hand‐collected and existing data on age‐specific mortality rates from emerging and developed economies to understand how secular changes in mortality vary within and across APAC countries. We use our results to identify cross‐hedging opportunities among longevity risk exposures in the APAC region. We also introduce k‐forward contracts, which offer natural risk‐sharing opportunities to hedgers in different countries. We consider the example of Korea and Japan as a case study.
A ROP2‐RIC1 pathway fine‐tunes microtubule reorganization for salt tolerance in Arabidopsis
Authors: Li Changjiang , Lu Hanmei , Li Wei , Yuan Ming , Fu Ying
Published: January 2017

The reorganization of microtubules induced by salt stress is required for Arabidopsis survival under high salinity conditions. RIC1 is an effector of Rho‐related GTPase from plants (ROPs) and a known microtubule‐associated protein. In this study, we demonstrated that RIC1 expression decreased with long‐term NaCl treatment, and ric1‐1 seedlings exhibited a higher survival rate under salt stress. We found that RIC1 reduced the frequency of microtubule transition from shortening to growing status and knockout of RIC1 improved the reassembly of depolymerized microtubules caused by either oryzalin treatment or salt stress. Further investigation showed that constitutively active ROP2 promoted the reassembly of microtubules and the survival of seedlings under salt stress. A rop2‐1 ric1‐1 double mutant rescued the salt‐sensitive phenotype of rop2‐1, indicating that ROP2 functions in salt tolerance through RIC1. Although ROP2 did not regulate RIC1 expression upon salt stress, a quick but mild increase of ROP2 activity was induced, led to reduction of RIC1 on microtubules. Collectively, our study reveals an ROP2‐RIC1 pathway that fine‐tunes microtubule dynamics in response to salt stress in Arabidopsis. This finding not only reveals a new regulatory mechanism for microtubule reorganization under salt stress but also the importance of ROP signalling for salinity tolerance.
Improving Profits by Bundling Vertically Differentiated Products
Authors: Honhon Dorothée , Pan Xiajun Amy
Published: January 2017

We consider a firm managing a category of vertically differentiated goods, that is, products which differ with respect to an attribute for which all consumers prefer more to less. The goods can be sold individually, in which case they are referred to as components, or in bundles. The firm chooses the assortment of components and bundles and their selling prices to maximize profit. We show that each bundling strategy (pure components, pure bundling or mixed bundling) can be optimal and obtain closed‐form expressions for the optimal selling prices. We provide insights on the structure of the optimal assortment and prices. In particular, we show that, when consumers benefit from consuming the components jointly, the products in the optimal assortment form nested sets. When consumers do not benefit from the joint consumption of components, the bundles should be offered at a positive discount. We find that bundling vertically differentiated products can significantly improve profits, even if consumers do not benefit from consuming the components jointly. The value of bundling comes from increased sales: a firm, which understands that its customers may buy multiple types of components, offers bundles of components, incentivizing customers to buy more.
Demand–Supply Mismatches and Stock Market Performance: A Retailing Perspective
Authors: Ullrich Kristoph K. R. , Transchel Sandra
Published: January 2017

We provide empirical evidence that the volatility of inventory productivity relative to the volatility of demand is a predictor of future stock returns in a sample of publicly listed U.S. retailers over the period 1985–2013. This key performance indicator, entitled demand–supply mismatch (DSM), captures the fact that low variation in inventory productivity relative to variation in demand is indicative of the superior synchronization of demand‐ and supply‐side operations. Applying the Fama and French (1993) three‐factor model augmented with a momentum factor (Carhart 1997), we find that zero‐cost portfolios formed by buying the two lowest and selling the two highest quintiles of DSM stocks yield abnormal stock returns of up to 1.13%. These strong market anomalies related to DSM are observed over the entire sample period and persist after controlling for alternative inventory productivity measures and firm characteristics that are known to predict future stock returns. Further, we reveal that DSM is indicative of lower future earnings and lower sales growth and provide evidence that the observed market inefficiency results from investors’ failure to incorporate all of the information that inventory contains into the pricing of stocks.
Entrepreneurial Saving Practices and Reinvestment: Theory and Evidence
Authors: Beck Thorsten , Pamuk Haki , Uras Burak R.
Published: January 2017

We use a novel enterprise survey to gauge the relationship between saving instruments and entrepreneurial reinvestment. We show that while most informal saving practices are not associated with a lower likelihood of reinvestment when compared with formal saving practices, there is a significantly lower association of saving within the household with the likelihood of reinvesting profits than other savings form, most importantly, formal saving forms. This result is robust to the model specification and controlling for a large array of variables including district‐level fixed effects. We also provide empirical tests to address reverse causation and omitted variable concerns. Our work contributes to the debate on the implications of different saving instruments in developing countries and expands the entrepreneurial financing constraints literature by focusing on internal rather than external funding constraints.
Identifying Effective Nurse‐Led Care Transition Interventions for Older Adults With Complex Needs Using a Structured Expert Panel
Authors: Jeffs Lianne , Kuluski Kerry , Law Madelyn , Saragosa Marianne , Espin Sherry , Ferris Ella , Merkley Jane , Dusek Brenda , Kastner Monika , Bell Chaim M.
Published: January 2017

Background

Nursing plays a central role in facilitating care transitions for complex older adults, yet there is no consensus of the components of nurse‐led care transitions interventions to facilitate high quality care transitions among complex older adults. A structured expert panel was established with the purpose of identifying effective nurse‐led care transition interventions.

Methods

A modified Delphi consensus technique based on the RAND method was employed. Panelists (n = 23) were asked to individually rate a series of statements derived from a realist synthesis of the literature for relevance, feasibility and likely impact. Statements receiving an aggregate score of ≥75% (7/9) were reviewed and revised at a face‐to‐face consensus meeting. A second round of rating following the same process as round one was used, followed by a final ranking of the statements.

Results

The five highest ranked intervention components and contextual factors were: (a) educating and coaching patients, their family members and caregivers about self‐management skills; (b) ensuring patients, their family members and caregivers are aware of follow‐up medical appointments and postdischarge care plan; (c) using standardized documentation tools and comprehensive communication strategies during care transitions; (d) optimizing nurses’ roles and scopes of practice across the care transitions spectrum; and (e) having strong leadership, strategic alignment and accountability structures in organizations to enable quality care transitions for the complex older person population.

Linking Evidence to Action

Key insights on optimizing the nurses’ roles and scope of practice during care transitions included having nurses provide “warm hand‐offs” and serve as the “go‐to person.” The panel also identified current challenges to optimizing the nurses’ roles and scope of practice across care transition points. Future research is required to determine effective nurse‐led intervention components and in which context do they work or do not.
Reviewer Acknowledgements
Authors: Gibbs Nikki
Published: January 2017

Applied Economics and Finance [AEF] would like to acknowledge the following reviewers for their assistance with peer review of manuscripts for this issue. Many authors, regardless of whether AEF publishes their work, appreciate the helpful feedback provided by the reviewers. Their comments and suggestions were of great help to the authors in improving the quality of their papers. Each of the reviewers listed below returned at least one review for this issue. Reviewers for Volume 3, Number 2     Aleksandar Vasilev Ali Massoud Arash Riasi Dimitrios Vortelinos Erdal Gumus George Theocharides Getamesay Bekele Ian Mcfarlane Igor Matyushenko Iulia Lupu Jin Yong Yang Magdalena Zioło Manuel Caravaca Martin Jaekel Ramona Orastean Ruhet Genc,Vice Dean Steven V. Cates Vilas Gaikar                 Nikki Gibbs Editorial Assistant On behalf of, The Editorial Board of Applied Economics and Finance Redfame Publishing 9450 SW Gemini Dr. #99416 Beaverton, OR 97008, USA URL: http://aef.redfame.com
Reviewer Acknowledgements
Authors: Smith Robert
Published: January 2017

Journal of Education and Training Studies (JETS) would like to acknowledge the following reviewers for their assistance with peer review of manuscripts for this issue. Many authors, regardless of whether JETS publishes their work, appreciate the helpful feedback provided by the reviewers. Their comments and suggestions were of great help to the authors in improving the quality of their papers. Each of the reviewers listed below returned at least one review for this issue. Reviewers for Volume 4, Number 5 Ardi Marwan Begoña Montero-Fleta Cynthia M. Compton Dodzi Amemado Elena Jerves Enisa Mede Jeyavel Sundaramoorthy John Cowan Katya De Giovanni Laima Kyburiene Mara Carsote Marcie Zaharee Michael Baron Mustafa Çakır Richard Beresford Richard H. Martin Sahar Younes Othman Sandra Kaplan Yerlan Seisenbekov     Robert Smith Editorial Assistant On behalf of, The Editorial Board of Journal of Education and Training Studies Redfame Publishing 9450 SW Gemini Dr. #99416 Beaverton, OR 97008, USA URL: http://jets.redfame.com
Reviewer Acknowledgements
Authors: Johnson Patricia
Published: January 2017

Studies in Media and Communication (SMC) would like to thank the following reviewers for reviewing manuscripts from December 1, 2013, to May 31, 2014. Their comments and suggestions were of great help to the authors in improving the quality of their papers. Many authors, regardless of whether SMC publishes their work, appreciate the helpful feedback provided by the reviewers. Redfame Publishing appreciates the following reviewers’ rigorous and conscientious efforts for this journal. Each of the reviewers listed below returned at least one review during this period.   Ahmed K. Al-Rawi Androniki Kavoura Ann Grand Bernard Naledzani Rasila Camelia Cmeciu Christos Giannoulis Dorina Ticu Javier Serrano Puche Jenny-Ann Danell Joerg Tropp John Mills Margarida Sardo Mark Stuhlfaut Nina Gunnarsson Rodney S. Ciboh Simone Tosoni
Effects of exercise training on brain‐derived neurotrophic factor in skeletal muscle and heart of rats post myocardial infarction
Authors: Lee Heow Won , Ahmad Monir , Wang Hong‐Wei , Leenen Frans H. H.
Published: January 2017

New Findings

What is the central question of this study?

Exercise training increases brain‐derived neurotrophic factor (BDNF) in the hippocampus, which depends on a myokine, fibronectin type III domain‐containing protein 5 (FNDC5). Whether exercise training after myocardial infarction induces parallel increases in FNDC5 and BDNF expression in skeletal muscle and the heart has not yet been studied.

What is the main finding and its importance?

Exercise training after myocardial infarction increases BDNF protein in skeletal muscle and the non‐infarct area of the LV without changes in FNDC5 protein, suggesting that BDNF is not regulated by FNDC5 in skeletal muscle and heart. An increase in cardiac BDNF may contribute to the improvement of cardiac function by exercise training.

Exercise training after myocardial infarction (MI) attenuates progressive left ventricular (LV) remodelling and dysfunction, but the peripheral stimuli induced by exercise that trigger these beneficial effects are still unclear. We investigated as possible mediators fibronectin type III domain‐containing protein 5 (FNDC5) and brain‐derived neurotrophic factor (BDNF) in the skeletal muscle and heart. Male Wistar rats underwent either sham surgery or ligation of the left descending coronary artery, and surviving MI rats were allocated to either a sedentary (Sed‐MI) or an exercise group (ExT‐MI). Exercise training was done for 4 weeks on a motor‐driven treadmill. At the end, LV function was evaluated, and FNDC5 and BDNF mRNA and protein were assessed in soleus muscle, quadriceps and non‐, peri‐ and infarct areas of the LV. At 5 weeks post MI, FNDC5 mRNA was decreased in soleus muscle and all areas of the LV, but FNDC5 protein was increased in the soleus muscle and the infarct area. Mature BDNF (mBDNF) protein was decreased in the infarct area without a change in mRNA. Exercise training attenuated the decrease in ejection fraction and the increase in LV end‐diastolic pressure post MI. Exercise training had no effect on FNDC5 mRNA and protein, but increased mBDNF protein in soleus muscle, quadriceps and the non‐infarct area of the LV. The mBDNF protein in the non‐infarct area correlated positively with ejection fraction and inversely with LV end‐diastolic pressure. In conclusion, mBDNF is induced by exercise training in skeletal muscle and the non‐infarct area of the LV, which may contribute to improvement of muscle dysfunction and cardiac function post MI.
In situ absolute magnetometry in an UHV scanning probe microscope using conducting polymer-thin film
Authors: Ambal Kapildeb , Williams Clayton C. , Boehme Christoph
Published: January 2017

The in situ measurement and control of the direction and magnitude of the magnetic field is demonstrated within the sample plane of a low-temperature ultra-high vacuum scanning probe microscope. These measurements utilized electrically detected magnetic resonance magnetometry based on the spin-dependent recombination current in a conducting polymer-thin film. The presented magnetometry approach allows the absolute measurement of systematic magnetic offset fields with a resolution on the order of ≈5μT/Hz with an angular resolution below ≈1°. As the polymer film covers a macroscopic area within the sample plane, magnetometry becomes possible at various locations within the sample plane and thus the determination of magnetic field gradients.
Postdeposition annealing on RF-sputtered SrTiO3 thin films
Authors: Bayrak Türkan , Kizir Seda , Kahveci Enver , Bıyıklı Necmi , Goldenberg Eda
Published: January 2017

Understanding of structural, optical, and electrical properties of thin films are very important for a reliable device performance. In the present work, the effect of postdeposition annealing on stoichiometric SrTiO3 (STO) thin films grown by radio frequency magnetron sputtering at room temperature on p-type Si (100) and quartz substrates were studied. Highly transparent and well adhered thin films were obtained in visible and near infrared regions. As-deposited films were amorphous, while nanocrystalline and polycrystalline phases of the STO thin films formed as a function of annealing temperature. Films annealed at 300 °C showed nanocrystallinity with some amorphous phase. Crystallization started after 15 min annealing at 700 °C, and further improved for films annealed at 800 °C. However, crystallinity reduced for films which were annealed at 900 °C. The optical and electrical properties of STO thin films affected by postdeposition annealing at 800 °C: Eg values decreased from 4.50 to 4.18 eV, n(λ) values (at 550 nm) increased from 1.81 to 2.16. The surface roughness increased with the annealing temperature due to the increased crystallite size, densification and following void formation which can be seen from the scanning electron microscopy images. The highest dielectric constants (46 at 100 kHz) observed for films annealed at 800 °C; however, it was lower for 300 °C annealed (25 at 100 kHz) and as-deposited (7 at 100 kHz) STO films having ∼80 nm thickness.
Reduced abundance of the E3 ubiquitin ligase E6AP contributes to decreased expression of the
INK4/ARF
locus in non–small cell lung cancer
Authors: Gamell Cristina , Gulati Twishi , Levav-Cohen Yaara , Young Richard J. , Do Hongdo , Pilling Pat , Takano Elena , Watkins Neil , Fox Stephen B. , Russell Prudence , Ginsberg Doron , Monahan Brendon J. , Wright Gavin , Dobrovic Alex , Haupt Sue , Solomon Ben , Haupt Ygal
Published: January 2017

E6AP exhibits tumor suppressor activity that may help stratify NSCLC patients.
Tumors block pain with CXCL12
Authors: Gough Nancy R.
Published: January 2017

The chemokine CXCL12 released from early stage pancreatic cancer recruits Schwann cells and suppresses pain signaling.
Reduced Chance of Hearing Loss Associated with Therapeutic Drug Monitoring of Aminoglycosides in the Treatment of Multidrug-Resistant Tuberculosis
Authors: van Altena R. , Dijkstra J. A. , van der Meer M. E. , Borjas Howard J. F. , Kosterink J. G. W. , van Soolingen D. , van der Werf T. S. , Alffenaar J. W. C.
Published: January 2017

Hearing loss and nephrotoxicity are associated with prolonged treatment duration and higher dosage of amikacin and kanamycin. In our tuberculosis center, we used therapeutic drug monitoring (TDM) targeting preset pharmacokinetic/pharmacodynamic (PK/PD) surrogate endpoints in an attempt to maintain efficacy while preventing (oto)toxicity. To evaluate this strategy, we retrospectively evaluated medical charts of tuberculosis (TB) patients treated with amikacin or kanamycin in the period from 2000 to 2012. Patients with culture-confirmed multiresistant or extensively drug-resistant tuberculosis (MDR/XDR-TB) receiving amikacin or kanamycin as part of their TB treatment for at least 3 days were eligible for inclusion in this retrospective study. Clinical data, including maximum concentration (
C
max
),
C
min
, and audiometry data, were extracted from the patients' medical charts. A total of 80 patients met the inclusion criteria. The mean weighted
C
max
/MIC ratios obtained from 57 patients were 31.2 for amikacin and 12.3 for kanamycin. The extent of hearing loss was limited and correlated with the cumulative drug dose per kg of body weight during daily administration. At follow-up, 35 (67.3%) of all patients had successful outcome; there were no relapses. At a median dose of 6.5 mg/kg, a correlation was found between the dose per kg of body weight during daily dosing and the extent of hearing loss in dB at 8,000 Hz. These findings suggest that the efficacy at this lower dosage is maintained with limited toxicity. A randomized controlled trial should provide final proof of the safety and efficacy of TDM-guided use of aminoglycosides in MDR-TB treatment.
Evidence To Support Continuation of Statin Therapy in Patients with Staphylococcus aureus Bacteremia
Authors: Caffrey Aisling R. , Timbrook Tristan T. , Noh Eunsun , Sakoulas George , Opal Steven M. , Nizet Victor , LaPlante Kerry L.
Published: January 2017

In addition to cholesterol-lowering capabilities, statins possess anti-inflammatory and immunomodulatory effects. We sought to quantify the real-world impact of different statin exposure patterns on clinical outcomes in
Staphylococcus aureus
bacteremia. We conducted a retrospective cohort study among hospitalized patients with positive
S. aureus
blood cultures receiving appropriate antibiotics within 48 h of culture collection (Veterans Affairs hospitals, 2002 to 2013). Three statin exposure groups were compared to nonusers: pretreated statin users initiating therapy in the 30 days prior to culture and either (i) continuing statin therapy after culture or (ii) not continuing after culture, and (iii)
de novo
users initiating at culture. Nonusers included patients without statins in the year prior to culture through discharge. Propensity score-matched Cox proportional hazards regression models were developed. We were able to balance significantly different baseline characteristics using propensity score matching for pretreated without continuation (
n
= 331), pretreated with continuation (
n
= 141), and
de novo
(
n
= 177) statin users compared to nonusers. We observed a significantly lower 30-day mortality rate (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.25 to 0.84; number needed to treat [NNT], 10) among pretreated and continued statin users, while protective effects were not observed in
de novo
(HR, 1.04; 95% CI, 0.60 to 1.82; NNT, undefined) or pretreated but not continued (HR, 0.92; 95% CI, 0.64 to 1.32; NNT, 47) users. In our national cohort study among patients with
S. aureus
bacteremia, continuation of statin therapy among incident statin users was associated with significant beneficial effects on mortality, including a 54% lower 30-day mortality rate.
High Incidence of Escherichia coli Strains Coharboring
mcr-1
and
bla
NDM
from Chickens
Authors: Liu Bao-Tao , Song Feng-Jing , Zou Ming , Zhang Qi-Di , Shan Hu
Published: January 2017

This study investigated the characteristics of
Escherichia coli
isolates carrying
mcr-1-bla
NDM
from a chicken farm in China. Of the 78
E. coli
isolates, 21 clonally unrelated isolates carried
mcr-1-bla
NDM
. Diverse IncI2 plasmids disseminated
mcr-1
, while the dissemination of
bla
NDM
was mediated by diverse IncB/O plasmids. More striking was the colocalization of resistance genes
mcr-1
and
bla
NDM-4
in an IncHI2/ST3 plasmid, which might pose a great challenge for public health.
Characterization of BRP
MBL
, the Bleomycin Resistance Protein Associated with the Carbapenemase NDM
Authors: Dortet Laurent , Girlich Delphine , Virlouvet Anne-Laure , Poirel Laurent , Nordmann Patrice , Iorga Bogdan I. , Naas Thierry
Published: January 2017

The metallo-β-lactamase NDM-1 is among the most worrisome resistance determinants and is spreading worldwide among Gram-negative bacilli. A bleomycin resistance gene,
ble
MBL
, downstream of the
bla
NDM-1
gene has been associated with resistance almost systematically. Here, we characterized the corresponding protein, BRP
MBL
, conferring resistance to bleomycin, an antitumoral glycopeptide molecule. We have determined whether the expression of the
bla
NDM-1
-
ble
MBL
operon is inducible in the presence of carbapenems and/or bleomycin-like molecules using quantitative reverse transcription-PCR (qRT-PCR), determination of imipenem and zeocin MICs, and carbapenemase-specific activity assays. We showed that the
bla
NDM-1
-
ble
MBL
operon is constitutively expressed. Using electrophoretic mobility shift and DNA protection assays performed with purified glutathione
S
-transferase (GST)-BRP
MBL
, we demonstrated that BRP
MBL
is able to bind and sequester bleomycin-like molecules, thus preventing bleomycin-dependent DNA degradation.
In silico
modeling confirmed that the mechanism of action required the dimerization of the BRP
MBL
protein in order to sequester bleomycin and prevent DNA damage. BRP
MBL
acts specifically on bleomycin-like molecules since cloning and expression of
ble
MBL
in
Staphyloccoccus aureus
did not confer cross-resistance to any other antimicrobial glycopeptides such as vancomycin and teicoplanin.
Interaction of the CD43 Sialomucin with the Mycobacterium tuberculosis Cpn60.2 Chaperonin Leads to Tumor Necrosis Factor Alpha Production
Authors: Torres-Huerta Alvaro , Villaseñor Tomás , Flores-Alcantar Angel , Parada Cristina , Alemán-Navarro Estefanía , Espitia Clara , Pedraza-Alva Gustavo , Rosenstein Yvonne
Published: January 2017

Mycobacterium tuberculosisis the causal agent of tuberculosis. Tumor necrosis factor alpha (TNF-α), transforming growth factor β (TGF-β), and gamma interferon (IFN-γ) secreted by activated macrophages and lymphocytes are considered essential to containMycobacterium tuberculosisinfection. The CD43 sialomucin has been reported to act as a receptor for bacilli through its interaction with the chaperonin Cpn60.2, facilitating mycobacterium-macrophage contact. We report here that Cpn60.2 induces both human THP-1 cells and mouse-derived bone marrow-derived macrophages (BMMs) to produce TNF-α and that this production is CD43 dependent. In addition, we present evidence that the signaling pathway leading to TNF-α production upon interaction with Cpn60.2 requires active Src family kinases, phospholipase C-γ (PLC-γ), phosphatidylinositol 3-kinase (PI3K), p38, and Jun N-terminal protein kinase (JNK), both in BMMs and in THP-1 cells. Our data highlight the role of CD43 and Cpn60.2 in TNF-α production and underscore an important role for CD43 in the host-mycobacterium interaction.
Quorum Sensing Regulators Are Required for Metabolic Fitness in Vibrio parahaemolyticus
Authors: Kalburge Sai Siddarth , Carpenter Megan R. , Rozovsky Sharon , Boyd E. Fidelma
Published: January 2017

Quorum sensing (QS) is a process by which bacteria alter gene expression in response to cell density changes. In
Vibrio
species, at low cell density, the sigma 54-dependent response regulator LuxO is active and regulates the two QS master regulators AphA, which is induced, and OpaR, which is repressed. At high cell density the opposite occurs: LuxO is inactive, and therefore OpaR is induced while AphA is repressed. In
Vibrio parahaemolyticus
, a significant enteric pathogen of humans, the roles of these regulators in pathogenesis are less known. We examined deletion mutants of
luxO
,
opaR
, and
aphA
for
in vivo
fitness using an adult mouse model. We found that the
luxO
and
aphA
mutants were defective in colonization compared to levels in the wild type. The
opaR
mutant did not show any defect
in vivo
. Colonization was restored to wild-type levels in a
luxO opaR
double mutant and was also increased in an
opaR aphA
double mutant. These data suggest that AphA is important and that overexpression of
opaR
is detrimental to
in vivo
fitness. Transcriptome sequencing (RNA-Seq) analysis of the wild type and
luxO
mutant grown in mouse intestinal mucus showed that 60% of the genes that were downregulated in the
luxO
mutant were involved in amino acid and sugar transport and metabolism. These data suggest that the
luxO
mutant has a metabolic disadvantage, which was confirmed by growth pattern analysis using phenotype microarrays. Bioinformatics analysis revealed OpaR binding sites in the regulatory region of 55 carbon transporter and metabolism genes. Biochemical analysis of five representatives of these regulatory regions demonstrated direct binding of OpaR in all five tested. These data demonstrate the role of OpaR in carbon utilization and metabolic fitness, an overlooked role in the QS regulon.
The origin of contractional structures in extensional gneiss domes
Authors: Rey P.F. , Mondy L. , Duclaux G. , Teyssier C. , Whitney D.L. , Bocher M. , Prigent C.
Published: January 2017

The juxtaposition of domains of shortening and extension at different scales in orogens has fueled many debates about driving forces and tectonic interpretations, including timing of deformation. At the orogen scale, gravitational collapse and mass transfer from orogenic plateaux to forelands explain some of these juxtapositions. At a regional scale, structures in gneiss domes are commonly contractional yet are coeval with regional extension and denudation. Here we use three-dimensional numerical experiments to show that crustal flow in orogenic domains does not necessarily conform to plate motion. We document contractional crustal flow associated with the formation of a gneiss dome in an orogenic pull-apart setting where localized extension and crustal thinning focus the exhumation of deep crust. We show that the flow field results in a complex strain pattern in which an extensional strain regime that is collinear with the direction of plate motion is partitioned into the shallow crust, whereas contractional structures and fabrics at a high angle to the direction of imposed transport develop in the deep crust. Advective mass transfer across regions of contrasting yet coeval strain regimes leads to a polyphase tectonic history. We observe structural features remarkably similar to those documented in some natural gneiss domes such as the Montagne Noire, which developed in a dextral pull-apart domain at the southern margin of the French Massif Central.
What sets the size of current ripples?
Authors: Lapotre Mathieu G.A. , Lamb Michael P. , McElroy Brandon
Published: January 2017

Water flowing over sand in fluvial and marine settings often results in the formation of current ripples. Found in modern and ancient deposits on Earth and Mars, ripple stratification records flow directions and fluid properties that are crucial to interpreting sedimentary records. Despite decades of observations of current ripples, there is no universal scaling relation to predict their size or to distinguish them from dunes. Here we use dimensional analysis and a new data compilation to develop a scaling relation that collapses data for equilibrium wavelengths of ripples forming under unidirectional flows. Results show that ripples are larger with more viscous fluids, coarser grains, smaller bed shear stresses, and smaller specific gravity of sediment. The scaling relation also segregates ripples from dunes, highlighting a narrow regime of transitional bedforms that have morphologic properties and sediment transport conditions that overlap with both ripples and dunes. Our analysis shows that previous absolute size–based definitions of ripples and dunes only hold for certain conditions, such as water flows transporting siliciclastic grains on Earth. The new theory allows estimates of ripple sizes in foreign fluids and on other planets, including meter-scale ripples in methane flows on Titan or in viscous brines on Mars.
Ultrafast magmatic buildup and diversification to produce continental crust during subduction
Authors: Ducea Mihai N. , Bergantz George W. , Crowley James L. , Otamendi Juan
Published: January 2017

The processes and fluxes that produce the distinct compositional structure of Earth’s continental crust by subduction remain controversial. The rates of oceanic crust production, in contrast, are well quantified and are generally believed to be faster than those responsible for building magmatic systems in subduction settings. Here we show that a recently recognized crustal section, the 30-km-thick Ordovician Sierra Valle Fértil–Sierra Famatina complex in Argentina, was built magmatically within only ∼4 m.y. More than half of the crustal section represents additions from the mantle, and is preserved as mafic igneous rocks and mafic-ultramafic cumulates; the remainder is tonalite to granodiorite with evidence for widespread assimilation from highly melted metasedimentary units. U-Pb zircon geochronology reveals that the construction of the arc was not a simple bottom-up construction process. This continuous exposure of the arc crust allows the quantification of field constrained magmatic addition rates of 300–400 km3 km–1 m.y.–1. These rates are similar to those determined for modern slow-spreading mid-ocean ridges and are of the same magnitude as magmatic addition rates required to build certain large segments of the continental masses such as the Arabian-Nubian shield, among others. The implication is that significant convective removal of arc roots is required over time in order to build the modern continental crust via subduction-related magmatism.
Pyritized in situ trilobite eggs from the Ordovician of New York (Lorraine Group): Implications for trilobite reproductive biology
Authors: Hegna Thomas A. , Martin Markus J. , Darroch Simon A.F.
Published: January 2017

Despite a plethora of exceptionally preserved trilobites, trilobite reproduction has remained a mystery. No previously described trilobite has unambiguous eggs or genitalia preserved. This study reports the first occurrence of in situ preserved eggs belonging to Triarthrus eatoni (Hall, 1838) trilobites from the Lorraine Group in upstate New York, USA. Like other exceptionally preserved trilobites from the Lorraine Group, the complete exoskeletons are replaced with pyrite. The eggs are spherical to elliptical in shape, nearly 200 µm in size, and are clustered in the genal area of the cephalon. The fact that the eggs are smaller than the earliest-known trilobite ontogenetic (protaspis) stage suggests that trilobites may have had an unmineralized preliminary stage in their ontogeny, and that the protaspis shield formed only after hatching. The eggs are only visible ventrally with no dorsal brood pouch or recognized sexual dimorphism. The location of the eggs is consistent with where modern female horseshoe crabs release their unfertilized eggs from the ovarian network within their head. Trilobites likely released their gametes (eggs and sperm) through a genital pore of as-yet unknown location (likely near the posterior boundary of the head). If the T. eatoni reproductive biology is representative of other trilobites, they spawned with external fertilization, possibly the ancestral mode of reproduction for early arthropods. Because pyritization preferentially preserves the external rather than internal features of fossils, it is suggested that there is likely a bias in the fossil record toward the preservation of arthropods that brood eggs externally: arthropods that brood their eggs internally are unlikely to preserve any evidence of their mode of reproduction.
Donor-derived mycosis fungoides following reduced intensity haematopoietic stem cell transplantation from a matched unrelated donor
Authors: Kinsella Francesca A M , Amel Kashipaz Mohammad Rasoul , Scarisbrick Julia , Malladi Ram
Published: January 2017

A 46-year-old woman with a history of dasatinib-resistant chronic myeloid leukaemia, clonal evolution and monosomy 7 underwent reduced intensity conditioned in vivo T-cell-depleted allogeneic haematopoietic stem cell transplantation (HSCT) from a matched unrelated donor. Following the transplantation, she developed recurrent cutaneous graft versus host disease (GvHD), which required treatment with systemic immunosuppression and electrocorporeal photophoresis. Concurrently, she developed a lichenoid rash with granulomatous features suggestive of cutaneous sarcoidosis. Additional treatment with hydroxychloroquine was initially successful, but 2 months later, she developed erythroderma with palpable lymphadenopathy. Repeated histological analysis established a diagnosis of folliculotropic mycosis fungoides stage IVA2, and the malignant clone was confirmed to be of donor origin. A positive response to brentuximab has been shown. This is the first reported case of primary mycosis fungoides after matched unrelated donor HSCT, and in a patient still undergoing treatment for GvHD.
Prenatal exposure to antiepileptic drugs and use of primary healthcare during childhood: a population-based cohort study in Denmark
Authors: Würtz Anne Mette , Rytter Dorte , Vestergaard Claus Høstrup , Christensen Jakob , Vestergaard Mogens , Bech Bodil Hammer
Published: January 2017

Objective

Prenatal exposure to antiepileptic drugs (AEDs) has been associated with adverse outcomes in the offspring such as congenital malformations and neuropsychiatric disorders. The objective of this study was to investigate whether prenatal exposure to AEDs is also associated with more frequent use of primary healthcare during childhood.

Design

Population-based cohort study.

Setting

Nationwide national registers in Denmark.

Participants

All live-born singletons in Denmark during 1997–2012 identified in the Danish National Patient Register and followed until 31 December 2013 (n=963 010). Information on prenatal exposure to AEDs for maternal indication of epilepsy and other neurological conditions was obtained from the Danish Register of Medicinal Product Statistics.

Main outcome measures

The primary outcome measure was the number and type of contacts with the general practitioner (GP), excluding routine well-child visits and vaccinations. The secondary outcome measure was specific services provided at the GP contact. The association between prenatal exposure to AEDs and contacts with the GP was estimated by using negative binomial regression adjusting for sex and date of birth of the child, maternal age, cohabitation status, income, education, substance abuse, depression, severe psychiatric disorders and use of antipsychotics, antidepressants and insulin.

Results

Children exposed prenatally to AEDs (n=4478) had 3% (95% CI 0 to 5%) more GP contacts during the study period than unexposed children. This was primarily accounted for by the number of phone contacts. Within each year of follow-up, exposed children tended to have more contacts than unexposed children, but the differences were small. We found no difference between exposed and unexposed children with regard to specific services provided at the GP contact. For the individual AEDs, we found that exposure to valproate or oxcarbazepine was associated with more GP contacts.

Conclusions

We found only minor differences between prenatally AED-exposed and unexposed children in the number of GP contacts.