bluuebunny/crossref_metadata_2025 huggingface dataset:
Perforation in Submucous Cleft Palate Due to Methotrexate-Induced Mucositis in a Patient With Rheumatoid Arthritis
Authors: Nam Jung Woo
Published: February 2018

Spontaneous palatal perforation can be rarely developed by several causes, such as tumor, trauma, and infection. This article reports a patient with large mid-palatal perforation after suffering from severe oral mucositis, which occurred about a month after taking methotrexate (MTX) for rheumatoid arthritis. Through computed tomography and clinical examination, this patient was diagnosed with perforation in unrecognized submucous cleft palate (SMCP) due to drug-induced mucositis. After MTX discontinuation, the oral mucositis was almost healed completely in a month, and the hole was successfully closed by palatoplasty. The author can see that the palatal perforation can occur by oral complication of MTX in SMCP patient. It is an important awareness to dentists as the use of MTX continues to increase for antirheumatic therapy.
Chemogenetic Manipulations of Ventral Tegmental Area Dopamine Neurons Reveal Multifaceted Roles in Cocaine Abuse
Authors: Mahler Stephen V , Brodnik Zachary D , Cox Brittney M , Buchta William C , Bentzley Brandon S , Cope Zackary A , Lin Edwin C , Riedy Matthew D , Scofield Michael D , Messinger Justin , Riegel Arthur C , España Rodrigo A , Aston-Jones Gary
Published: February 2018

Ventral tegmental area (VTA) dopamine (DA) neurons perform diverse functions in motivation and cognition, but their precise roles in addiction-related behaviors are still debated. Here, we targeted VTA DA neurons for bidirectional chemogenetic modulation during specific tests of cocaine reinforcement, demand, and relapse-related behaviors, querying the roles of DA neuron inhibitory and excitatory G-protein signaling in these processes. Designer receptor stimulation of Gq-, but not Gs-signaling in DA neurons enhanced cocaine seeking via functionally distinct projections to forebrain limbic regions. In contrast, engaging inhibitory Gi/o signaling in DA neurons blunted cocaine’s reinforcing and priming effects, reduced stress-potentiated reinstatement, and altered cue-induced cocaine seeking strategy, but not the motivational impact of cocaine cues per se. Results demonstrate that DA neurons play several distinct roles in cocaine seeking, depending on behavioral context, G-protein signaling, and DA neuron efferent target, highlighting their multifaceted roles in addiction.

Significance Statement

G-protein coupled receptors are crucial modulators of VTA dopamine neuron activity, but how metabotropic signaling impacts dopamine’s complex roles in reward and addiction is poorly understood. Here, we bidirectionally modulate dopamine neuron G-protein signaling with DREADDs during a variety of cocaine seeking behaviors, revealing nuanced, pathway-specific roles in cocaine reward, effortful seeking, and relapse-like behaviors. Gq- and Gs-stimulation activated dopamine neurons, but only Gq stimulation robustly enhanced cocaine seeking. Gi/o inhibitory signaling altered the response strategy employed during cued reinstatement, and reduced some, but not all types of cocaine seeking. Results show that VTA dopamine neurons modulate numerous distinct aspects of cocaine addiction- and relapse-related behaviors, and indicate potential new approaches for intervening in these processes to treat addiction.
Arabidopsis inositol phosphate kinases, IPK1 and ITPK1, constitute a metabolic pathway in maintaining phosphate homeostasis
Authors: Kuo Hui-Fen , Hsu Yu-Ying , Lin Wei-Chi , Chen Kai-Yu , Munnik Teun , Brearley Charles A. , Chiou Tzyy-Jen
Published: February 2018

Emerging studies have implicated a close link between inositol phosphate (InsP) metabolism and cellular phosphate (Pi) homeostasis in eukaryotes; however, whether a common InsPspecies is deployed as an evolutionarily conserved metabolic messenger to mediate Pisignaling remains unknown. Here, using genetics and InsPprofiling combined with Pistarvation response (PSR) analysis inArabidopsis thaliana, we showed that the kinase activity of inositol pentakisphosphate 2-kinase (IPK1), an enzyme required for phytate (inositol hexakisphosphates; InsP6) synthesis, is indispensable for maintaining Pihomeostasis under Pi-replete conditions, and inositol 1,3,4-trisphosphate 5/6-kinase 1 (ITPK1) plays an equivalent role. Although bothipk1-1anditpk1mutants exhibited decreased levels of InsP6and diphosphoinositol pentakisphosphate (PP-InsP5; InsP7), disruption of another ITPK family enzyme, ITPK4, which correspondingly caused depletion of InsP6and InsP7, did not display similar Pi-related phenotypes, which precludes these InsPspecies as effectors. Notably, the level of D/L-Ins(3,4,5,6)P4was concurrently elevated in bothipk1-1anditpk1mutants, which implies a potential role for InsP4in regulating Pihomeostasis. However, the level of D/L-Ins(3,4,5,6)P4is not responsive to Pistarvation that instead manifests a shoot-specific increase in InsP7level. This study demonstrates a more nuanced picture of intersection of InsPmetabolism and Pihomeostasis and PSR than has previously been elaborated, and additionally establishes intermediate steps to phytate biosynthesis in plant vegetative tissues.

Significance Statement

Regulation of phosphate homeostasis and adaptive responses to phosphate limitation is critical for plant growth and crop yield. Accumulating studies implicate inositol phosphates as regulators of phosphate homeostasis in eukaryotes; however, the relationship between inositol phosphate metabolism and phosphate signaling in plants remain elusive. This study dissected the step where inositol phosphate metabolism intersects with phosphate homeostasis regulation and phosphate starvation responses.
Do pneumococcal conjugate vaccines (PCVs) reduce childhood pneumonia mortality? An assessment across socioeconomic groups in Brazil
Authors: Schuck-Paim Cynthia , Taylor Robert J. , Alonso Wladimir J. , Weinberger Daniel M. , Simonsen Lone
Published: February 2018

Background

Understanding the real-world impact of pneumococcal conjugate vaccines (PCVs) on pneumonia mortality is critical, given the expectation that PCVs can substantially reduce the burden of pneumonia deaths in children under five years. However, surprisingly few post-vaccine introduction studies have estimated the benefit of PCVs for childhood mortality, and results have been inconsistent.

Methods

We investigated the long-term trends in child pneumonia mortality in Brazil (1980-present) and assessed the impact of PCV10 on childhood pneumonia mortality, both nationally and in municipalities stratified by socioeconomic status (SES), after the vaccine was introduced in Brazil in 2010.

Findings

Between 1980 and 2010, a period when Brazil’s Human Development Index (HDI) rose from 0.55 to 0.71, national pneumonia mortality in children under five decreased 10-fold. Despite rapid uptake of PCV10 following its introduction in 2010, our primary analytical method found no significant decline in national childhood pneumonia mortality, although a secondary analysis found a 10 percent decline in some but not all strata. However, at the municipal level we found significant reductions in childhood pneumonia mortality of up to 24% in low SES strata.

Interpretation

Contrary to expectations, we found that PCV use led to at best modest savings in childhood pneumonia mortality at the national level in a middle-income country. In contrast, we found evidence that PCV led to larger reductions in low-income settings; a similar benefit might occur when PCVs are introduced in other low-SES settings. The long-term findings underscore that improvements in nutrition, hygiene, education, and healthcare play a major role in reducing pneumonia mortality.

Funding

This work was funded by a grant from the Bill & Melinda Gates Foundation (OPP1114733). DMW also acknowledges support from the Bill and Melinda Gates Foundation (OPP1176267) and the National Institute of Allergy and Infectious Diseases (R01AI123208)
A Genetic Program Mediates Cold-warming Response and Promotes Stress-induced Phenoptosis in C. elegans
Authors: Jiang Wei , Wei Yuehua , Long Yong , Owen Arthur , Wang Bingying , Wu Xuebing , Luo Shuo , Dang Yongjun , Ma Dengke K.
Published: February 2018

How multicellular organisms respond to and are impacted by severe hypothermic stress is largely unknown. From C. elegans screens for mutants abnormally responding to cold-warming stimuli, we identify a molecular genetic pathway comprising ISY-1, a conserved uncharacterized protein, and ZIP-10, a bZIP-type transcription factor. ISY-1 gatekeeps the ZIP-10 transcriptional program by regulating the microRNA mir-60. Downstream of ISY-1 and mir-60, zip-10 levels rapidly and specifically increase upon transient cold-warming response. Prolonged zip-10 up-regulation induces several protease-encoding genes and promotes stress-induced organismic death, or phenoptosis, of C. elegans. zip-10 deficiency confers enhanced resistance to prolonged cold-warming stress, more prominently in adults than larvae. We conclude that the ZIP-10 genetic program mediates cold-warming response and may have evolved to promote wild population kin selection under resource-limiting and thermal stress conditions.
Sensitive periods for the effect of childhood adversity on DNA methylation: Results from a prospective, longitudinal study
Authors: Dunn Erin C. , Soare Thomas W. , Simpkin Andrew J. , Suderman Matthew J. , Zhu Yiwen , Klengel Torsten , Smith Andrew D.A.C. , Ressler Kerry , Relton Caroline L.
Published: February 2018

Background

Exposure to “early life” adversity is known to predict DNA methylation (DNAm) patterns that may be related to prolonged psychiatric risk. However, few studies have investigated whether adversity has time-dependent effects based on the age at exposure.

Methods

Using a two-stage structured life course modeling approach (SLCMA), we tested the hypothesis that there are sensitive periods when adversity induced greater DNAm changes. We tested this hypothesis in relation to two alternative explanations: an accumulation hypothesis, in which the effect of adversity on DNAm increases with the number of occasions exposed, regardless of timing, and a recency model, in which the effect of adversity is stronger for more proximal events. Data came from the Accessible Resource for Integrated Epigenomics Studies (ARIES), a subsample of mother-child pairs from the Avon Longitudinal Study of Parents and Children (ALSPAC; n=670-776).

Results

After covariate adjustment and multiple testing correction, we identified 40 CpG sites that were differentially methylated at age 7 following exposure to adversity. Most loci (n=32) were predicted by the timing of adversity, namely exposures during infancy. Neither the accumulation nor recency of the adversity explained considerable variability in DNAm. A standard EWAS of lifetime exposure (vs. no exposure) failed to detect these associations.

Conclusions

The developmental timing of adversity explains more variability in DNAm than the accumulation or recency of exposure. Infancy appears to be a sensitive period when exposure to adversity predicts differential DNAm patterns. Classification of individuals as exposed vs. unexposed to “early life” adversity may dilute observed effects.
Nicotinic cholinergic receptors in VTA glutamate neurons modulate excitatory transmission
Authors: Yan Yijin , Peng Can , Arvin Matthew C. , Jin Xiao-Tao , Kim Veronica J. , Ramsey Matthew D. , Wang Yong , Banala Sambashiva , Wokosin David L. , McIntosh J. Michael , Lavis Luke D. , Lavis Luke D. , Drenan Ryan M.
Published: February 2018

Ventral tegmental area (VTA) glutamate neurons are important components of brain reward circuitry, but whether they are subject to cholinergic modulation is unknown. To study this, we used an array of molecular, physiological, and photostimulation techniques to examine nicotinic acetylcholine receptors (nAChRs) in VTA glutamate neurons. VTA neurons positive for the vesicular glutamate transporter 2 (VGLUT2+) are responsive to acetylcholine (ACh) released from mesopontine cholinergic axons. VTA VGLUT2+ neurons express mRNA and protein subunits known to comprise typical heteromeric nAChRs. Electrophysiology, coupled with 2-photon microscopy and laser flash photolysis of a photoactivatable nicotine probe, was used to demonstrate nAChR functional activity in the somatodendritic subcellular compartment of VTA VGLUT2+ neurons. Finally, optogenetic isolation of intrinsic VTA glutamatergic microcircuits demonstrated that nicotine potently modulates excitatory transmission within the VTA. These results indicate that VTA glutamate neurons are modulated by cholinergic mechanisms and participate in the cascade of physiological responses to nicotine exposure.
The contraction in inverted repeat regions in the complete plastome sequence ofCressa creticaL
Authors: Bhatt Pritesh P. , Thaker Vrinda S.
Published: February 2018

Plastome studies have been the focus of research in plant molecular evolution and systematics.C. creticaL. (Convolvulaceae) is a halophyte, habitat in the ecologically challenged area with high salinity and drought. The complete physical map of plastome revealed that it is 141,419bp long, circular molecule. It contains typical quadripartite structure of large single copy region (LSC 94,808bp), small single copy region (SSC 32,527bp) separated by a pair of inverted repeat regions (IRs 7042bp). This plastome is compared with the complete plastomes of other members of Convolvulaceae showed notable distinctions. An exceptional shift in IRs to SC regions is experienced inC. creticaled to many genes shift in both SC regions and contraction in IRs. The size of IRs reduced to 2 to 4 times as compared to those of the Convolvulaceae members studied. The shifted IRs regions showed remarkable variation in nucleotides patterns. Further, the shift was from the IR boundaries and in between the IR regions led to segment IRs. It is concluded that the shift in IRs may be the strategic move for adaptation in the harsh environment.
Yeast heterochromatin regulators Sir2 and Sir3 act directly at euchromatic DNA replication origins
Authors: Hoggard Timothy A , Chang FuJung , Perry Kelsey Rae , Subramanian Sandya , Kenworthy Jessica , Chueng Julie , Shor Erika , Cosgrove Michael , Boeke Jef D. , Fox Catherine A , Weinreich Michael
Published: February 2018

Most active DNA replication origins are found within euchromatin, while origins within heterochromatin are often inactive or inhibited. In yeast, origin activity within heterochromatin is negatively controlled by the histone H4K16 deacetylase, Sir2, and at some heterochromatic loci also by the nucleosome binding protein, Sir3. The prevailing view has been that direct functions of Sir2 and Sir3 are confined to heterochromatin. However, growth defects in yeast mutants compromised for loading the MCM helicase, such ascdc6-4, are robustly suppressed by deletion of eitherSIR2orSIR3. While this and other observations indicate thatSIR2,3can have a negative impact on at least some euchromatic origins, the genomic scale of this effect was unknown. It was also unknown whether this suppression resulted from direct functions of Sir2,3 within euchromatin, or was an indirect effect of their previously established roles within heterochromatin. Using both MCM ChIP-Seq and MNase-H4K16ac ChIP-Seq data, we show that aSIR2deletion rescues MCM complex loading at ~80% of euchromatic origins incdc6-4cells. Therefore, Sir2 exhibits a pervasive effect at the majority of euchromatic origins. Importantly, in wild type (i.e.CDC6) cells, origin-adjacent nucleosomes were depleted for H4K16 acetylation in aSIR2-dependent manner. In addition, both Sir2 and Sir3 directly bound to nucleosomes adjacent to euchromatic origins. The relative levels of each of these molecular hallmarks of yeast heterochromatin –SIR2-dependent H4K16 hypoacetylation, Sir2, and Sir3 – correlated with how strongly aSIR2deletion suppressed the MCM loading defect incdc6-4cells. Finally, a screen for histone H3 and H4 mutants that could suppress thecdc6-4growth defect identified amino acids that map to a surface of the nucleosome important for Sir3 binding. We conclude that heterochromatin proteins directly bind euchromatic DNA replication origins and modify their local chromatin environment.
One man’s trash is another man’s treasure - the effect of bacteria on phytoplankton-zooplankton interactions in chemostat systems
Authors: Raatz M , Schälicke S , Sieber M , Wacker A , Gaedke U
Published: February 2018

Chemostat experiments are employed to study predator-prey and other trophic interactions, frequently using phytoplankton-zooplankton systems. These experiments often use population dynamics as fingerprints of ecological and evolutionary processes, assuming that the contributions of all major actors to these dynamics are known. However, bacteria are often neglected although they are frequently present. We argue that even without external carbon sources bacteria may affect the experimental outcomes depending on experimental conditions and the physiological traits of bacteria, phytoplankton and zooplankton. Using a static carbon flux model and a dynamic simulation model we predict the minimum and maximum impact of bacteria on phytoplankton-zooplankton population dynamics. Under bacteria-suppressing conditions, we find that the effect of bacteria is indeed negligible and their omission justified. Under bacteria-favouring conditions, however, bacteria may strongly affect average biomasses. Furthermore, the population dynamics may become highly complex resulting in wrong conclusions if bacteria are not considered. Our model results provide suggestions to reduce the bacterial impact experimentally. Next to optimizing experimental conditions (e.g. the dilution rate) the appropriate choice of the zooplankton predator is decisive. Counterintuitively, bacteria have a larger impact if they are not ingested by the predator as high bacterial biomasses and complex population dynamics arise via competition for nutrients with the phytoplankton. Only if the predator is at least partly bacterivorous the impact of bacteria is minimized. Our results help to improve both the design of chemostat experiments and their interpretation and thus advance the study of ecological and evolutionary processes in aquatic food webs.
Identification of changing ribosome protein compositions using cryo-EM and mass spectrometry
Authors: Sun Ming , Samir Parimal , Shen Bingxin , Li Wen , Browne Christopher M. , Rahul  , Frank Joachim , Link Andrew J.
Published: February 2018

The regulatory role of the ribosome in gene expression has come into sharper focus. It has been proposed that ribosomes are dynamic complexes capable of changing their protein composition in response to enviromental stimuli. We applied both cryo-EM and mass spectrometry to identify such changes in S. cerevisiae 80S ribosomes. Cryo-EM shows a fraction (17%) of the ribosome population in yeast growing in glucose lack the ribosomal proteins RPL10 (ul16) and RPS1A/B (eS1). Unexpectedly, this fraction rapidly increases to 34% after the yeast are switched to growth in glycerol. Using quantitative mass spectrometry, we found that the paralog yeast ribosomal proteins RPL8A (eL8A) and RPL8B (eL8B) change their relative proportions in the 80S ribosome when yeast are switched from growth in glucose to glycerol. Using yeast genetics and polysome profiling, we show that yeast ribosomes containing either RPL8A or RPL8B are not functionally interchangeable. Our combined cryo-EM and quantitative proteomic data support the hypothesis that ribosomes are dynamic complexes that alter their composition and functional activity in response to changes in growth or environmental conditions.
Hypoarousal non-stationary ADHD biomarker based on echo-state networks
Authors: Ibanez-Soria D. , Soria-Frisch A. , Garcia-Ojalvo J. , Picardo Jacobo , García-Banda Gloria , Servera Mateu , Ruffini Giulio
Published: February 2018

Attention-Deficit Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity and impulsivity. It is one of the most commonly diagnosed neurodevelopmental and psychiatric disorders of childhood and therefore presents a very high prevalence rate. However the high rate of ADHD misdiagnosis makes the discovery of neurophysiological ADHD biomarkers an important clinical challenge. This study proposes a novel non-stationary ADHD biomarker based on Echo State Networks to quantify EEG dynamical changes between low attention/arousal states (resting with eyes closed, or EC) and normal attention/arousal states (resting with eyes open, or EO). Traditionally, EEG biomarkers have revealed an increase in stationary power in the theta band along with a decrease in beta, with these frequencies largely accepted to be altered in the ADHD population. We successfully verify the hypothesis that measured differences between these two conditions are altered in the ADHD population. Statistically significant differences between a group of ADHD subjects and an aged-matched control population were obtained in theta and beta rhythms. Our network discriminates between EO/EC EEG regimes in the ADHDs better than in controls, suggesting that differences in EEG patterns between low and normal arousal/attention states are larger in the ADHD population.
Sex-specific additive genetic variances and correlations for fitness in a song sparrow (Melospiza melodia) population subject to natural immigration and inbreeding
Authors: Wolak Matthew E. , Arcese Peter , Keller Lukas F. , Nietlisbach Pirmin , Reid Jane M.
Published: February 2018

Quantifying sex-specific additive genetic variance (VA) in fitness, and the cross-sex genetic correlation (rA), is pre-requisite to predicting evolutionary dynamics and the magnitude of sexual conflict. Quantifying VAand rAin underlying fitness components, and multiple genetic consequences of immigration and resulting gene flow, is required to identify mechanisms that maintain VAin fitness. However, these key parameters have rarely been estimated in wild populations experiencing natural environmental variation and immigration. We used comprehensive pedigree and life-history data from song sparrows (Melospiza melodia) to estimate VAand rAin sex-specific fitness and underlying fitness components, and to estimate additive genetic effects of immigrants as well as inbreeding depression. We found substantial VAin female and male fitness, with a moderate positive cross-sex rA. There was also substantial VAin adult reproductive success in males but not females, and moderate VAin juvenile survival but not adult survival. Immigrants introduced alleles for which additive genetic effects on local fitness were negative, potentially reducing population mean fitness through migration load, yet alleviating expression of inbreeding depression. Substantial VAfor fitness can consequently be maintained in the wild, and be concordant between the sexes despite marked sex-specific VAin reproductive success.
Linking international experience and cultural intelligence development
Authors: Michailova Snejina , Ott Dana L.
Published: February 2018

Purpose

The purpose of this paper is to critically examine the literature on the relationship between international experience (IE) and cultural intelligence (CQ) development, and advocate for the utilization of theory to explain this relationship.

Design/methodology/approach

On the basis of the premise that CQ can be developed through IE, the authors review existing empirical research in regards to this relationship. The authors conducted a search of the main business, education, and psychology databases for articles published from 2003, the year when the CQ construct was introduced, through 2017. The search focused on studies where CQ was tested as a dependent variable or as a mediator between IE and a dependent variable, and resulted in 15 empirical articles and three book chapters.

Findings

A critical analysis of the relationship between IE and CQ reveals considerable variation and inconsistencies among findings within the extant empirical literature. The authors argue that this is mainly because most studies fail to apply a theory to explain the link between these two constructs. The authors draw from social learning theory (SLT) to illustrate how it can be utilized to detail the relationship between IE and CQ development. The authors also suggest how future research can advance the understanding of this relationship, and outline the implications of such examinations for practice.

Originality/value

While substantive knowledge has been generated to understand CQ as an antecedent, the authors investigate CQ development as the dependent variable. The critical review of this literature identifies a specific weakness within previous research and the authors offer a way to resolve it. SLT, which views learning as being affected by both observation and experience, and includes attention, retention, and participative reproduction, is one potentially powerful tool that can explain why and how IE can lead to CQ development. This is a far more fine- grained and detailed approach to understanding and explaining the relationship between the two constructs than provided by previous studies.
A Bayesian Nonparametric Approach to Causal Inference on Quantiles
Authors: Xu Dandan , Daniels Michael J. , Winterstein Almut G.
Published: February 2018

We propose a Bayesian nonparametric approach (BNP) for causal inference on quantiles in the presence of many confounders. In particular, we define relevant causal quantities and specify BNP models to avoid bias from restrictive parametric assumptions. We first use Bayesian additive regression trees (BART) to model the propensity score and then construct the distribution of potential outcomes given the propensity score using a Dirichlet process mixture (DPM) of normals model. We thoroughly evaluate the operating characteristics of our approach and compare it to Bayesian and frequentist competitors. We use our approach to answer an important clinical question involving acute kidney injury using electronic health records.
Frequency of unsatisfactory cervical cytology smears in cancer screening of Japanese women: A systematic review and meta‐analysis
Authors: Hosono Satoyo , Terasawa Teruhiko , Katayama Takafumi , Sasaki Seiju , Hoshi Keika , Hamashima Chisato
Published: February 2018

The Bethesda system (TBS) has been used for cervical cytological diagnosis in Japan since 2008. Evaluation of specimen adequacy is the most important aspect of quality assurance and for precise diagnosis in TBS. A systematic review and meta‐analysis were carried out to assess the unsatisfactory specimen rate in the primary cervical cancer screening setting in Japan. Ovid Medline and Ichushi‐Web databases were searched from inception through to May 2017. Prospective and retrospective studies that reported the proportion of unsatisfactory specimens in healthy asymptomatic Japanese women in a cervical cancer screening program were eligible for inclusion; 17 studies were included in the meta‐analysis. The random‐effects model meta‐analysis calculated summary estimates of the unsatisfactory rate of 0.60% (95% confidence interval [CI], 0.18‐1.96%; I2 = 99%) for conventional cytology and 0.04% (95% CI, 0.00‐0.35%; I2 = 99%) for liquid‐based cytology (LBC). However, comparative results between conventional and liquid‐based cytology, based on four direct and nine comparative studies, showed no significant difference (summary odds ratio = 3.5 × 10−2 favoring LBC [95% CI, 6.9 × 10−4‐1.7]; I2 = 98%). In the subgroup analyses and meta‐regressions, use of non‐cotton devices for conventional cytology and use of a particular platform for LBC were associated with lower unsatisfactory rates. Meta‐regression also suggested chronological improvement in unsatisfactory rates for both tests. In Japanese cervical cancer screening programs, conventional cytology remains prevalent. Future research needs to focus on evaluating the impact of screening programs using LBC by comparing the accuracy, performance, and cost‐effectiveness with conventional cytology in the Japanese population.
Long non‐coding RNA RP11‐552M11.4 promotes cells proliferation, migration and invasion by targeting BRCA2 in ovarian cancer
Authors: Huang Kejin , Geng Jiashi , Wang Jing
Published: February 2018

The present study aimed to investigate the effect of long non‐coding RNA (lncRNA) RP11‐552M11.4 on cell proliferation, apoptosis, migration and invasion as well as its targeting genes in epithelial ovarian cancer (EOC) cells. LncRNA RP11‐552M11.4 expression was detected in 67 tumor tissues and paired adjacent tissues obtained from EOC patients. lncRNA RP11‐552M11.4 mimic/inhibitor plasmids were transferred into ovarian cancer cells (SKOV3, A‐2780) and normal ovarian epithelial cells (IOSE80 cells). In addition, rescue experiment was carried out by transferring BRCA2 inhibitor&lncRNA RP11‐552M11.4 inhibitor plasmids into SKOV3 and A‐2780 cells. qPCR, western blot, CKK‐8, Annexin V/propidium iodide (AV/PI), wound‐healing and Matrigel invasion assays were carried out to detect RNA expression, protein expression, cell proliferation, apoptosis, migration, and invasion, respectively. LncRNA RP11‐552M11.4 expression was elevated in tumor tissues compared with paired adjacent tissues and correlated with higher pathological grade, International Federation of Gynecology and Obstetrics stage and worse overall survival in EOC patients. LncRNA RP11‐552M11.4 promoted SKOV3 cell proliferation, migration and invasion whereas it inhibited apoptosis. Rescue experiment and luciferase reporter assay showed that lncRNA RP11‐552M11.4 regulated SKOV3 cells functions through binding BRCA2. Further experiments in A‐2780 cells also validated that lncRNA RP11‐552M11.4 induced A‐2780 cell proliferation while repressing apoptosis by targeting BRCA2. In addition, upregulation of lncRNA RP11‐552M11.4 increased IOSE80 cell proliferation, migration and invasion while decreasing apoptosis. In conclusion, lncRNA RP11‐552M11.4 correlates with worse prognosis, and promotes cell proliferation, migration, invasion, and inhibits cell apoptosis by down‐regulating BRCA2 in EOC.
Both sarcopenia and frailty determine suitability of patients for liver transplantation—A systematic review and meta‐analysis of the literature
Authors: Kahn Judith , Wagner Doris , Homfeld Nicole , Müller Helmut , Kniepeiss Daniela , Schemmer Peter
Published: February 2018

Liver grafts are allocated based on both urgency and utility. Due to a tremendous shortage of suitable organs for liver transplantation (LT), a careful selection of suitable recipients is of utmost importance. While the sickest first principle for organ allocation based on MELD score goes along with poor utility, other parameters reflecting the general health condition like frailty and sarcopenia might be essential to detect suitable patients for the waiting list. Thus, this study was designed to evaluate both frailty and sarcopenia in LT. A systematic review of the literature on sarcopenia and frailty measurements in liver transplant recipients was performed. Thirteen of 238 studies were selected for full paper review. Six of the studies investigating the impact of frailty on waitlist mortality were subjected to a meta‐analysis. Despite the different methodologies to assess sarcopenia, reports showed that sarcopenia was highly related to waitlist mortality with a sum of all that highly favored negative outcome in case of sarcopenia. The existing literature clearly underlines that frailty and sarcopenia are important to determine in LT candidates. One unique index for transplant candidates reflecting frailty should be developed and be used as a standard in all transplant centers to facilitate comparability.
Impact of early reoperation on graft survival after liver transplantation: Univariate and multivariate analysis
Authors: Elsabbagh Ahmed M. , Girlanda Raffaele , Hawksworth Jason , Pichert Matthew D. , Williams Cassie , Pozzi Agostino , Kroemer Alexander , Nookala Anupama , Smith Coleman , Matsumoto Cal S. , Fishbein Thomas M.
Published: February 2018

Background

Data on rate, risk factors, and consequences of early reoperation after liver transplantation are still limited.

Study design

Single‐center retrospective analysis of data of 428 patients, who underwent liver transplantation in period between January 2009 and December 2014. Univariate and multivariate analysis were used to study the risk factors of early reoperation and its impact on graft survival.

Results

Of 428 patients, 74 (17.3%) underwent early reoperation. Of them, 46 (62.2%) underwent reoperation within the first week and 28 (37.8%) underwent reoperation later than 1 week after transplantation. With multivariate analysis, significant risk factors of early reoperation included pretransplant ICU admission, previous abdominal surgery and diabetes. Early reoperation itself was not found to be an independent predictor of graft loss. However, early reoperation later than 7 days from transplant was found to be independent predictor of graft loss (odds ratio [OR] = 5.125; 95% CI, 1.358‐19.552; P = .016). In our series, other independent predictors of graft loss were MELD score (P = .010) and operative time (P = .048).

Conclusions

This analysis demonstrates that early reoperations later than a week appear to negatively impact the graft survival. The timing of early reoperation should be a focus of additional studies.
Use of glucagon‐like peptide‐1 receptor agonists among individuals on basal insulin requiring treatment intensification
Authors: Trautmann M. E. , Vora J.
Published: February 2018

As Type 2 diabetes progresses, treatment is intensified with additional therapies in an effort to manage hyperglycaemia effectively and therefore avoid complications. When greater efficacy is required, options for injectable treatments include glucagon‐like peptide‐1 receptor agonists and insulin, which may be added on to oral glucose‐lowering treatments. Among individuals receiving long‐acting basal insulin as their first injectable treatment, ~40−60% are unable to achieve or maintain their target HbA1c goals. For these people, treatment intensification options are relatively limited and include the addition of short‐acting prandial insulin or a glucagon‐like peptide‐1 receptor agonist. Glucagon‐like peptide‐1 receptor agonists vary in their effects, with short‐ and long‐acting agents having a greater impact on postprandial and fasting hyperglycaemia, respectively. Studies comparing treatment intensification options have found both glucagon‐like peptide‐1 receptor agonists and prandial insulin to be effective in reducing HbA1c concentrations; however, recipients of glucagon‐like peptide‐1 receptor agonists lost weight and had a greater frequency of gastrointestinal adverse events, whereas those receiving prandial insulin gained weight and had a greater incidence of hypoglycaemia. In addition to the separate administration of a glucagon‐like peptide‐1 receptor agonist and basal insulin, fixed‐ratio combinations of a glucagon‐like peptide‐1 receptor agonist and basal insulin offer a single administration for both treatments but have less flexibility in dose titration than treatment with their individual components. For individuals who require treatment intensification beyond basal insulin, use of these various options allows physicians to target the individual needs of their patients for the achievement of optimal long‐term glycaemic control.
Setting the top 10 research priorities to improve the health of people with Type 2 diabetes: a Diabetes UK–James Lind Alliance Priority Setting Partnership
Authors: Finer S. , Robb P. , Cowan K. , Daly A. , Shah K. , Farmer A.
Published: February 2018

Aims

To describe processes and outcomes of a priority setting partnership to identify the ‘top 10 research priorities’ in Type 2 diabetes, involving people living with the condition, their carers, and healthcare professionals.

Methods

We followed the four‐step James Lind Alliance Priority Setting Partnership process which involved: gathering uncertainties using a questionnaire survey distributed to 70 000 people living with Type 2 diabetes and their carers, and healthcare professionals; organizing the uncertainties; interim priority setting by resampling of participants with a second survey; and final priority setting in an independent group of participants, using the nominal group technique. At each step the steering group closely monitored and guided the process.

Results

In the first survey, 8227 uncertainties were proposed by 2587 participants, of whom 18% were from black, Asian and minority ethnic groups. Uncertainties were formatted and collated into 114 indicative questions. A total of 1506 people contributed to a second survey, generating a shortlist of 24 questions equally weighted to the contributions of people living with diabetes and their carers and those of healthcare professionals. In the final step the ‘top 10 research priorities’ were selected, including questions on cure and reversal, risk identification and prevention, and self‐management approaches in Type 2 diabetes.

Conclusion

Systematic and transparent methodology was used to identify research priorities in a large and genuine partnership of people with lived and professional experience of Type 2 diabetes. The top 10 questions represent consensus areas of research priority to guide future research, deliver responsive and strategic allocation of research resources, and improve the future health and well‐being of people living with, and at risk of, Type 2 diabetes.
Migrant CEOs: Barriers and Strategies on the Way to the Top
Authors: Legrand Celine , Al Ariss Akram , Bozionelos Nikos
Published: February 2018

This study discusses the main barriers that qualified migrants face in their route towards becoming chief executive officers (CEOs) along with the strategies they employ in their quest to reach the top. The study was conducted in France, a leading economic power with a long history of migration. A relational analytic framework was adopted, where in‐depth interviews with migrant CEOs were triangulated with accounts from native CEOs, organizational leaders, and institutional actors. It emerged that meso‐ and macro‐level factors created powerful barriers to advancement, while migrant CEOs tended to deploy four career strategies, two of them reactive – adaptation/adjustment and overcompensation – and the other two proactive – differentiation and manoeuvring. In addition, substantial differences were identified in the accounts of migrant CEOs and the other participants as to the existence of barriers and awareness of these by organizational actors.
Factors associated with equine shedding of multi‐drug‐resistantSalmonella entericaand its impact on health outcomes
Authors: Burgess B. A. , Bauknecht K. , Slovis N. M. , Morley P. S.
Published: February 2018

Background

Salmonella entericais an important cause of healthcare‐associated infections in veterinary hospitals – with outbreaks of multi‐drug resistant (MDR)Salmonellaamong equine cases resulting in high case fatality rates and substantial financial cost.

Objectives

Study objectives were to 1) investigate factors associated with shedding ofMDR‐Salmonella entericaand 2) evaluate the effect shedding may have on health outcomes of previously hospitalised horses and their stablemates.

Study design

Retrospective case–control study with prospective cohort study.

Methods

Analysis of medical records (N = 373; 94 culture positive, 279 culture negative) was undertaken to determine factors associated with shedding ofMDR‐Salmonella. Additionally, a follow‐up study was conducted to assess long‐term outcomes associated with shedding among previously hospitalised horses and their stablemates. Data regarding exposures of interest were collected retrospectively from medical records. Information on long‐term outcomes was obtained by phone interview of owners. Multivariable regression techniques were used to investigate factors associated with shedding and subsequent health outcomes.

Results

Horses experiencing diarrhoea during hospitalisation were more likely to shedSalmonella(OR1.88; 95%CI1.02, 3.45) compared with horses without diarrhoea, but isolates tended to be susceptible strains. Antimicrobial therapy during hospitalisation was not associated with shedding or recovery ofMDRstrains. Shedding did not increase long‐term risk for non‐survival, colic or abnormal faeces after hospital discharge; nor increase risk for hospitalisation or occurrence of abnormal faeces in stablemates.

Main limitations

Data collection was reliant upon the quality of medical records and owner recall, which may have led to information bias. The study population was derived from central Kentucky and may differ from horse populations in other regions.

Conclusions and clinical importance

In general,Salmonellashedding was not associated with decreased average survival times or impacts to health of stablemates, perhaps due to owner implemented biosecurity precautions. Regardless, recently hospitalised horses should be segregated after discharge, in addition to employing rigorous hygiene practices.

The Summary is available in Spanish – seeSupporting Information.
Blood vessel occlusion with erythrocyte aggregates causes burn injury progression—microvasculature dilation as a possible therapy
Authors: Clark Richard A. F. , Fenner Justine , Sasson Arielle , McClain Steve A. , Singer Adam J. , Tonnesen Marcia G.
Published: February 2018

Burns are dynamic injuries characterized by progressive tissue death and continuous severe pain over the course of several days. The extent of burn injury progression determines the ultimate patient outcome. Initial burns result in a central zone of necrosis surrounded by a potentially viable zone of ischemia. Several mechanisms have been proposed to explain injury progression, including oxidant and cytokine stress resulting from either ischemia/reperfusion and/or inflammation, but no proven therapy has emerged. To address the unmet need to limit burn injury progression, the root cause of this process must be delineated. For this reason, we have recently focused on post‐burn blood vessel occlusion, currently ascribed to microthrombi. We have found that blood vessel occlusion is initially, mainly and persistently caused by erythrocyte aggregation. Although thermal‐induced cell necrosis is the immediate cause of cell death, apoptotic cells from persistent ischemia/anoxia, admixed with inflammatory cells, form a band between viable and nonviable tissue 24 hours later. The delayed cell death by apoptosis appears to be the main attractant for inflammatory cells. Finally, we posit that fibrinogen elevation arising from inflammation provides stimulus for additional erythrocyte aggregation, further extending blood vessel occlusion. In our view this persistent occlusion with resultant prolonged tissue ischemia/anoxia, not ischemia/reperfusion, is the root cause of burn injury progression concomitant with associated severe and persistent pain. Epiviosamines, a new class of peptides, appear to selectively dilate microvasculature, and may provide therapy for burn injury progression.
Impact of the access tunnel engineering on catalysis is strictly ligand‐specific
Authors: Kaushik Shubhangi , Marques Sérgio M. , Khirsariya Prashant , Paruch Kamil , Libichova Lenka , Brezovsky Jan , Prokop Zbynek , Chaloupkova Radka , Damborsky Jiri
Published: February 2018

The traditional way of rationally engineering enzymes to change their biocatalytic properties utilizes the modifications of their active sites. Another emerging approach is the engineering of structural features involved in the exchange of ligands between buried active sites and the surrounding solvent. However, surprisingly little is known about the effects of mutations that alter the access tunnels on the enzymes’ catalytic properties, and how these tunnels should be redesigned to allow fast passage of cognate substrates and products. Thus, we have systematically studied the effects of single‐point mutations in a tunnel‐lining residue of a haloalkane dehalogenase on the binding kinetics and catalytic conversion of both linear and branched haloalkanes. The hotspot residue Y176 was identified using computer simulations and randomized through saturation mutagenesis, and the resulting variants were screened for shifts in binding rates. Strikingly, opposite effects of the substituted residues on the catalytic efficiency toward linear and branched substrates were observed, which was found to be due to substrate‐specific requirements in the critical steps of the respective catalytic cycles. We conclude that not only the catalytic sites, but also the access pathways must be tailored specifically for each individual ligand, which is a new paradigm in protein engineering and de novo protein design. A rational approach is proposed here to address more effectively the task of designing ligand‐specific tunnels using computational tools.
Precarity is a Feminist Issue: Gender and Contingent Labor in the Academy
Authors: Zheng Robin
Published: February 2018

Feminist philosophers have challenged a wide range of gender injustices in professional philosophy. However, the problem of precarity, that is, the increasing numbers of contingent faculty who cannot find permanent employment, has received scarcely any attention. What explains this oversight? In this article, I argue, first, that academics are held in the grips of an ideology that diverts attention away from the structural conditions of precarity, and second, that the gendered dimensions of such an ideology have been overlooked. To do so, I identify two myths: the myth of meritocracy and the myth of work as its own reward. I demonstrate that these myths—and the two‐tier system itself—manifest an unmistakably gendered logic, such that gender and precarity are mutually reinforcing and co‐constitutive. I conclude that feminist philosophers have particular reason to organize against the casualization of academic work.
Prevalence of vertical root fractures in teeth planned for apical surgery. A retrospective cohort study
Authors: Maddalone M. , Gagliani M. , Citterio C. L. , Karanxha L. , Pellegatta A. , Del Fabbro M.
Published: February 2018

Aim

To evaluate retrospectively the prevalence of vertical root fractures (VRFs) in a cohort of patients during apical surgery and the factors possibly associated with VRF.

Methodology

The sample consisted of 944 root filled teeth belonging to 768 patients (49.3% males and 50.7% females; mean age 43.5 ± 11.2 years, range 22–68 years), consecutively referred for endodontic surgery over a six‐year period. All patients underwent a clinical assessment of their signs and symptoms. Periapical radiographs of teeth that were candidates for endodontic surgery were taken. Sixty‐eight teeth with VRF were identified. Vertical root fractures were identified in pre‐surgical screenings in 32 cases (47.1%), and these did not undergo surgery. Another 36 cases of VRF were noted during the intervention for root‐end resection. The influence of posts, post type, tooth type, periodontal probing defects, spontaneous pain, sinus tract and follow‐up duration was assessed using a logistic regression analysis.

Results

Vertical root fractures occurred significantly more frequently (P < 0.001) when a post was present (61 VRF out of 377 teeth with post, prevalence 16.2%) than in teeth without a post (1.2%). Threaded posts and cast posts were significantly more involved in VRF than fibre, silica or carbide posts (P < 0.001). Most fractures (80.9%) occurred 1–5 years after root canal treatment. Sinus tracts, probing defects and spontaneous pain were significantly more associated with VRF cases than with nonfractured teeth.

Conclusions

In the present group of teeth, the major risk for VRF was represented by posts retained by actively engaging the canal via mechanical design (thread) or by frictional fit (cast).