bluuebunny/crossref_metadata_2025 huggingface dataset:
Current interventions to promote safe and appropriate pain management
Authors: Jones Laney K , Lussier Mia E , Brar Jasmit , Byrne Mary C , Durham Melissa , Kiokemeister Fleurette , Kjaer Klaus , Le Huy , Magee Chelsea , McKnight Erin , Mehta Neel , Papp Joan , Pastwa Elzbieta , Radovich Patti , Ravin Kristopher , Ruther Michelle , Woodie Gloriana , Wrona Sharon , Yousefvand Gholamreza , Greskovic Gerard
Published: May 2019

Purpose

Describe patient-, clinician-, system-, and community-level interventions for pain management developed and employed by 9 healthcare systems across the United States and report on lessons learned from the implementation of these interventions.

The high cost associated with pain coupled with the frequent use of opioid analgesics as primary treatment options has made novel pain management strategies a necessity. Interventions that target multiple levels within healthcare are needed to help combat the opioid epidemic and improve strategies to manage chronic pain. Patient-level interventions implemented ranged from traditional paper-based educational tools to videos, digital applications, and peer networks. Clinician-level interventions focused on providing education, ensuring proper follow-up care, and establishing multidisciplinary teams that included prescribers, pharmacists, nurses, and other healthcare professionals. System- and community-level interventions included metric tracking and analytics, electronic health record tools, lockbox distribution for safe storage, medication return bins for removal of opioids, risk assessment tool utilization, and improved access to reversal agents.

Conclusion

Strategies to better manage pain can be implemented within health systems at multiple levels and on many fronts; however, these changes are most effective when accepted and widely used by the population for which they are targeted.
Prediction of survival risks with adjusted gene expression through risk-gene networks
Authors: Lee Minhyeok , Han Sung Won , Seok Junhee
Published: May 2019

Motivation

Network-based analysis of biomedical data has been extensively studied over the last decades. As a successful application, gene networks have been used to illustrate interactions among genes and explain the associated phenotypes. However, the gene network approaches have not been actively applied for survival analysis, which is one of the main interests of biomedical research. In addition, a few previous studies using gene networks for survival analysis construct networks mainly from prior knowledge, such as pathways, regulations and gene sets, while the performance considerably depends on the selection of prior knowledge.

Results

In this paper, we propose a data-driven construction method for survival risk-gene networks as well as a survival risk prediction method using the network structure. The proposed method constructs risk-gene networks with survival-associated genes using penalized regression. Then, gene expression indices are hierarchically adjusted through the networks to reduce the variance intrinsic in datasets. By illustrating risk-gene structure, the proposed method is expected to provide an intuition for the relationship between genes and survival risks. The risk-gene network is applied to a low grade glioma dataset, and produces a hypothesis of the relationship between genetic biomarkers of low and high grade glioma. Moreover, with multiple datasets, we demonstrate that the proposed method shows superior prediction performance compared to other conventional methods.

Availability and implementation

The R package of risk-gene networks is freely available in the web at http://cdal.korea.ac.kr/NetDA/.

Supplementary information

Supplementary data are available at Bioinformatics online.
TPES: tumor purity estimation from SNVs
Authors: Locallo Alessio , Prandi Davide , Fedrizzi Tarcisio , Demichelis Francesca
Published: May 2019

Motivation

Tumor purity (TP) is the proportion of cancer cells in a tumor sample. TP impacts on the accurate assessment of molecular and genomics features as assayed with NGS approaches. State-of-the-art tools mainly rely on somatic copy-number alterations (SCNA) to quantify TP and therefore fail when a tumor genome is nearly euploid, i.e. ‘non-aberrant’ in terms of identifiable SCNAs.

Results

We introduce a computational method, tumor purity estimation from single-nucleotide variants (SNVs), which derives TP from the allelic fraction distribution of SNVs. On more than 7800 whole-exome sequencing data of TCGA tumor samples, it showed high concordance with a range of TP tools (Spearman’s correlation between 0.68 and 0.82; >9 SNVs) and rescued TP estimates of 1, 194 samples (15%) pan-cancer.

Availability and implementation

TPES is available as an R package on CRAN and at https://bitbucket.org/l0ka/tpes.git.

Supplementary information

Supplementary data are available at Bioinformatics online.
Profiles of prostaglandin F2α metabolite in dairy cattle during luteal regression and pregnancy: implications for corpus luteum maintenance†
Authors: Mezera Megan A , Hamm Caleb S , Gamarra Caio A , Gennari Rodrigo S , Prata Alexandre B , Sartori Roberto , Wiltbank Milo C
Published: May 2019

Mechanisms of bovine corpus luteum (CL) maintenance during the second month of pregnancy have not been adequately investigated, despite significant reproductive losses. In the first month, interferon-tau is believed to suppress oxytocin-stimulated prostaglandin F2α (PGF) production, yet there are conflicting reports of circulating PGF metabolite (PGFM). In this study, characterization of PGFM and P4 occurred through continuous bihourly blood sampling in cows undergoing CL regression (day 18–21, n = 5), and during the first (day 18–21, n = 5) and second month (day 47–61; n = 16) of pregnancy. Cattle in the second month were assigned to control (n = 8) or oxytocin treatment (n = 8; three pulses to mimic luteolysis) to evaluate if oxytocin receptors were active. All cows but one (which had elevated PGFM prior to oxytocin treatment) maintained the pregnancy. Basal PGFM concentrations were low (11.6 ± 0.7 pg/mL) in the first month but increased 2.54-fold in the second month. Few (0.26 ± 0.12 pulses/day) PGFM pulses with low peak concentrations (28.8 ± 3.1 pg/mL) were observed during the first month of pregnancy, similar to cows not undergoing regression. However, in the second month, frequency (1.10 ± 0.26 pulses/day) and peak concentration (67.2 ± 5.0 pg/mL) of PGFM pulses increased, displaying similar frequency but lower peak PGFM than seen in regression (1.44 ± 0.14 pulses/day; 134.5 ± 18.9 pg/mL). Oxytocin treatment increased likelihood of PGFM pulses post-treatment and increased peak concentration (89.7 ± 10.1 pg/mL) in cows during the second month. Thus, cows have more PGFM pulses during second than first month of pregnancy, possibly induced by endogenous oxytocin, indicating suppression of PGF production is an important mechanism for CL maintenance during first but not second month of pregnancy.
Long-Term Test–Retest Reliability of the UPSIT in Cognitively Intact Older Adults
Authors: Devanand Davangere P , Liu Xinhua , Cohen Hannah , Budrow John , Schupf Nicole , Manly Jennifer , Lee Seonjoo
Published: May 2019

The objective of this study was to determine the long-term test–retest reliability of the University of Pennsylvania Smell Identification Test (UPSIT), and its individual items, in cognitively intact older adults. A community sample of older adults received a neuropsychological test battery, including the 12-item, 6-trial Selective Reminding Test (SRT). The UPSIT was administered at baseline and follow-up that occurred between 1 and 4 years after baseline. UPSIT scores of participants who were cognitively intact and did not decline cognitively were examined for test–retest reliability. In 92 older adults with mean age 77.6 years followed for 2.79 (standard deviation [SD] 0.69) years, mean UPSIT score declined from 30.29 (SD 5.83) to 27.80 (SD 5.50). In linear mixed models that adjusted for time, age, sex, and education, intraclass correlation coefficients for UPSIT were 0.65, SRT delayed recall 0.59, and SRT total immediate recall 0.49. Among 4 possible response combinations, the largest proportion of participants had correct responses at both visits for 35 out of 40 items. Consistency of item responses ranged from 50% to 90% across the 2 time points. The long-term test–retest reliability of the UPSIT was moderately strong without practice effects over long periods of time in older adults. These results provide indirect support to prior findings on odor identification impairment predicting cognitive decline and dementia, and suggest potential use of olfactory testing as a biomarker in prevention and treatment trials of cognitive enhancers.
Mr.Vc: a database of microarray and RNA-seq of Vibrio cholerae
Authors: Zhang Zhiyuan , Chen Guozhong , Hu Jun , Hussain Wajid , Fan Fenxia , Yang Yalin , Zhou Zhigang , Fang Xiaodong , Zhu Jun , Chen Wei-Hua , Liu Zhi
Published: May 2019

Gram-negative bacterium Vibrio cholerae is the causative agent of cholera, a life-threatening diarrheal disease. During its infectious cycle, V. cholerae routinely switches niches between aquatic environment and host gastrointestinal tract, in which V. cholerae modulates its transcriptome pattern accordingly for better survival and proliferation. A comprehensive resource for V. cholerae transcriptome will be helpful for cholera research, including prevention, diagnosis and intervention strategies. In this study, we constructed a microarray and RNA-seq database of V. cholerae (Mr.Vc), containing gene transcriptional expression data of 145 experimental conditions of V. cholerae from various sources, covering 25 937 entries of differentially expressed genes. In addition, we collected relevant information including gene annotation, operons they may belong to and possible interaction partners of their protein products. With Mr.Vc, users can easily find transcriptome data they are interested in, such as the experimental conditions in which a gene of interest was differentially expressed in, or all genes that were differentially expressed in an experimental condition. We believe that Mr.Vc database is a comprehensive data repository dedicated to V. cholerae and could be a useful resource for all researchers in related fields. Mr.Vc is available for free at http://bioinfo.life.hust.edu.cn/mrvc.
Assessment of Alternative Candidate Subcortical Insect Vectors From Walnut Crowns in Habitats Quarantined for Thousand Cankers Disease
Authors: Chahal Karandeep , Gazis Romina , Klingeman William , Hadziabdic Denita , Lambdin Paris , Grant Jerome , Windham Mark
Published: May 2019

Thousand cankers disease (TCD) results from the combined activity of the fungal pathogen, Geosmithia morbida Kolařík, Freeland, Utley, and Tisserat and its principle vector, Pityophthorus juglandis (Blackman) (Coleoptera: Curculionidae: Scolytinae) in Juglans L. spp. and Pterocarya Kunth spp. host plants. TCD has been reported from the eastern and western United States. To evaluate potential for other beetle species to vector the fungus in east Tennessee, specimens were collected using ethanol-baited traps that were suspended beneath crowns of TCD-symptomatic trees. Associations of G. morbida with insect species collected in traps were assessed in an unsuccessful, preliminary culture-based fungal assay, and then with a molecular-based detection method. For culture-based assays, rinsate from washed, individual insects was plated on nutrient media and growing colonies were subcultured to obtain axenic G. morbida cultures for identification. For the molecular-based method, G. morbida presence was detected by amplifying the previously developed, species-specific microsatellite locus GS004. Capillary electrophoresis was used to detect the amplified amplicons and representative reactions were validated using Sanger sequencing. Eleven beetle species were found to carry G. morbida, including Cnestus mutilatus (Blandford), Dryoxylon onoharaensum (Murayama), Hylocurus rudis (LeConte), Monarthrum fasciatum (Say), Monarthrum mali (Fitch), Xyleborinus saxesenii (Ratzeburg), Xylosandrus crassiusculus (Motschulsky), Xylosandrus germanus (Blandford) (all Coleoptera: Curculionidae: Scolytinae), Stenomimus pallidus (Boheman) (Coleoptera: Curculionidae: Cossoninae), Oxoplatypus quadridentatus (Olivier) (Coleoptera: Curculionidae: Platypodinae), and Xylops basilaris (Say) (Coleoptera: Bostrichidae). These findings raise concerns that alternative subcortical insect species that already occur within quarantined habitats can sustain incidence of introduced G. morbida and contribute to spread within the native range of black walnut, Juglans nigra L., in the eastern United States.
English as an international language beyond the ELT classroom
Authors: Lee Ju Seong , Drajati Nur Arifah
Published: May 2019

While previous interventional studies on English as an international language (EIL) have focused on the role of teachers, recent studies have begun viewing how students engage autonomously in informal digital learning of English (IDLE) activities that are associated with their perception of English varieties and cross-cultural communication strategies. This mixed-method study examined the empirical relationship between IDLE and these two aspects of EIL involving 324 Indonesian EFL students. Results showed that receptive IDLE activity (e.g. watching English content) significantly predicted positive perception of English varieties, whereas quantity (frequency) of IDLE and productive IDLE activity (e.g. communicating with English users) significantly predicted the development of cross-cultural communication strategies. This study sheds light on the emerging phenomenon of how contemporary EFL students are exposed to and interact with diverse forms, accents, and users of English in a range of IDLE environments, along with the pedagogical implications for ELT.
Literary Concordances in the Twenty-First Century
Authors: Gramigna Valeria
Published: May 2019

In the context of the most recent experiments involving dance–literature relations, I would like to focus on Concordan(s)e, a fascinating literary and artistic adventure that has been ongoing since 2007. A collaborative encounter between a writer and a choreographer leads to the co-creation of a new, shared work, which is a sort of prolongation or extension of their individual artistic worlds. This ‘shared artistic act’ invites reflection on a possible transformation that affects not only the novel but also creativity itself. The novel is changed by the ‘mutation’ of the act of writing. This ‘mutation’ both nourishes the reader-spectator and serves as the foundation for thinking about the writer’s creative process; it also gives the literary text another form. Might not this change in the act of writing be the main issue to be considered if we are to understand one of the ways the contemporary novel is developing, and to broaden the scope of studies on the relationship between dance and literature?
A Manganese-Superoxide Dismutase From Thermus thermophilus HB27 Suppresses Inflammatory Responses and Alleviates Experimentally Induced Colitis
Authors: Sheng Yang , Li Hailong , Liu Minjun , Xie Bingxian , Wei Wen , Wu Jiawei , Meng Fanguo , Wang Hong Yu , Chen Shuai
Published: May 2019

Background

Superoxide dismutase (SOD) is an attractive therapeutic agent to ameliorate oxidative stress that is critical for the initiation and progression of inflammatory bowel disease (IBD). However, the short life of SOD limits its clinical application. In this study, we aim to examine the therapeutic effects of a hyperthermostable SOD from the Thermus thermophilus HB27 (TtSOD) for treatment of experimentally induced IBD.

Methods

A recombinant TtSOD was expressed and purified from Escherichia coli, and its therapeutic effects were examined in 2 experimental IBD animal models.

Results

In IBD induced by 2,4,6-trinitrobenzenesulfonic acid in zebrafish, TtSOD treatment decreased intestinal enlargement and attenuated neutrophil infiltration, resulting in alleviation of enterocolitis. In mice, SOD activity was substantially increased in the intestine after oral gavage of TtSOD, which ameliorated gut inflammation, preserved gut barrier function, and attenuated the severity of dextran sulfate sodium–induced colitis. Furthermore, TtSOD inhibited lipopolysaccharide-induced production of reactive oxygen species and inflammatory responses in mouse bone marrow–derived macrophages.

Conclusions

Our results demonstrate that TtSOD possesses therapeutic activities toward experimentally induced IBD, offering new clinical treatment options for patients with IBD.
Race differences in cardiovascular disease and breast cancer mortality among US women diagnosed with invasive breast cancer
Authors: Troeschel Alyssa N , Liu Yuan , Collin Lindsay J , Bradshaw Patrick T , Ward Kevin C , Gogineni Keerthi , McCullough Lauren E
Published: May 2019

Background

Breast cancer (BC) survivors are at increased risk of cardiovascular disease (CVD) due to shared risk factors with BC and cardiotoxic treatment effects. We aim to investigate racial differences in mortality due to CVD and BC among women diagnosed with invasive BC.

Methods

Data from 407 587 non-Hispanic Black (NHB) and White (NHW) women diagnosed with malignant BC (1990–2014) were obtained from the Surveillance, Epidemiology, and End Results database. Cumulative incidence of mortality due to CVD and BC was calculated by race and age (years). Cox models were used to obtain hazard ratios (HR) and 95% confidence intervals (95%CI) for the association of race/ethnicity with cause-specific mortality.

Results

The 20-year cumulative incidence of CVD-related mortality was higher among younger NHBs than NHWs (e.g. age 55–69: 13.3% vs 8.9%, respectively). NHBs had higher incidence of BC-specific mortality than NHWs, regardless of age. There was a monotonic reduction in CVD-related mortality disparities with increasing age (age <55: HR = 3.71, 95%CI: 3.29, 4.19; age 55–68: HR = 2.31, 95%CI: 2.15, 2.49; age 69+: HR = 1.24, 95%CI: 1.19, 1.30). The hazard of BC-specific mortality among NHBs was approximately twice that of NHWs (e.g. age <55: HR = 1.98, 95%CI: 1.92, 2.04).

Conclusions

There are substantial differences in mortality due to CVD and BC between NHB and NHW women diagnosed with invasive BC. Racial differences were greatest among younger women for CVD-related mortality and similar across age groups for BC-specific mortality. Future studies should identify pathways through which race/ethnicity affects cause-specific mortality, to inform efforts towards reducing disparities.
TIPE2 Suppresses Pseudomonas aeruginosa Keratitis by Inhibiting NF-κB Signaling and the Infiltration of Inflammatory Cells
Authors: Wang Qun , Ma Li , Liu Ting , Ge Cheng , Zhou Qingjun , Wei Chao , Shi Weiyun
Published: May 2019

Background

The role of tumor necrosis factor α (TNF-α) induced protein 8-like-2 (TIPE2) in Pseudomonas aeruginosa (PA) keratitis was explored.

Methods

Eight-week-old TIPE2 knockout (TIPE2−/−) C57BL/6 mice and their wild-type (WT) littermates were used. Corneal disease was graded at 1, 2, and 3 days postinfection, and slit lamp, clinical score, histopathology, and immunostaining were performed in the infected corneas. The corneas were harvested, and messenger ribonucleic acid (mRNA) levels of TNF-α, interleukin-1β (IL-1β), and interleukin-6 (IL-6) were tested. Enzyme-linked immunosorbent assay (ELISA) determined the protein levels, and nuclear factor κ-light-chain-enhancer of activated B cell (NF-κB) signaling molecules were tested by Western blot. In vitro human corneal epithelial cells (HCECs) were used to determine the relationship between TIPE2 and TAK1. The HCECs were treated with TIPE2 short hairpin ribonucleic acid (shRNA) and lipopolysaccharide (LPS) to test the NF-κB signaling molecules by Western blot.

Results

Pseudomonas aeruginosa infection induced a decreased expression of TIPE2 in mouse corneas 2 days postinfection. Compared with the control group, TIPE2-deficient mice were susceptible to infection with PA and showed increased corneal inflammation. Reduced NF-κB signaling and inflammatory cell infiltration were required in the TIPE2-mediated immune modulation.

Conclusions

TIPE2 promoted host resistance to PA infection by suppressing corneal inflammation via regulating TAK1 signaling negatively and inhibiting the infiltration of inflammatory cells.
The mechanism of action of pepR, a viral-derived peptide, against Staphylococcus aureus biofilms
Authors: Pinto Sandra N , Dias Susana A , Cruz Ana F , Mil-Homens Dalila , Fernandes Fabio , Valle Javier , Andreu David , Prieto Manuel , Castanho Miguel A R B , Coutinho Ana , Veiga Ana Salomé
Published: May 2019

Objectives

To investigate the mechanism of action at the molecular level of pepR, a multifunctional peptide derived from the Dengue virus capsid protein, against Staphylococcus aureus biofilms.

Methods

Biofilm mass, metabolic activity and viability were quantified using conventional microbiology techniques, while fluorescence imaging methods, including a real-time calcein release assay, were employed to investigate the kinetics of pepR activity at different biofilm depths.

Results

Using flow cytometry-based assays, we showed that pepR is able to prevent staphylococcal biofilm formation due to a fast killing of planktonic bacteria, which in turn resulted from a peptide-induced increase in the permeability of the bacterial membranes. The activity of pepR against pre-formed biofilms was evaluated through the application of a quantitative live/dead confocal laser scanning microscopy (CLSM) assay. The results show that the bactericidal activity of pepR on pre-formed biofilms is dose and depth dependent. A CLSM-based assay of calcein release from biofilm-embedded bacteria was further developed to indirectly assess the diffusion and membrane permeabilization properties of pepR throughout the biofilm. A slower diffusion and delayed activity of the peptide at deeper layers of the biofilm were quantified.

Conclusions

Overall, our results show that the activity of pepR on pre-formed biofilms is controlled by its diffusion along the biofilm layers, an effect that can be counteracted by an additional administration of peptide. Our study sheds new light on the antibiofilm mechanism of action of antimicrobial peptides, particularly the importance of their diffusion properties through the biofilm matrix on their activity.
Is direct oral amoxicillin challenge a viable approach for ‘low-risk’ patients labelled with penicillin allergy?
Authors: Krishna Mamidipudi T , Misbah Siraj A
Published: May 2019

Spurious penicillin allergy (PenA) is a major public health problem. Up to 10% of the population and 20% of inpatients are labelled with PenA, but only <5%–10% have a proven allergy following comprehensive investigations. PenA tests are labour intensive and require specialist input, which may not be readily available due to limited allergy services. Therefore, patients with PenA receive alternative antibiotics that are associated with higher rates of iatrogenic infections, antimicrobial resistance and a longer hospital stay with consequent increased costs. Recent evidence suggests that a supervised ‘direct’ oral amoxicillin challenge (without performing allergy tests) is a safe option in low-risk patients (those least likely to be allergic based on history). Patient selection for this procedure is based on a careful guideline-based risk stratification process. Further research is needed to validate this intervention in routine clinical practice and explore potential facilitators and barriers to implementation in different healthcare settings.
ML-Net: multi-label classification of biomedical texts with deep neural networks
Authors: Du Jingcheng , Chen Qingyu , Peng Yifan , Xiang Yang , Tao Cui , Lu Zhiyong
Published: May 2019

Objective

In multi-label text classification, each textual document is assigned 1 or more labels. As an important task that has broad applications in biomedicine, a number of different computational methods have been proposed. Many of these methods, however, have only modest accuracy or efficiency and limited success in practical use. We propose ML-Net, a novel end-to-end deep learning framework, for multi-label classification of biomedical texts.

Materials and Methods

ML-Net combines a label prediction network with an automated label count prediction mechanism to provide an optimal set of labels. This is accomplished by leveraging both the predicted confidence score of each label and the deep contextual information (modeled by ELMo) in the target document. We evaluate ML-Net on 3 independent corpora in 2 text genres: biomedical literature and clinical notes. For evaluation, we use example-based measures, such as precision, recall, and the F measure. We also compare ML-Net with several competitive machine learning and deep learning baseline models.

Results

Our benchmarking results show that ML-Net compares favorably to state-of-the-art methods in multi-label classification of biomedical text. ML-Net is also shown to be robust when evaluated on different text genres in biomedicine.

Conclusion

ML-Net is able to accuractely represent biomedical document context and dynamically estimate the label count in a more systematic and accurate manner. Unlike traditional machine learning methods, ML-Net does not require human effort for feature engineering and is a highly efficient and scalable approach to tasks with a large set of labels, so there is no need to build individual classifiers for each separate label.
Biological Features of Neoseiulus californicus (Acari: Phytoseiidae) Feeding on Schizotetranychus oryzae (Acari: Tetranychidae) Kept on Rice Leaves
Authors: Gonçalves Dinarte , Cunha da Uemerson Silva , Rode Priscila de Andrade , Toldi Maicon , Ferla Noeli Juarez
Published: May 2019

Schizotetranychus oryzae Rossi de Simons attains pest level in rice crops. This study aimed to evaluate the biological features of Neoseiulus californicus (McGregor) feeding on S. oryzae on leaves of flooded rice. We also evaluated N. californicus behavior in response to S. oryzae and conspecific cues. Thirty-two eggs were individually placed in arenas on rice leaves and fed on S. oryzae for the biological test. Three cultivars were used to test the behavior of N. californicus in response to S. oryzae and conspecific cues. The intrinsic rate of increase (rm) of the predator feeding on S. oryzae was 0.21 female/female/day. Schizotetranychus oryzae was considered a suitable prey for N. californicus under laboratory conditions. The results obtained in behavioral tests showed that N. californicus preferred laying eggs on leaves uninfested by S. oryzae and it did not show oviposition preference in arenas with conspecific predator cues. This predator was found in all rice cultivation areas in the state of Rio Grande do Sul, Brazil. Neoseiulus californicus proved to be a control agent for S. oryzae.
Long-term exposure to a 40-GHz electromagnetic field does not affect genotoxicity or heat shock protein expression in HCE-T or SRA01/04 cells
Authors: Koyama Shin , Narita Eijiro , Suzuki Yukihisa , Shiina Takeo , Taki Masao , Shinohara Naoki , Miyakoshi Junji
Published: May 2019

Millimeter waves are used in various fields, and the risks of this wavelength range for human health must be carefully evaluated. In this study, we investigated the effects of millimeter waves on genotoxicity and heat shock protein expression in human corneal epithelial (HCE-T) and human lens epithelial (SRA01/04) cells. We exposed the cells to 40-GHz millimeter waves at 1 mW/cm2 for 24 h. We observed no statistically significant increase in the micronucleus (MN) frequency or the level of DNA strand breaks in cells exposed to 40-GHz millimeter waves relative to sham-exposed and incubator controls. Heat shock protein (Hsp) expression also exhibited no statistically significant response to the 40-GHz exposure. These results indicate that exposure to 40 GHz millimeter waves under these conditions has little or no effect on MN formation, DNA strand breaks, or Hsp expression in HCE-T or SRA01/04 cells.
Direct role for the Drosophila GIGYF protein in 4EHP-mediated mRNA repression
Authors: Ruscica Vincenzo , Bawankar Praveen , Peter Daniel , Helms Sigrun , Igreja Cátia , Izaurralde Elisa
Published: May 2019

The eIF4E-homologous protein (4EHP) is a translational repressor that competes with eIF4E for binding to the 5′-cap structure of specific mRNAs, to which it is recruited by protein factors such as the GRB10-interacting GYF (glycine-tyrosine-phenylalanine domain) proteins (GIGYF). Several experimental evidences suggest that GIGYF proteins are not merely facilitating 4EHP recruitment to transcripts but are actually required for the repressor activity of the complex. However, the underlying molecular mechanism is unknown. Here, we investigated the role of the uncharacterized Drosophila melanogaster (Dm) GIGYF protein in post-transcriptional mRNA regulation. We show that, when in complex with 4EHP, Dm GIGYF not only elicits translational repression but also promotes target mRNA decay via the recruitment of additional effector proteins. We identified the RNA helicase Me31B/DDX6, the decapping activator HPat and the CCR4–NOT deadenylase complex as binding partners of GIGYF proteins. Recruitment of Me31B and HPat via discrete binding motifs conserved among metazoan GIGYF proteins is required for downregulation of mRNA expression by the 4EHP–GIGYF complex. Our findings are consistent with a model in which GIGYF proteins additionally recruit decapping and deadenylation complexes to 4EHP-containing RNPs to induce translational repression and degradation of mRNA targets.
Highly efficient single-stranded DNA ligation technique improves low-input whole-genome bisulfite sequencing by post-bisulfite adaptor tagging
Authors: Miura Fumihito , Shibata Yukiko , Miura Miki , Sangatsuda Yuhei , Hisano Osamu , Araki Hiromitsu , Ito Takashi
Published: May 2019

Whole-genome bisulfite sequencing (WGBS) is the current gold standard of methylome analysis. Post-bisulfite adaptor tagging (PBAT) is an increasingly popular WGBS protocol because of high sensitivity and low bias. PBAT originally relied on two rounds of random priming for adaptor-tagging of single-stranded DNA (ssDNA) to attain high efficiency but at a cost of library insert length. To overcome this limitation, we developed terminal deoxyribonucleotidyl transferase (TdT)-assisted adenylate connector-mediated ssDNA (TACS) ligation as an alternative to random priming. In this method, TdT attaches adenylates to the 3′-end of input ssDNA, which are then utilized by RNA ligase as an efficient connector to the ssDNA adaptor. A protocol that uses TACS ligation instead of the second random priming step substantially increased the lengths of PBAT library fragments. Moreover, we devised a dual-library strategy that splits the input DNA to prepare two libraries with reciprocal adaptor polarity, combining them prior to sequencing. This strategy ensured an ideal base–color balance to eliminate the need for DNA spike-in for color compensation, further improving the throughput and quality of WGBS. Adopting the above strategies to the HiSeq X Ten and NovaSeq 6000 platforms, we established a cost-effective, high-quality WGBS, which should accelerate various methylome analyses.
A Cost-effectiveness Analysis of an Adjuvanted Subunit Vaccine for the Prevention of Herpes Zoster and Post-herpetic Neuralgia
Authors: Carpenter Christopher F , Aljassem Annas , Stassinopoulos Jerry , Pisacreta Giovanni , Hutton David
Published: May 2019

Background

Herpes zoster (HZ) develops in up to 50% of unvaccinated individuals, accounting for >1 million cases annually in the United States. A live attenuated HZ vaccine (LAV) is Food and Drug Administration approved for those age 50 years or older, though Advisory Committee on Immunization Practices recommendations are only for those age 60 years or older. LAV efficacy is ~70% for persons 50–59 years of age, with lower efficacy in older adults. A new 2-dose adjuvanted subunit vaccine (SUV) has >95% efficacy in persons 50–69 years of age and remains ~90% efficacious in persons vaccinated at age 70 years.

Methods

To estimate the relative cost-effectiveness of SUV, LAV, and no vaccination (NoV) strategies, a Markov model was developed based on published data on vaccine efficacy, durability of protection, quality of life, resource utilization, costs, and disease epidemiology. The perspective was US societal, and the cycle length was 1 year with a lifelong time horizon. SUV efficacy was estimated to wane at the same rate as LAV. Outcomes evaluated included lifetime costs, discounted life expectancy, and incremental cost-effectiveness ratios (ICERs).

Results

For individuals vaccinated at age 50 years, the ICER for LAV vs NoV was $118 535 per quality-adjusted life-year (QALY); at age 60 years, the ICER dropped to $42 712/QALY. SUV was more expensive but had better ICERs than LAV. At age 50, the ICER was $91 156/QALY, and it dropped to $19 300/QALY at age 60.

Conclusions

Vaccination with SUV was more cost-effective than LAV in all age groups studied. Vaccination with SUV at age 50 years appears cost-effective, with an ICER <$100 000/QALY.
Religious Faith and the Fallibility of Public Reasons
Authors: Bespalov Andrei
Published: May 2019

Rawlsian liberals define legitimacy in terms of the public justification principle (PJP): the exercise of political power is legitimate only if it is justified on the grounds of reasons that all may reasonably be expected to accept. Does PJP exclude religious reasons from public justification of legal provisions? I argue that the requirement of ‘reasonable acceptability’ is not clear enough to answer this question. Furthermore, it fails to address the problematic fact that justification on the grounds of religious faith involves non-negotiable claims, which is incompatible with respect for fellow citizens as co-legislators. Accordingly, I reformulate PJP in fallibilistic terms: the exercise of political power is legitimate only if it is justified on the grounds of reasons that can be subject to reasonable criticism. I show that reasons based on religious faith do not meet this principle, just like any other reasons that involve claims about final values.
Empirical modelling and optimization of pressure-coupled infusion gyration parameters for the nanofibre fabrication
Authors: Hong Xianze , Harker Anthony , Edirisinghe Mohan
Published: May 2019

Pressure-coupled infusion gyration (PCIG) is a novel promising technique for economical and effective mass production of nanofibres with desirable geometrical characteristics. The average diameter of spun fibres significantly influences the structural, mechanical and physical properties of the produced fibre mats. Having a comprehensive understanding of the significant effects of PCIG experimental variables on the spun fibres is beneficial. In this work, response surface methodology was used to explore the interaction effects and the optimal PCIG experimental variables for achieving the desired morphological characteristics of fibres. The effect of experimental variables, namely solution concentration, infusion (flow) rate, applied pressure and rotational speed, was studied on the average fibre diameter and standard deviations. A numerical model for the interactional influences of experimental variables was developed and optimized with a nonlinear interior point method that can be used as a framework for selecting the optimal conditions to obtain poly-ethylene oxide fibres with desired morphology (targeted average diameter and narrow standard deviation). The adequacy of the models was verified by a set of validation experiments. The results proved that the predicted optimal conditions were able to achieve the average diameter that matched the pre-set desired value with less than 10% of difference.
S-money: virtual tokens for a relativistic economy
Authors: Kent Adrian
Published: May 2019

We propose definitions and implementations of ‘S-money’—virtual tokens designed for high-value fast transactions on networks with relativistic or other trusted signalling constraints, defined by inputs that in general are made at many network points, some or all of which may be space-like separated. We argue that one significant way of characterizing types of money in space–time is via the ‘summoning’ tasks they can solve: that is, how flexibly the money can be propagated to a desired space–time point in response to relevant information received at various space–time points. We show that S-money is more flexible than standard quantum or classical money in the sense that it can solve deterministic summoning tasks that they cannot. It requires the issuer and user to have networks of agents with classical data storage and communication, but no long-term quantum state storage, and is feasible with current technology. User privacy can be incorporated by secure bit commitment and zero-knowledge proof protocols. The level of privacy feasible in given scenarios depends on efficiency and composable security questions that remain to be systematically addressed.
Parasite resource manipulation drives bimodal variation in infection duration
Authors: van Leeuwen Anieke , Budischak Sarah A. , Graham Andrea L. , Cressler Clayton E.
Published: May 2019

Over a billion people on earth are infected with helminth parasites and show remarkable variation in parasite burden and chronicity. These parasite distributions are captured well by classic statistics, such as the negative binomial distribution. But the within-host processes underlying this variation are not well understood. In this study, we explain variation in macroparasite infection outcomes on the basis of resource flows within hosts. Resource flows realize the interactions between parasites and host immunity and metabolism. When host metabolism is modulated by parasites, we find a positive feedback of parasites on their own resources. While this positive feedback results in parasites improving their resource availability at high burdens, giving rise to chronic infections, it also results in a threshold biomass required for parasites to establish in the host, giving rise to acute infections when biomass fails to clear the threshold. Our finding of chronic and acute outcomes in bistability contrasts with classic theory, yet is congruent with the variation in helminth burdens observed in human and wildlife populations.
Prey body mass and richness underlie the persistence of a top predator
Authors: Guzman Laura Melissa , Srivastava Diane S.
Published: May 2019

Predators and prey often differ in body mass. The ratio of predator to prey body mass influences the predator's functional response (how consumption varies with prey density), and therefore, the strength and stability of the predator–prey interaction. The persistence of food chains is maximized when prey species are neither too big nor too small relative to their predator. Nonetheless, we do not know if (i) food web persistence requires that all predator–prey body mass ratios are intermediate, nor (ii) if this constraint depends on prey diversity. We experimentally quantified the functional response for a single predator consuming prey species of different body masses. We used the resultant allometric functional response to parametrize a food web model. We found that predator persistence was maximized when the minimum prey size in the community was intermediate, but as prey diversity increased, the minimum body size could take a broader range of values. This last result occurs because of Jensen's inequality: the average handling time for multiple prey of different sizes is higher than the handling time of the average sized prey. Our results demonstrate that prey diversity mediates how differences between predators and prey in body mass determine food web stability.
A phylogenomic rodent tree reveals the repeated evolution of masseter architectures
Authors: Swanson Mark T. , Oliveros Carl H. , Esselstyn Jacob A.
Published: May 2019

Understanding the number of times a trait has evolved is a necessary foundation for comprehending its potential relationships with selective regimes, developmental constraints and evolutionary diversification. Rodents make up over 40% of extant mammalian species, and their ecological and evolutionary success has been partially attributed to the increase in biting efficiency that resulted from a forward shift of one or two portions of the masseter muscle from the zygomatic arch onto the rostrum. This forward shift has occurred in three discrete ways, but the number of times it has occurred has never been explicitly quantified. We estimated an ultrametric phylogeny, the first to include all rodent families, using thousands of ultraconserved elements. We examined support for evolutionary relationships among the five rodent suborders and then incorporated relevant fossils, fitted models of character evolution, and used stochastic character mapping to determine that a portion of the masseter muscle has moved forward onto the rostrum at least seven times (with one reversal) during the approximately 70 Myr history of rodents. Combined, the repeated evolution of this key innovation, its increasing prevalence through time, and the species diversity of clades with this character underscores the adaptive value of improved biting efficiency and the relative ease with which some advantageous traits arise.
Natural and sexual selection on cuticular hydrocarbons: a quantitative genetic analysis
Authors: Berson Jacob D. , Zuk Marlene , Simmons Leigh W.
Published: May 2019

While the reproductive benefits of sexual displays have been widely studied, we have relatively limited evidence of the fitness costs associated with most display traits. Insect cuticular hydrocarbon (CHC) profiles are sexually selected traits that also protect against desiccation. These two functions are thought to oppose each other, with investment in particular compounds believed to increase attractiveness at the expense of compounds that protect against water loss. We investigated this potential trade-off in a quantitative genetic framework using the Australian field cricket,Teleogryllus oceanicus. Several compounds were significantly genetically correlated with either attractiveness or desiccation resistance. Of these compounds, one was negatively genetically correlated with attractiveness but positively genetically correlated with desiccation resistance. Furthermore, scoring each individual's overall CHC profile for its level of attractiveness and desiccation resistance indicated a negative genetic correlation between these multivariate phenotypes. Together, our results provide evidence for a genetic trade-off between sexually and naturally selected functions of the CHC profile. We suggest that the production of an attractive CHC profile may be costly for males, but highlight the need for further work to support this finding experimentally. Genetic covariation between the CHC profile and attractiveness suggests that females can gain attractive sons through female choice.
Genetic effects on planum temporale asymmetry and their limited relevance to neurodevelopmental disorders, intelligence or educational attainment
Authors: Carrion-Castillo Amaia , Pepe Antonietta , Kong Xiang-Zhen , Fisher Simon E , Mazoyer Bernard , Tzourio-Mazoyer Nathalie , Crivello Fabrice , Francks Clyde
Published: May 2019

Previous studies have suggested that altered asymmetry of the planum temporale (PT) is associated with neurodevelopmental disorders, including dyslexia, schizophrenia, and autism. Shared genetic factors have been suggested to link PT asymmetry to these disorders. In a dataset of unrelated subjects from the general population (UK Biobank, N= 18,057), we found that PT volume asymmetry had a significant heritability of roughly 14%. In genome-wide association analysis, two loci were significantly associated with PT asymmetry, including a coding polymorphism within the gene ITIH5 that is predicted to affect the protein’s function and to be deleterious (rs41298373, P=2.01×10-15), and a locus that affects the expression of the genes BOK and DTYMK (rs7420166, P=7.54×10-10). DTYMK showed left-right asymmetry of mRNA expression in post mortem PT tissue. Cortex-wide mapping of these SNP effects revealed influences on asymmetry that went somewhat beyond the PT. Using publicly available genome-wide association statistics from large-scale studies, we saw no significant genetic correlations of PT asymmetry with autism spectrum disorder, attention deficit hyperactivity disorder, schizophrenia, educational attainment or intelligence. Of the top two individual loci associated with PT asymmetry, rs41298373 showed a tentative association with intelligence (unadjusted P=0.025), while the locus at BOK/DTYMK showed tentative association with educational attainment (unadjusted Ps<0.05). These findings provide novel insights into the genetic contributions to human brain asymmetry, but do not support a substantial polygenic association of PT asymmetry with cognitive variation and mental disorders, as far as can be discerned with current sample sizes.
A preliminary study of resting brain metabolism in treatment-resistant depression before and after treatment with olanzapine-fluoxetine combination
Authors: Pardo José V. , Sheikh Sohail A. , Schwindt Graeme , Lee Joel T. , Adson David E. , Rittberg Barry , Abuzzahab Faruk S.
Published: May 2019

Treatment-resistant depression (TRD) occurs in many patients and causes high morbidity and mortality. Because TRD subjects are particularly difficult to study especially longitudinally, biological data remain very limited. In a preliminary study to judge feasibility and power, 25 TRD patients were referred from specialty psychiatric practices. All were severely and chronically depressed and mostly had comorbid psychiatric disorders as is typical in TRD. Nine patients were able to complete all required components of the protocol that included diagnostic interview; rating scales; clinical magnetic resonance imaging; medication washout; treatment with maximally tolerated olanzapine-fluoxetine combination for 8 weeks; and pre- and post-treatment fluorodeoxyglucose positron emission tomography. This drug combination is an accepted standard of treatment for TRD. Dropouts arose from worsening depression, insomnia, and anxiety. One patient remitted; three responded. A priori regions of interest included the amygdala and subgenual cingulate cortex (sgACC; BA25). Responders showed decreased metabolism with treatment in the right amygdala that correlated with clinical response; no significant changes in BA25; better response to treatment the higher the baseline BA25 metabolism; and decreased right ventromedial prefrontal metabolism (VMPFC; broader than BA25) with treatment which did not correlate with depression scores. The baseline metabolism of all individuals showed heterogeneous patterns when compared to a normative metabolic database. Although preliminary given the sample size, this study highlights several issues important for future work: marked dropout rate in this study design; need for large sample size for adequate power; baseline metabolic heterogeneity of TRD requiring careful subject characterization for future studies of interventions; relationship of amygdala activity decreases with response; and the relationship between baseline sgACC and VMPFC activity with response. Successful treatment of TRD with olanzapine-fluoxetine combination shows changes in cerebral metabolism similar to those seen in treatment-responsive major depression.