bluuebunny/crossref_metadata_2025 huggingface dataset:
Adaptive evolution to a high purine and fat diet of carnivorans revealed by gut microbiomes and host genomes
Authors: Zhu Lifeng , Wu Qi , Deng Cao , Zhang Mengjie , Zhang Chenglin , Chen Hua , Lu Guoqing , Wei Fuwen
Published: March 2018

Carnivorous members of the Carnivora reside at the apex of food chains and consume meat‐only diets, rich in purine, fats and protein. Here, we aimed to identify potential adaptive evolutionary signatures compatible with high purine and fat metabolism based on analysis of host genomes and symbiotic gut microbial metagenomes. We found that the gut microbiomes of carnivorous Carnivora (e.g., Felidae, Canidae) clustered in the same clade, and other clades comprised omnivorous and herbivorous Carnivora (e.g., badgers, bears and pandas). The relative proportions of genes encoding enzymes involved in uric acid degradation were higher in the gut microbiomes of meat‐eating carnivorans than plant‐eating species. Adaptive amino acid substitutions in two enzymes, carnitine O‐palmitoyltransferase 1 (CPT1A) and lipase F (LIPF), which play a role in fat digestion, were identified in Felidae‐Candidae species. Carnivorous carnivorans appear to endure diets high in purines and fats via gut microbiomic and genomic adaptations.
Development of Enriched Core Competencies for Health Services and Policy Research
Authors: Bornstein Stephen , Heritage Melissa , Chudak Amanda , Tamblyn Robyn , McMahon Meghan , Brown Adalsteinn D.
Published: March 2018

Objective

To develop an enriched set of core competencies for health services and policy research (HSPR) doctoral training that will help graduates maximize their impact across a range of academic and nonacademic work environments and roles.

Data Sources/Study Setting

Data were obtained from multiple sources, including literature reviews, key informant interviews, stakeholder consultations, and Expert Working Group (EWG) meetings between January 2015 and March 2016. The study setting is Canada.

Study Design

The study used qualitative methods and an iterative development process with significant stakeholder engagement throughout.

Data Collection/Extraction Methods

The literature reviews, key informant interviews, existing data on graduate career trajectories, and EWG deliberations informed the identification of career profiles for HSPR graduates and the competencies required to succeed in these roles. Stakeholder consultations were held to vet, refine, and validate the competencies.

Principal Findings

The EWG reached consensus on six sectors and eight primary roles in which HSPR doctoral graduates can bring value to employers and the health system. Additionally, 10 core competencies were identified that should be included or further emphasized in the training of HSPR doctoral students to increase their preparedness and potential for impact in a variety of roles within and outside of traditional academic workplaces.

Conclusion

The results offer an expanded view of potential career paths for HSPR doctoral graduates and provide recommendations for an expanded set of core competencies that will better equip graduates to maximize their impact on the health system.
Distribution of CD68‐, CD8‐, MHCI‐ and MHCII‐positive cells in the bull and ram testis and epididymis
Authors: Güney Saruhan B. , Sağsöz H. , Akbalık E. , Ketani M. A. , Erdoğan S.
Published: March 2018

The mammalian testis possesses a special immunological environment because of its properties of remarkable immune privilege and effective local innate immunity. The testicular immune privilege protects immunogenic germ cells from systemic immune attack, and local innate immunity is important in preventing testicular microbial infections. Thus, this study aimed to immunohistochemically demonstrate the distribution and localization of CD68‐, CD8‐, MHCI‐ and MHCII‐positive immune cells in the testes and epididymes. Negative immunoreactivity was detected in the seminiferous tubule epithelium and peritubular myoid cells of the testes upon staining in CD68, CD8 and MHC Class I. Positive CD68 immunoreaction was determined in the Sertoli cells and some Leydig cells. The detection of positive cells for CD8 clearly indicated the presence of lymphocytes. Furthermore, the staining with MHCI intensity was ascertained to vary from weak to moderate in the Sertoli and Leydig cells and connective tissue cells. MHCII‐positive immunoreactivity was determined in myoid cells and Leydig cells in the interstitial area. The epithelium of the epididymis showed positive staining for CD68 and CD8, but the stroma displayed a rather weak staining. In the ram epididymis, neither intraepithelial nor interstitial positive reaction was observed for MHCI. In the epididymis, the basal cells displayed a stronger staining for MHCII. In conclusion, these cells not only contribute to local immunity through their direct effects on the quality of fertility in males, but also contribute either directly or indirectly to immune privilege by minimizing the development of both autoimmune reactions and potentially harmful risks.
The IL‐13/periostin/IL‐24 pathway causes epidermal barrier dysfunction in allergic skin inflammation
Authors: Mitamura Y. , Nunomura S. , Nanri Y. , Ogawa M. , Yoshihara T. , Masuoka M. , Tsuji G. , Nakahara T. , Hashimoto‐Hachiya A. , Conway S. J. , Furue M. , Izuhara K.
Published: March 2018

Background

Barrier dysfunction is an important feature of atopic dermatitis (AD) in which IL‐4 and IL‐13, signature type 2 cytokines, are involved. Periostin, a matricellular protein induced by IL‐4 or IL‐13, plays a crucial role in the onset of allergic skin inflammation, including barrier dysfunction. However, it remains elusive how periostin causes barrier dysfunction downstream of the IL‐13 signal.

Methods

We systematically identified periostin‐dependent expression profile using DNA microarrays. We then investigated whether IL‐24 downregulates filaggrin expression downstream of the IL‐13 signals and whether IL‐13‐induced IL‐24 expression and IL‐24‐induced downregulation of filaggrin expression are dependent on the JAK/STAT pathway. To build on the significance of in vitro findings, we investigated expression of IL‐24 and activation of STAT3 in mite‐treated mice and in AD patients.

Results

We identified IL‐24 as an IL‐13‐induced molecule in a periostin‐dependent manner. Keratinocytes are the main IL‐24‐producing tissue‐resident cells stimulated by IL‐13 in a periostin‐dependent manner via STAT6. IL‐24 significantly downregulated filaggrin expression via STAT3, contributing to barrier dysfunction downstream of the IL‐13/periostin pathway. Wild‐type mite‐treated mice showed significantly enhanced expression of IL‐24 and activation of STAT3 in the epidermis, which disappeared in both STAT6‐deficient and periostin‐deficient mice, suggesting that these events are downstream of both STAT6 and periostin. Moreover, IL‐24 expression was enhanced in the epidermis of skin tissues taken from AD patients.

Conclusions

The IL‐13/periostin pathway induces IL‐24 production in keratinocytes, playing an important role in barrier dysfunction in AD.
Intra‐ and interobserver variability in nodule size of rectosigmoid endometriosis measured by two‐ and three‐dimensional transvaginal sonography
Authors: Egekvist Anne G. , Forman Axel , Riiskjær Mads , Kesmodel Ulrik S. , Mathiasen Mie , Seyer‐Hansen Mikkel
Published: March 2018

Introduction

The aim of the study was to assess the intra‐ and interobserver variability of two‐ and three‐dimensional rectosigmoid nodule size measurements by transvaginal sonography in patients with rectosigmoid endometriosis.

Material and methods

Intra‐ and interobserver variability was assessed in 10 and 30 patients, respectively. Measurements in two dimensions were performed in real‐time during the scan, and three‐dimensional measurements of volume were done on a computer. Differences within and between observers were expressed in absolute units (mm) and percentage (%) of average nodule size. Coefficient of repeatability and Bland–Altman plots with limits of agreement were used to evaluate the intra‐ and interobserver variability.

Results

Intra‐ and interobserver variability in two‐dimensional sonography ranged from 11 to 14 mm (46–51%) for length, 3 to 6 mm (32–57%) for depth and 5 to 9 mm (33–58%) for width of the nodule. Results of three‐dimensional sonography, with assessment of nodule volume, showed intra‐ and interobserver variability 0.4 to 2.5 times the average nodule size.

Conclusions

Measurements of rectosigmoid endometriosis nodule size with two‐ and three‐ dimensional transvaginal sonography were associated with large intra‐ and interobserver variability. These techniques should therefore be used with caution in clinical control and research of nodule growth.
Do Votes Speak Louder than Motives? Moral Judgments and Tolerance in the 2016 Presidential Election
Authors: Huff Sarah T. , Hall Michael P.
Published: March 2018

When judging a voter's decision, does that voter's reason for casting their vote influence moral and interpersonal judgments about them? In the context of the 2016 U.S. Presidential Election, past research suggests two competing predictions. First, people regularly account for an actor's intentions when forming judgments of the actor, indicating that judgments may vary according to a voter's motives. However, people are unlikely to see nuance among outgroups, especially amid divisive political partisanship, suggesting that judgments would ignore information about voters’ motives. In Study 1, results supported the first prediction, showing that both Hillary Clinton and Donald Trump supporters distinguished between different voting motives when making moral and interpersonal judgments of outgroup voters. In Studies 2 and 3, when some voters’ motives became more extreme, Clinton and Trump supporters again distinguished between voting motives for outgroup and ingroup voters, respectively, albeit in a different pattern of results.
Renal protection by atorvastatin in a murine model of sickle cell nephropathy
Authors: Zahr Rima S. , Chappa Prasanthi , Yin Hong , Brown Lou A. , Ataga Kenneth I. , Archer David R.
Published: March 2018

Recent studies have demonstrated pleiotropic effects of statins in various mouse models of kidney disease. In this study, Townes humanized sickle cell mice were treated for 8 weeks with atorvastatin at a dose of 10 mg/kg/day starting at 10 weeks of age. Treatment with atorvastatin significantly reduced albuminuria, and improved both urine concentrating ability and glomerular filtration rate. Atorvastatin also decreased markers of kidney injury and endothelial activation, and ameliorated oxidant stress in renal tissues and peripheral macrophages. Atorvastatin downregulated the expression of mRNA levels of the NADPH oxidases, Cybb (also termed Nox2) and Nox4, which are major sources of oxidant stress in the kidney. These findings highlight the pleiotropic effects of atorvastatin and suggest that it may provide beneficial effects in sickle cell nephropathy.
The Uganda version of the Pediatric Evaluation of Disability Inventory (PEDI). Part I: Cross‐cultural adaptation
Authors: Kakooza‐Mwesige A. , Tumwine J. K. , Forssberg H. , Eliasson A.‐C.
Published: March 2018

Background

The Pediatric Evaluation of Disability Inventory (PEDI) was developed and standardized to measure functional performance in American children. So far, no published study has examined the use of the PEDI in sub‐Saharan Africa. This study describes the adaptation, translation, and validation process undertaken to develop a culturally relevant PEDI for Uganda (PEDI‐UG).

Method

The cross‐cultural adaptation and translation of the PEDI was performed in a series of steps. A project manager and a technical advisory group were involved in all steps of adaptation, translation, cognitive debriefing, and revision. Translation and back‐translation between English and Luganda were performed by professional translators. Cognitive debriefing of two subsequent adapted revisions was performed by a field‐testing team on a total of 75 caregivers of children aged 6 months to 7.5 years.

Results

The PEDI‐UG was established in both English (the official language) and Luganda (a local language) and comprises 185 items. Revisions entailed deleting irrelevant items, modifying wording, inserting new items, and incorporating local examples while retaining the meaning of the original PEDI. Item statements were rephrased as questions. Seven new items were inserted and 19 items deleted. To accommodate major differences in living conditions between rural and urban areas, 10 alternative items were provided.

Conclusions

The PEDI‐UG is to be used to measure functional limitations in both clinical practice and research, in order to assess and evaluate rehabilitative procedures in children with developmental delay and disability in Uganda. In this study, we take the first step by translating and adapting the original PEDI version to the culture and life conditions in both rural and urban Uganda. In subsequent studies, the tool's psychometric properties will be examined, and the tool will be tested in children with developmental delay and disability.
Use of a metabolomic approach to non‐invasively diagnose non‐alcoholic fatty liver disease in patients with type 2 diabetes mellitus
Authors: Bril Fernando , Millán Laura , Kalavalapalli Srilaxmi , McPhaul Michael J. , Caulfield Michael P. , Martinez‐Arranz Ibon , Alonso Cristina , Ortiz Betes Pablo , Mato José M. , Cusi Kenneth
Published: March 2018

Aims

To assess the utility of existing metabolomics scores to classify liver disease in patients with type 2 diabetes mellitus (T2DM).

Materials and methods

A total of 220 patients with T2DM were recruited. Patients underwent routine laboratory tests, liver proton magnetic resonance spectroscopy (1H‐MRS), a 75‐g oral glucose tolerance test, and liver biopsy if 1H‐MRS findings indicated non‐alcoholic fatty liver disease. A serum sample was blindly provided to OWL Metabolomics on which to run the OWLiver Care and OWLiver tests.

Results

When compared with liver biopsy, the OWLiver Care and OWLiver tests had a suboptimal performance in patients with T2DM (areas under the receiver‐operating characteristic [AUROC] curve both <0.70). Given the discordance of these results in this heterogeneous, multiethnic cohort compared with those of a previous report in predominantly white patients without diabetes, we examined the influence of age, ethnicity and other variables on test performance. A specific subset of patients was selected to mirror the characteristics of the population used for the development of this model (ie, white patients without T2DM). Among white patients with good glycaemic control (glycated haemoglobin <53mmol/mol [or <7%]) and without cirrhosis, the AUROC curve was significantly improved (0.79 [CI 95%: 0.68‐0.90]). Among white patients with lower insulin resistance (homeostatic model assessment of insulin resistance <3) and without cirrhosis, the AUROC was even higher: 0.87 (CI 95%: 0.76‐0.97).

Conclusions

There is a great need to develop non‐invasive approaches to diagnose non‐alcoholic steatohepatitis in patients with T2DM; models originally developed for patients without diabetes cannot be directly applied to patients with T2DM.
Striatal cholinergic receptor activation causes a rapid, selective and state‐dependent rise in cortico‐striatal β activity
Authors: Pittman‐Polletta Benjamin R. , Quach Allison , Mohammed Ali I. , Romano Michael , Kondabolu Krishnakanth , Kopell Nancy J. , Han Xue , McCarthy Michelle M.
Published: March 2018

Cortico‐basal ganglia‐thalamic (CBT) β oscillations (15–30 Hz) are elevated in Parkinson's disease and correlated with movement disability. To date, no experimental paradigm outside of loss of dopamine has been able to specifically elevate β oscillations in the CBT loop. Here, we show that activation of striatal cholinergic receptors selectively increased β oscillations in mouse striatum and motor cortex. In individuals showing simultaneous β increases in both striatum and M1, β partial directed coherence (PDC) increased from striatum to M1 (but not in the reverse direction). In individuals that did not show simultaneous β increases, β PDC increased from M1 to striatum (but not in the reverse direction), and M1 was characterized by persistent β‐high frequency oscillation phase–amplitude coupling. Finally, the direction of β PDC distinguished between β sub‐bands. This suggests that (1) striatal cholinergic tone exerts state‐dependent and frequency‐selective control over CBT β power and coordination; (2) ongoing rhythmic dynamics can determine whether elevated β oscillations are expressed in striatum and M1; and (3) altered striatal cholinergic tone differentially modulates distinct β sub‐bands.
DEMOCRATIC FILM AND THE AESTHETICS OF CHOICE
Authors: Fay Jennifer
Published: March 2018

Both the Germans and their American occupiers understood that films were supposed to support a democratic culture and worldview during the occupation following the Second World War. This essay explores how democratic culture comes to be defined at mid‐century through choice, and how two films that played in the Western Zones, Der Apfel ist ab (1948) and The Best Years of Our Lives (1946), take up choice as a formal aesthetic closely tied to a fraught democratic experience. Best Years, praised by German critics as a realistic portrait of American life, also adopts what the film critic André Bazin calls a democratic and liberal film style of deep focus compositions and shots of long duration that allow the spectator to choose what to look at in the frame. Yet, as even Bazin notes, this choice is slyly coercive. Der Apfel was a critical failure and thematises indecision within the narrative. In contrast to Best Years, it turns the optics of choice into vertiginous confusion in which there are no good choices. This essay argues that the democratic refusal in Der Apfel ist ab is an apt critique of ‘democracy as choice’, and that the film opens up new horizons of political invention.
Transcranial Magnetic Stimulation for Migraine Prevention in Adolescents: A Pilot Open‐Label Study
Authors: Irwin Samantha L. , Qubty William , Allen I. Elaine , Patniyot Irene , Goadsby Peter J. , Gelfand Amy A.
Published: March 2018

Objective

To assess the feasibility, tolerability, and patient acceptability of single‐pulse transcranial magnetic stimulation (sTMS) for migraine prevention in adolescents in an open‐label pilot study.

Background

Migraine is common in adolescents and can be disabling. Well tolerated preventative therapies that are safe and effective are needed.

Methods

This was an open‐label prospective pilot feasibility study of sTMS for migraine prevention in adolescents aged 12‐17 years. Participants used sTMS twice daily in a preventative fashion, as well as additional pulses as needed acutely. A 4‐week baseline run‐in period (weeks 1‐4) was followed by a 12‐week treatment period. Feasibility was the primary outcome. Secondary outcomes included tolerability and acceptability, as well as the change in headache days, number of moderate/severe headache days, days of acute medication use, and PedMIDAS (headache disability) scores between the run‐in period (weeks 1‐4) and the third month of treatment (weeks 13‐16).

Results

Twenty‐one participants enrolled. Nineteen completed the baseline run‐in, and 12 completed the study. Using sTMS proved feasible and acceptable with overall high compliance once treatment administration was streamlined. Initially, for preventive treatment, participants were asked to give 2 pulses, wait 15 minutes, then give 2 additional pulses twice daily. This 15‐minute delay proved challenging for adolescents, particularly on school days, and therefore was dropped. Study completion rate went from 4/13 (31%) to 7/8 (88%) once this change was made,P = .024. On average, participants used the device preventively between 22 and 24 days over a 28‐day block. There were no serious adverse events. Two participants reported mild discomfort with device use.

Conclusion

sTMS appears to be a feasible, well‐tolerated, and acceptable nonpharmacologic preventive treatment for migraine in adolescents. In designing future trials of sTMS for migraine prevention in adolescents, streamlined treatment administration will be essential to minimize drop‐out. Efficacy needs to be assessed in a larger trial.
Antibiotics resistance of Helicobacter pylori in children with upper gastrointestinal symptoms in Hangzhou, China
Authors: Shu Xiaoli , Yin Guofeng , Liu Mingnan , Peng Kerong , Zhao Hong , Jiang Mizu
Published: March 2018

Background

The decreasing eradication rate of Helicobacter pylori is mainly because of the progressive increase in its resistance to antibiotics. Studies on antimicrobial susceptibility of H. pylori in children are limited. This study aimed to investigate the resistance rates and patterns of H. pylori strains isolated from children.

Materials and Methods

Gastric mucosa biopsy samples obtained from children who had undergone upper gastrointestinal endoscopy were cultured for H. pylori, and susceptibility to six antibiotics (clarithromycin, amoxicillin, gentamicin, furazolidone, metronidazole, and levofloxacin) was tested from 2012‐2014.

Results

A total of 545 H. pylori strains were isolated from 1390 children recruited. The total resistance rates of H. pylori to clarithromycin, metronidazole, and levofloxacin were 20.6%, 68.8%, and 9.0%, respectively. No resistance to amoxicillin, gentamicin, and furazolidone was detected. 56.1% strains were single resistance, 19.6% were resistant to more than one antibiotic, 16.7% for double resistance, and 2.9% for triple resistance in 413 strains against any antibiotic. And the H. pylori resistance rate increased significantly from 2012‐2014. There was no significant difference in the resistance rates to clarithromycin, metronidazole, and levofloxacin between different gender, age groups, and patients with peptic ulcer diseases or nonulcer diseases.

Conclusions

Antibiotic resistance was indicated in H. pylori strains isolated from children in Hangzhou, and it increased significantly during the 3 years. Our data strongly support current guidelines, which recommend antibiotic susceptibility tests prior to eradication therapy.
The wisdom nexus: Guiding information systems research, practice, and education
Authors: Dalal Nikunj , Pauleen David J.
Published: March 2018

“Wisdom” has been at the heart of practical, philosophical, and spiritual disciplines since antiquity and is now increasingly receiving organizational as well as academic attention in scholarly areas that include psychology and organizational studies among others. However, practical wisdom has not received adequate focus in the information systems (IS) discipline. In this commentary, we make the case for a systemic focus on the role of wisdom in IS research, teaching, and practice. We introduce underlying theoretical concepts of wisdom; review relevant key research linking wisdom and IS; propose a framework to link wisdom with IS research, practice, and education; and discuss the implications of the framework and illustrate how it can be used to generate research opportunities for IS. We conclude that wisdom, whose goal is the common good, can provide a foundation to discover, view, understand, and resolve myriad issues that lie at the nexus of wisdom and information technologies.
DO SCANDALS TRIGGER GOVERNANCE CHANGES? EVIDENCE FROM OPTION BACKDATING
Authors: Gupta Atul , Misra Lalatendu , Shi Yilun
Published: March 2018

We examine whether firms charged with backdating option grants make discernible changes to board structure and activity and whether such changes help recoup value losses from the revelation of option backdating. We find that these firms increased board size, reduced duality, and increased board independence. In addition, the boards and the compensation committees of these firms experienced significant increases in meeting frequency. We also find that firms in the same sectors that had not been identified as backdating option grants experienced similar changes in board activity and some elements of board structure. Additional analysis reveals that increases in board size, chief excutive officer turnover, and the meeting frequency of the audit committee are related to buy‐and‐hold abnormal returns in the postscandal period.
WHOM YOU CONNECT WITH MATTERS: DIRECTOR NETWORKS AND FIRM LOCATION
Authors: Baran Lindsay , Wilson Rachel
Published: March 2018

We examine whether board members serve as a channel for remotely located firms to access the benefits from business‐dense areas due to economies of agglomeration. We find that geographically remote firms benefit from connections to firms in top metropolitan statistical areas (MSAs) for business density. After controlling for director compensation, we find connections to top MSA firms mitigate the negative effect of increased distance from business‐dense areas. We address concerns of endogeneity by exploring a sample of firms whose directors gain board seats at top MSA firms and find a similar positive impact of connections to top MSA firms.
DO DIVIDEND FLOWS AFFECT STOCK RETURNS?
Authors: Kvamvold Joakim , Lindset Snorre
Published: March 2018

We examine price impacts from dividend flows. Event‐study estimates show that stocks experience abnormal returns on the dividend distribution day. Results also show a spillover effect to non‐dividend‐paying stocks that are likely to be part of the same benchmark portfolio as the dividend‐paying stocks. Regression results indicate that the effect is dependent on the ownership share by professional investors. The temporary nature of the effect on returns is in line with the literature's demand‐driven price pressure hypothesis.
Exhumation of eclogite and blueschist (Cyclades, Greece): Pressure–temperature evolution determined by thermobarometry and garnet equilibrium modelling
Authors: Laurent Valentin , Lanari Pierre , Naïr Inès , Augier Romain , Lahfid Abdeltif , Jolivet Laurent
Published: March 2018

High‐P rocks such as eclogite and blueschist are metamorphic markers of palaeo‐subduction zones, and their formation at high‐P and low‐T (HP–LT) conditions is relatively well understood since it has been the focus of numerous petrological investigations in the past 40 years. The tectonic mechanisms controlling their exhumation back to the surface are, however, diverse, complex and still actively debated. Although the Cycladic Blueschist Unit (CBU, Greece) is among the best worldwide examples for the preservation of eclogite and blueschist, the proposed P–T evolution followed by this unit within the Hellenic subduction zone is quite different from one study to another, hindering the comprehension of exhumation processes. In this study, we present an extensive petrological data set that permits refinement of the shape of the P–T trajectory for different subunits of the CBU on Syros. High‐resolution quantitative compositional mapping has been applied to support the thermobarometric investigations, which involve semi‐empirical thermobarometry, garnet equilibrium modelling and P–T isochemical phase diagrams. The thermodynamic models highlight the powerful use of reactive bulk compositions approximated from local bulk compositions. The results are also combined with Raman spectrometry of carbonaceous material (RSCM) to retrieve the metamorphic peak temperature distribution at the scale of the island. A major result of this study is the good agreement between all the independent thermobarometric methods, permitting reconstruction of the prograde and retrograde P–T trajectories. Garnet compositional zoning was used to retrieve prograde, peak and retrograde growth stages in line with the results of the P–T isochemical phase diagrams, RSCM temperature and peak‐pressure crystallization of the garnet–omphacite–phengite assemblage. Our results are consistent with previous thermobarometric estimates from other occurrences of CBU rocks (Tinos, Andros), suggesting a multistage exhumation process with (1) early syn‐orogenic exhumation within the subduction channel, (2) isobaric heating at mid‐crustal depths (~10–12 kbar) following thermal re‐equilibration of the lithosphere from a cold syn‐orogenic regime in the subduction zone to a warmer post‐orogenic regime in the back‐arc domain and (3) exhumation and cooling related to a post‐orogenic phase of extension following slab retreat. Expanding to the general aspects of subduction zones, we suggest that such metamorphic evolution of HP–LT units should be regarded as a characteristic feature of exhumation driven by slab rollback.
Delivery of an anti‐transthyretin Nanobody to the brain through intranasal administration reveals transthyretin expression and secretion by motor neurons
Authors: Gomes João R. , Cabrito Inês , Soares Hugo R. , Costelha Susete , Teixeira Anabela , Wittelsberger Angela , Stortelers Catelijne , Vanlandschoot Peter , Saraiva Maria J.
Published: March 2018

Transthyretin (TTR) is a transport protein of retinol and thyroxine in serum andCSF, which is mainly secreted by liver and choroid plexus, and in smaller amounts in other cells throughout the body. The exact role ofTTRand its specific expression in Central Nervous System (CNS) remains understudied. We investigatedTTRexpression and metabolism inCNS, through the intranasal and intracerebroventricular delivery of a specific anti‐TTRNanobody to the brain, unveiling Nanobody pharmacokinetics to theCNS. InTTRdeficient mice, we observed that anti‐TTRNanobody was successfully distributed throughout all brain areas, and also reaching the spinal cord. In wild‐type mice, a similar distribution pattern was observed. However, in areas known to be rich inTTR, reduced levels of Nanobody were found, suggesting potential target‐mediated effects. Indeed, in wild‐type mice, the anti‐TTRNanobody was specifically internalized in a receptor‐mediated process, by neuronal‐like cells, which were identified as motor neurons. Whereas inKO TTRmice Nanobody was internalized by all cells, for late lysosomal degradation. Moreover, we demonstrate thatin vivomotor neurons also actively synthesizeTTR. Finally,in vitrocultured primary motor neurons were also found to synthesize and secreteTTRinto culture media. Thus, through a novel intranasalCNSdistribution study with an anti‐TTRNanobody, we disclose a new cell type capable of synthesizingTTR, which might be important for the understanding of the physiological role ofTTR, as well as in pathological conditions whereTTRlevels are altered inCSF, such as amyotrophic lateral sclerosis.

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Effects of water viscosity and tongue ingestion site on tongue pressure during food bolus propulsion
Authors: Iguchi T. , Ohkubo M. , Sugiyama T. , Hori K. , Ono T. , Ishida R.
Published: March 2018

The purpose of this study was to help provide data to help to implement effective rehabilitation following surgery for oral cancer by comparing tongue pressure production for water and thickened water from the anterior and posterior parts of the tongue during swallowing. Ten healthy volunteers (7 men, 3 women; age 27.6 ± 1.5 years) participated in the experiments. Tongue pressure during 3 mL water and 3 mL thickened water at the anterior and posterior tongue during swallowing was measured using a sensor sheet system with five measuring points on the hard palate. The sequential order of the points, maximal magnitude and duration of tongue pressure at each point were compared based on water viscosity and tongue ingestion site. There was a common pattern in the sequential order of tongue pressure generation among the two swallowing conditions. The maximal magnitude of tongue pressure was significantly higher when swallowing thickened water than when swallowing water at all points except for the anterior‐median and mid‐median part. Moreover, the pressure at all sites during posterior ingestions was significantly lower than that during anterior ingestion. The present results provide mean values of tongue pressure during voluntarily triggered swallowing in anterior ingestion and posterior ingestion in young, healthy dentate individuals; these values can be clinically referenced for tongue pressure measurement in the evaluation of patients with dysphagia. The use of reference values may help streamline the diagnosis, treatment and rehabilitation of dysphagia.
Randomized Controlled Clinical Trial to Compare Posterior Implant‐Supported Modified Monolithic Zirconia and Metal‐Ceramic Single Crowns: One‐Year Results
Authors: Cheng Chih‐Wen , Chien Chia‐Hui , Chen Chun‐Jung , Papaspyridakos Panos
Published: March 2018

Purpose

The purpose of this randomized controlled clinical trial was to investigate the prosthetic outcomes of posterior implant‐supported single crowns (SCs) with a modified monolithic zirconia or metal‐ceramic design at 1 year of loading.

Materials and Methods

Forty participants with 73 dental implants in need of at least 1 maxillary or mandibular posterior implant‐supported SC were consecutively selected for this study. The included participants were randomly divided into modified monolithic zirconia (MMZ) and metal‐ceramic (MC) groups. The implant‐supported SCs were examined after 1 year for survival and technical complications. Descriptive statistics were used to illustrate the data, and the association associated risks of complications were estimated using the logistic regression model with Firth's approach for rare outcome (α = 0.05).

Results

During the observation period, 2 participants in the MC group were lost to follow‐up. A total of 38 participants with 70 posterior implant‐supported SCs (36 and 34 SCs in the MMZ and MC groups respectively) completed the 1‐year follow‐up examination. One implant failed in the MMZ group. The 1‐year survival rates for implants and crowns were both 97.2% in the MMZ group. The survival rates for implants and crowns were both 100% in the MC group. One screw loosening event was observed in one screw‐retained SC in the MMZ group; however, 8 complication events occurred in 7 SCs in the MC group. Therefore, the complication‐free rates were 97.1% and 79.4% in the MMZ and MC SCs respectively. The most common complication in the MC group was screw loosening (14.7%), followed by loss of retention (5.9%), and ceramic fracture (2.9%). Significantly more technical complications were observed in the MC SCs than MMZ SCs (p = 0.0432).

Conclusion

The modified monolithic zirconia design applied to the posterior implant‐supported SCs had a significantly lower technical complication rate than did the metal‐ceramic one.
Pharmacokinetics studies of 4′-cyano-2′-deoxyguanosine, a potent inhibitor of the hepatitis B virus, in rats
Authors: Hashimoto Mai , Taguchi Kazuaki , Ishiguro Takako , Kohgo Satoru , Imoto Shuhei , Yamasaki Keishi , Mitsuya Hiroaki , Otagiri Masaki
Published: March 2018

Objectives

4′-cyano-2′-deoxyguanosine (CdG), a novel nucleoside analogue, has a high degree of antiviral activity against the chronic hepatitis B virus (HBV). The objective of this study was to develop an analytical method for quantitatively determining CdG levels in biological samples by liquid chromatography–mass spectrometry (LC/MS) and to investigate the pharmacokinetic properties of CdG in rats after intravenous and oral administration.

Methods

An analytical method using a UPLC system interfaced with a TOF-MS system was developed and validated. The pharmacokinetic properties after the intravenous and oral administration of CdG to rats were evaluated. In vivo pharmacokinetic interactions between CdG and entecavir were also investigated.

Key findings

A rapid, simple and selective method for the quantification of CdG in biological samples was established using LC/MS with solid-phase extraction. In vivo pharmacokinetic studies of CdG in rats demonstrated that CdG is highly bioavailable, is rapidly absorbed from the intestinal tract, is then distributed to the liver rather than kidney and is ultimately excreted via the urine in an unchanged form. The co-administration of CdG and entecavir led to pharmacokinetic interactions with each other.

Conclusions

The data generated in this study provide support for the clinical development of CdG for use in the treatment of HBV.
Melatonin biosynthesis enzymes recruit WRKY transcription factors to regulate melatonin accumulation and transcriptional activity on W‐box in cassava
Authors: Wei Yunxie , Liu Guoyin , Chang Yanli , Lin Daozhe , Reiter Russel J. , He Chaozu , Shi Haitao
Published: March 2018

Melatonin is widely involved in growth, development, and stress responses in plants. Although the melatonin synthesis enzymes have been identified in various plants, their interacting proteins remain unknown. Herein, overexpression of tryptophan decarboxylase 2 (MeTDC2)‐interacting proteins, N‐acetylserotonin O‐methyltransferase 2 (MeASMT2) interacting proteins, and N‐acetylserotonin O‐methyltransferase 3 (MeASMT3) in cassava leaf protoplasts resulted in more melatonin than when other enzymes were overexpressed. Through yeast two‐hybrid, 14 MeTDC2‐interacting proteins, 24 MeASMT2 interacting proteins, and 9 MeASMT3‐interacting proteins were identified. Notably, we highlighted MeWRKY20 and MeWRKY75 as common interacting proteins of the 3 enzymes, as evidenced by yeast two‐hybrid, and in vivo bimolecular fluorescence complementation (BiFC). Moreover, co‐overexpression of MeTDC2/MeASMT2/3 with MeWRKY20/75 in cassava leaf protoplasts did not only activated the transcriptional activities of MeWRKY20 and MeWRKY75 on W‐box, but also induced the effects of MeTDC2, MeASMT2/3 on endogenous melatonin levels. Taken together, 3 melatonin synthesis enzymes (MeTDC2, MeASMT2/3) interact with MeWRKY20/75 to form a protein complex in cassava. This information significantly extends the knowledge of the complex modulation of plant melatonin signaling.
The environmental neurotoxin β‐N‐methylamino‐L‐alanine inhibits melatonin synthesis in primary pinealocytes and a rat model
Authors: Pierozan Paula , Andersson Marie , Brandt Ingvar , Karlsson Oskar
Published: March 2018

The environmental neurotoxin β‐N‐methylamino‐L‐alanine (BMAA) is a glutamate receptor agonist that can induce oxidative stress and has been implicated as a possible risk factor for neurodegenerative disease. Detection of BMAA in mussels, crustaceans, and fish illustrates that the sources of human exposure to this toxin are more abundant than previously anticipated. The aim of this study was to determine uptake of BMAA in the pineal gland and subsequent effects on melatonin production in primary pinealocyte cultures and a rat model. Autoradiographic imaging of 10‐day‐old male rats revealed a high and selective uptake in the pineal gland at 30 minutes to 24 hours after 14C‐L‐BMAA administration (0.68 mg/kg). Primary pinealocyte cultures exposed to 0.05‐3 mmol/L BMAA showed a 57%‐93% decrease in melatonin synthesis in vitro. Both the metabotropic glutamate receptor 3 (mGluR3) antagonist Ly341495 and the protein kinase C (PKC) activator phorbol‐12‐myristate‐13‐acetate prevented the decrease in melatonin secretion, suggesting that BMAA inhibits melatonin synthesis by mGluR3 activation and PKC inhibition. Serum analysis revealed a 45% decrease in melatonin concentration in neonatal rats assessed 2 weeks after BMAA administration (460 mg/kg) and confirmed an inhibition of melatonin synthesis in vivo. Given that melatonin is a most important neuroprotective molecule in the brain, the etiology of BMAA‐induced neurodegeneration may include mechanisms beyond direct excitotoxicity and oxidative stress.
Structure and substrate specificity of β‐ketoacyl‐acyl carrier protein synthase III from Acinetobacter baumannii
Authors: Lee Woo Cheol , Jeong Min‐Cheol , Lee Yeongjoon , Kwak Chulhee , Lee Jee‐Young , Kim Yangmee
Published: March 2018

Originally annotated as the initiator of fatty acid synthesis (FAS), β‐ketoacyl‐acyl carrier protein synthase III (KAS III) is a unique component of the bacterial FAS system. Novel variants of KAS III have been identified that promote the de novo use of additional extracellular fatty acids by FAS. These KAS III variants prefer longer acyl‐groups, notably octanoyl‐CoA. Acinetobacter baumannii, a clinically important nosocomial pathogen, contains such a multifunctional KAS III (AbKAS III). To characterize the structural basis of its substrate specificity, we determined the crystal structures of AbKAS III in the presence of different substrates. The acyl‐group binding cavity of AbKAS III and co‐crystal structure of AbKAS III and octanoyl‐CoA confirmed that the cavity can accommodate acyl groups with longer alkyl chains. Interestingly, Cys264 formed a disulfide bond with residual CoA used in the crystallization, which distorted helices at the putative interface with acyl‐carrier proteins. The crystal structure of KAS III in the alternate conformation can also be utilized for designing novel antibiotics.
Targeted resequencing reveals genomic signatures of barley domestication
Authors: Pankin Artem , Altmüller Janine , Becker Christian , von Korff Maria
Published: March 2018

Barley (Hordeum vulgare) is an established model to study domestication of the Fertile Crescent cereals. Recent molecular data suggested that domesticated barley genomes consist of the ancestral blocks descending from multiple wild barley populations. However, the relationship between the mosaic ancestry patterns and the process of domestication itself remained unclear.

To address this knowledge gap, we identified candidate domestication genes using selection scans based on targeted resequencing of 433 wild and domesticated barley accessions. We conducted phylogenetic, population structure, and ancestry analyses to investigate the origin of the domesticated barley haplotypes separately at the neutral and candidate domestication loci.

We discovered multiple selective sweeps that occurred on all barley chromosomes during domestication in the background of several ancestral wild populations. The ancestry analyses demonstrated that, although the ancestral blocks of the domesticated barley genomes were descended from all over the Fertile Crescent, the candidate domestication loci originated specifically in its eastern and western parts.

These findings provided the first molecular evidence implicating multiple wild or protodomesticated lineages in the process of barley domestication initiated in the Levantine and Zagros clusters of the origin of agriculture.
Mapping xylem failure in disparate organs of whole plants reveals extreme resistance in olive roots
Authors: Rodriguez‐Dominguez Celia M. , Carins Murphy Madeline R. , Lucani Christopher , Brodribb Timothy J.
Published: March 2018

The capacity of plant species to resist xylem cavitation is an important determinant of resistance to drought, mortality thresholds, geographic distribution and productivity. Unravelling the role of xylem cavitation vulnerability in plant evolution and adaptation requires a clear understanding of how this key trait varies between the tissues of individuals and between individuals of species.

Here, we examine questions of variation within individuals by measuring how cavitation moves between organs of individual plants. Using multiple cameras placed simultaneously on roots, stems and leaves, we were able to record systemic xylem cavitation during drying of individual olive plants.

Unlike previous studies, we found a consistent pattern of root > stem > leaf in terms of xylem resistance to cavitation. The substantial variation in vulnerability to cavitation, evident among individuals, within individuals and within tissues of olive seedlings, was coordinated such that plants with more resistant roots also had more resistant leaves.

Preservation of root integrity means that roots can continue to supply water for the regeneration of drought‐damaged aerial tissues after post‐drought rain. Furthermore, coordinated variation in vulnerability between leaf, stem and root in olive plants suggests a strong selective pressure to maintain a fixed order of cavitation during drought.
Identification of key amino acid residues determining product specificity of 2,3‐oxidosqualene cyclase in Oryza species
Authors: Xue Zheyong , Tan Zhengwei , Huang Ancheng , Zhou Yuan , Sun Juncong , Wang Xiaoning , Thimmappa Ramesha B. , Stephenson Michael J. , Osbourn Anne , Qi Xiaoquan
Published: March 2018

Triterpene synthases, also known as 2,3‐oxidosqualene cyclases (OSCs), synthesize diverse triterpene skeletons that form the basis of an array of functionally divergent steroids and triterpenoids. Tetracyclic and pentacyclic triterpene skeletons are synthesized via protosteryl and dammarenyl cations, respectively. The mechanism of conversion between two scaffolds is not well understood.

Here, we report a promiscuous OSC from rice (Oryza sativa) (OsOS) that synthesizes a novel pentacyclic triterpene orysatinol as its main product. The OsOS gene is widely distributed in indica subspecies of cultivated rice and in wild rice accessions. Previously, we have characterized a different OSC, OsPS, a tetracyclic parkeol synthase found in japonica subspecies.

Phylogenetic and protein structural analyses identified three key amino acid residues (#732, #365, #124) amongst 46 polymorphic sites that determine functional conversion between OsPS and OsOS, specifically, the chair–semi(chair)–chair and chair–boat–chair interconversions. The different orientation of a fourth amino acid residue Y257 was shown to be important for functional conversion

The discovery of orysatinol unlocks a new path to triterpene diversity in nature. Our findings also reveal mechanistic insights into the cyclization of oxidosqualene into tetra‐ and pentacyclic skeletons, and provide a new strategy to identify key residues determining OSC specificity.
An apple NAC transcription factor enhances salt stress tolerance by modulating the ethylene response
Authors: An Jian‐Ping , Yao Ji‐Fang , Xu Rui‐Rui , You Chun‐Xiang , Wang Xiao‐Fei , Hao Yu‐Jin
Published: March 2018

It is known that ethylene signaling is involved in the regulation of the salt stress response. However, the molecular mechanism of ethylene‐regulated salt stress tolerance remains largely unclear. In this study, an apple NAM ATAF CUC transcription factor, MdNAC047, was isolated and functionally characterized to be involved in ethylene‐modulated salt tolerance. MdNAC047 gene was significantly induced by salt treatment and its overexpression conferred increased tolerance to salt stress and facilitated the release of ethylene. Quantitative real‐time‐PCR analysis demonstrated that overexpression of MdNAC047 increased the expression of ethylene‐responsive genes. Electrophoretic mobility shift assay, yeast one‐hybrid and dual‐luciferase assays suggested that MdNAC047 directly binds to the MdERF3 (ETHYLENE RESPONSE FACTOR) promoter and activates its transcription. In addition, genetic analysis assays indicated that MdNAC047 regulates ethylene production at least partially in an MdERF3‐dependent pathway. Overall, we found a novel ‘MdNAC047‐MdERF3‐ethylene‐salt tolerance’ regulatory pathway, which provide new insight into the link between ethylene and salt stress.
Pulmonary hypertension in combined pulmonary fibrosis and emphysema: A tale of two cities
Authors: Goh Nicole S.L.
Published: March 2018

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