bluuebunny/crossref_metadata_2025 huggingface dataset:
Regional epigenetic variation in asexual snail populations among urban and rural lakes
Authors: Thorson Jennifer L M , Smithson Mark , Sadler-Riggleman Ingrid , Beck Daniel , Dybdahl Mark , Skinner Michael K
Published: November 2019

Epigenetic variation has the potential to influence environmentally dependent development and contribute to phenotypic responses to local environments. Environmental epigenetic studies of sexual organisms confirm the capacity to respond through epigenetic variation. An epigenetic response could be even more important in a population when genetic variation is lacking. A previous study of an asexual snail, Potamopyrgus antipodarum, demonstrated that different populations derived from a single clonal lineage differed in both shell phenotype and methylation signature when comparing lake versus river populations. Here, we examine methylation variation among lakes that differ in environmental disturbance and pollution histories. Snails were collected from a more pristine rural Lake 1 (Lake Lytle), and two urban lakes, Lake 2 (Capitol Lake) and Lake 3 (Lake Washington) on the Northwest Pacific coast. DNA methylation was assessed for each sample population using methylated DNA immunoprecipitation, MeDIP, followed by next-generation sequencing. The differential DNA methylation regions (DMRs) identified among the different lake comparisons suggested a higher number of DMRs and variation between rural Lake 1 and one urban Lake 2, and between the two urban Lakes 2 and 3, but limited variation between the rural Lake 1 and urban Lake 3. DMR genomic characteristics and gene associations were investigated. The presence of site-specific differences between each of these lake populations suggest an epigenetic response to varied environmental factors. The results do not support an effect of geographic distance in these populations. The role of dispersal distance among lakes, population history, environmental pollution and stably inherited methylation versus environmentally triggered methylation in producing the observed epigenetic variation are discussed. Observations support the proposal that epigenetic alterations may associate with phenotypic variation and environmental factors and history of the different lakes.
Impact of post-orthodontic dental occlusion on masticatory performance and chewing efficiency
Authors: Shim Jocelyne , Ho Ka Chun Jeremy , Shim Brian C , Metaxas Angelos , Somogyi-Ganss Eszter , Di Sipio Riccardo , Cioffi Iacopo
Published: November 2019

Background

Whether precise orthodontic detailing of occlusion impacts masticatory function is unknown. In this study, we aimed to assess the impact of post-orthodontic dental occlusion on masticatory performance and chewing efficiency.

Materials and methods

Fifty-four adults who completed orthodontic treatment were categorized into two groups using the American Board of Orthodontics (ABO) model grading system: one meeting ABO standards (ABO, N = 29), the other failing to meet them (non-ABO, N = 25). The electromyographic (EMG) signals of the anterior temporalis (AT) and superficial masseter muscles were recorded bilaterally during static (clenching) and dynamic (gum chewing) tests. Chewing efficiency was measured by calculating the median particle size (MPS) and broadness of particle distribution (BPD) after five chewing trials of experimental silicone food at a standardized chewing rate.

Results

Participants of the ABO group had a slightly more symmetric activation of the AT muscles during clenching (P = 0.016) and chewed a gum at a slower rate (P = 0.030). During the standardized chewing test with silicone food, ABO subjects had slightly greater EMG potentials at all muscle locations than non-ABO individuals (all P < 0.05). MPS and BDP did not differ significantly between groups (all P > 0.05).

Limitations

The severity of the initial malocclusion of the study participants was not in the statistical model as a potential confounder on the outcome measures.

Conclusions

Meeting ABO standards contributes to a slightly more balanced activation of the temporalis muscles during clenching and more efficient muscle recruitment during chewing but does not improve chewing efficiency.
IRAK1 and IRAK4 signaling proteins are dispensable in the response of human neutrophils to Mycobacterium tuberculosis infection
Authors: Kielbik Michal , Szulc-Kielbik Izabela , Klink Magdalena
Published: November 2019

The involvement of neutrophils in the host response to Mycobacterium tuberculosis (Mtb) infection is not as well recognized as the involvement of macrophages and dendritic cells. Thus, this study gives more insight on the impact of the virulent Mtb H37Rv strain on proapoptotic and proinflammatory functions of human neutrophils in vitro. We found that neutrophils are not able to kill Mtb during the infection process, probably due to the lack of reactive oxygen species and nitric oxide production in response to bacteria. However, infected neutrophils effectively released cytokines, chemoattractant interleukin (IL) 8 and proinflammatory IL-1β. Moreover, Mtb enhanced the early apoptosis of neutrophils at 2 h postinfection. Additionally, this proapoptotic and proinflammatory response of neutrophils to Mtb infection occurred in an IRAK1- and IRAK4-independent manner. We also found that Mtb did not affect the surface expression of Toll-like receptor (TLR) 2 and slightly enhanced the surface expression of TLR4, but did not influence mRNA levels of both TLRs during the infection process. In conclusion, we show that the inhibition of signaling proteins activated by MyD88-dependent pathway did not participate in the biological activity of neutrophils against Mtb.
Life in Limbo: Old-Age Transnationalism
Authors: Ciobanu Ruxandra Oana , Ludwig-Dehm Sarah M
Published: November 2019

Background and Objectives

Transnationalism, defined as migrants having ties to the country of origin and the destination country, is mostly explored with qualitative data. Quantitative studies only use a small number of indicators. This is one of only a few studies to examine transnationalism based on multiple indicators and elaborate classes of transnationalism. The research questions are: What are the forms of transnationalism in which older migrants engage? And how do age, gender, income, and country of origin affect these forms?

Research Design and Methods

The paper used the Vivre/Leben/Vivere (2011/2012) subsample of migrants in Switzerland, aged 65–82 years. Transnationalism was measured using 11 indicators, including nationality, having family abroad, and sending remittances. Latent class analysis was used to distinguish between several forms of transnationalism. Latent class regression models subsequently explore the effect of age, gender, income and country of origin on these transnationalism forms.

Results

Four different forms of transnationalism were found among older migrants: least transnational, distant transnational, active transnational, and returning transnational. The models suggest that country of origin and income are important predictors, while age is less important and gender has no effect on falling in these transnationalism classes.

Discussion and Implications

The results confirm that our measure of transnationalism is an innovative approach toward exploring the different forms older migrants engage in. The method has several advantages over usual methods and can be used in future studies to analyze, for example, how different forms of transnationalism emerge as a consequence of policies relevant for older migrants, like care arrangements and pensions.
Expression profiling in exercised mdx suggests a role for extracellular proteins in the dystrophic muscle immune response
Authors: Coles Chantal A , Gordon Lavinia , Hunt Liam C , Webster Tracie , Piers Adam T , Kintakas Christopher , Woodman Keryn , Touslon Su L , Smythe Gayle M , White Jason D , Lamandé Shireen R
Published: November 2019

Duchenne muscular dystrophy (DMD) is a lethal muscle wasting disorder caused by mutations in the DMD gene that lead to the absence or severe reduction of dystrophin protein in muscle. The mdx mouse, also dystrophin deficient, is the model most widely used to study the pathology and test potential therapies, but the phenotype is milder than human DMD. This limits the magnitude and range of histological damage parameters and molecular changes that can be measured in pre-clinical drug testing. We used three weeks of voluntary wheel running to exacerbate the mdx phenotype. In mdx mice voluntary exercise increased the amount of damaged necrotic tissue and macrophage infiltration. Global gene expression profiling revealed that exercise induced additional and larger gene expression changes in mdx mice and the pathways most impacted by exercise were all related to immune function or cell-extracellular matrix (ECM) interactions. When we compared the matrisome and inflammation genes that were dysregulated in mdx with those commonly differentially expressed in DMD, we found the exercised mdx molecular signature more closely resembled that of DMD. These gene expression changes in the exercised mdx model thus provide more scope to assess the effects of pre-clinical treatments. Our gene profiling comparisons also highlighted upregulation of extracellular matrix proteins involved in innate immunity pathways, proteases that can release them, and downstream receptors and signalling molecules in exercised mdx and DMD, suggesting that the ECM could be a major source of pro-inflammatory molecules that trigger and maintain the immune response in dystrophic muscle.
Dynamic effects of Fto in regulating the proliferation and differentiation of adult neural stem cells of mice
Authors: Cao Yuhang , Zhuang Yingliang , Chen Junchen , Xu Weize , Shou Yikai , Huang Xiaoli , Shu Qiang , Li Xuekun
Published: November 2019

N 6-methyladenosine (m6A) modification of RNA is deposited by the methyltransferase complex consisting of Mettl3 and Mettl14 and erased by demethylase Fto and Alkbh5 and is involved in diverse biological processes. However, it remains largely unknown the specific function and mechanism of Fto in regulating adult neural stem cells (aNSCs). In the present study, utilizing a conditional knockout (cKO) mouse model, we show that the specific ablation of Fto in aNSCs transiently increases the proliferation of aNSCs and promotes neuronal differentiation both in vitro and in vivo, but in a long term, the specific ablation of Fto inhibits adult neurogenesis and neuronal development. Mechanistically, Fto deficiency results in a significant increase in m6A modification in Pdgfra and Socs5. The increased expression of Pdgfra and decreased expression of Socs5 synergistically promote the phosphorylation of Stat3. The modulation of Pdgfra and Socs5 can rescue the neurogenic deficits induced by Fto depletion. Our results together reveal an important function of Fto in regulating aNSCs through modulating Pdgfra/Socs5-Stat3 pathway.
Foolishness without consequence? From physical to virtual modeling in the history of military aircraft development at Saab
Authors: Bengtsson Marie , Enberg Cecilia , Tell Fredrik
Published: November 2019

From Jim March we learned that organizational intelligence demands adaptation to the needs of a distant future as well as the efficient use of resources in the present. Commitment to new ideas that deviate from norm is necessary for long-term adaptation, but comes with great uncertainty as to if when or how success will come. This article uses a historical study of military aircraft manufacturer Saab to explore the transition from experimenting with physical models and dangerous test flights in the development of rather simple aircraft systems, to the development of complex integrated aircraft systems using virtual models that can be tested in a simulated world, thereby postponing choice and the need for commitment of resources in the physical world. We show how modeling techniques and tools were developed over five generations of aircraft to help developers represent and evaluate alternative ideas, in an increasingly realistic virtual reality, thereby reducing material and fatal consequences in aircraft development. We distinguish hybrid forms of evaluation and a transition that seems to be moving in the direction of “virtual online evaluation,” where empirically informed simulation models, based on real flight data reduces the fidelity gap between reality and representation. Drawing upon a selection of Jim March’s writings, we speculate what this transition implies for learning from experience and the possibility of foolishness without consequence.
Are we sacrificing the future of coral reefs on the altar of the “climate change” narrative?
Authors: Abelson Avigdor
Published: November 2019

Following a series of mass-bleaching events that have seriously degraded coral reefs, notably the Great Barrier Reef of Australia, a common narrative is now dominating the discourse, according to which “the only sure way to save the world’s coral reefs is climate change mitigation”. However, climate change is not a sole stressor. Most coral reefs around the world are threatened by a myriad of local stressors, including overfishing, destructive fishing, untreated sewage, agriculture effluents (nutrients and pesticides), and siltation due to deforestation. Reefs will not survive the severe effects of this plethora of stressors while waiting until we mitigate climate change. In order to safeguard reefs, we need to adopt a new narrative—“there are diverse ways in which we can improve the chances of saving coral reefs”—by acting now to: (i) improve their local protection and marine protected area networks, (ii) alleviate their critical local stressors, (iii) restore degraded and damaged reefs, and (iv) promote reef resilience and adaptation (e.g. adaptation networks, assisted evolution) to the changing conditions, notably climate change effects. It is time for us to move on from the impractical goals of the climate change narrative (“interventions beyond our field of expertise”) to building up resilience and adaptation of social-ecological systems of coral reefs.
Large Deviation Estimates and Hölder Regularity of the Lyapunov Exponents for Quasi-periodic Schrödinger Cocycles
Authors: Han Rui , Zhang Shiwen
Published: November 2019

We consider one-dimensional quasi-periodic Schrödinger operators with analytic potentials. In the positive Lyapunov exponent regime, we prove large deviation estimates, which lead to refined Hölder continuity of the Lyapunov exponents and the integrated density of states, in both small Lyapunov exponent and large coupling regimes. Our results cover all the Diophantine frequencies and some Liouville frequencies.
Association of HLA Genotype With T-Cell Activation in Human Immunodeficiency Virus (HIV) and HIV/Hepatitis C Virus–Coinfected Women
Authors: Kovacs Andrea A Z , Kono Naoko , Wang Chia-Hao , Wang Daidong , Frederick Toni , Operskalski Eva , Tien Phyllis C , French Audrey L , Minkoff Howard , Kassaye Seble , T. Golub Elizabeth , Aouizerat Bradley E , Kuniholm Mark H , Millstein Joshua
Published: November 2019

Background

Global immune activation and HLA alleles are each associated with the pathogenesis of human immunodeficiency virus (HIV) and hepatitis C virus .

Methods

We evaluated the relationship between 44 HLA class I and 28 class II alleles and percentages of activated CD8 (CD8+CD38+DR+) and CD4 (CD4+CD38+DR+) T cells in 586 women who were naive to highly active antiretroviral therapy. We used linear generalized estimating equation regression models, adjusting for race/ethnicity, age, HIV load, and hepatitis C virus infection and controlling for multiplicity using a false discovery rate threshold of 0.10.

Results

Ten HLA alleles were associated with CD8 and/or CD4 T-cell activation. Lower percentages of activated CD8 and/or CD4 T cells were associated with protective alleles B*57:03 (CD8 T cells, −6.6% [P = .002]; CD4 T cells, −2.7% [P = .007]), C*18:01 (CD8 T cells, −6.6%; P < .0008) and DRB1*13:01 (CD4 T cells, −2.7%; P < .0004), and higher percentages were found with B*18:01 (CD8 T cells, 6.2%; P < .0003), a detrimental allele. Other alleles/allele groups associated with activation included C*12:03, group DQA1*01:00, DQB1*03:01, DQB1*03:02, DQB1*06:02, and DQB1*06:03.

Conclusion

These findings suggest that a person’s HLA type may play a role in modulating T-cell activation independent of viral load and sheds light on the relationship between HLA, T-cell activation, immune control, and HIV pathogenesis.
Human Immunodeficiency Virus Exposure but Not Early Cytomegalovirus Infection Is Associated With Increased Hospitalization and Decreased Memory T-Cell Responses to Tetanus Vaccine
Authors: Smith Christiana , Moraka Natasha O , Ibrahim Maryanne , Moyo Sikhulile , Mayondi Gloria , Kammerer Betsy , Leidner Jean , Gaseitsiwe Simani , Li Shaobing , Shapiro Roger , Lockman Shahin , Weinberg Adriana
Published: November 2019

Background

Human immunodeficiency virus (HIV)-exposed, uninfected (HEU) infants experience high rates of infectious morbidity. We hypothesized that early cytomegalovirus (CMV) infection was associated with increased hospitalization rates and decreased vaccine responses in HEU compared with HIV-unexposed (HUU) infants.

Methods

Among infants enrolled in the Tshipidi study in Botswana, we determined CMV infection status by 6 months of age and compared hospitalization rates and responses to tetanus and Bacille Calmette-Guérin vaccines among HEU and HUU vaccinees.

Results

Fifteen of 226 (6.6%) HEU infants and 17 (19.3%) of 88 HUU infants were CMV-infected by 6 months. The HEU infants were approximately 3 times as likely to be hospitalized compared with HUU infants (P = .02). The HEU peripheral blood cells produced less interleukin (IL)-2 (P = .004), but similar amounts of interferon-γ, after stimulation with tetanus toxoid. Antitetanus immunoglobulin G titers were similar between groups. Cellular responses to purified protein derivative stimulation did not differ between groups. Maternal receipt of 3-drug antiretroviral therapy compared with zidovudine was associated with increased IL-2 expression after tetanus toxoid stimulation. The infants’ CMV infection status was not associated with clinical or vaccine response outcomes.

Conclusions

We observed that increased rates of hospitalization and decreased memory T-cell responses to tetanus vaccine were associated with HIV exposure and incomplete treatment of maternal HIV infection, but not early CMV infection.
Identification of AbaR4 Acinetobacter baumannii resistance island in clinical isolates of blaOXA-23-positive Proteus mirabilis
Authors: Octavia Sophie , Xu Weizhen , Ng Oon Tek , Marimuthu Kalisvar , Venkatachalam Indumathi , Cheng Bernadette , Lin Raymond T P , Teo Jeanette W P
Published: November 2019

Objectives

bla OXA-23 is a class D carbapenemase-encoding gene typical of the Acinetobacter genus. However, its occurrence in the Enterobacteriaceae is uncommon. Here we provide the genome characterization of blaOXA-23-positive Proteus mirabilis.

Methods

In Singapore, a national surveillance of carbapenem non-susceptible clinical Enterobacteriaceae has enabled the collection of OXA-23 bearing isolates. Three clinical P. mirabilis were whole-genome sequenced using Oxford Nanopore MinION and Illumina platforms. The sequence accuracy of MinION long-read contigs was enhanced by polishing with Illumina-derived short-read data.

Results

In two P. mirabilis genomes, blaOXA-23 was detected as two copies, present on the chromosome and on a 60018 bp plasmid. blaOXA-23 was associated with the classic Acinetobacter composite transposon Tn2006, bounded by two copies of ISAba1 bracketing the carbapenemase gene. The Tn2006 itself was embedded within an Acinetobacter baumannii AbaR4 resistance island. In the chromosome, the AbaR4 was found integrated into the comM gene, which is also the preferred ‘hotspot’ in A. baumannii. In the plasmid, AbaR4 integrated into a putative colicin gene.

Conclusions

Our description of an A. baumannii AbaR4 encoding blaOXA-23 in P. mirabilis is to our knowledge the first description of an Acinetobacter resistance island in Proteus and suggests that P. mirabilis may be a reservoir for this class D carbapenemase gene.
Detailing postoperative pain and opioid utilization after periacetabular osteotomy with automated mobile messaging
Authors: Hajewski Christina , Anthony Chris A , Rojas Edward O , Westermann Robert , Willey Michael
Published: November 2019

In the setting of periacetabular osteotomy (PAO), this investigation sought to (i) describe patient-reported pain scores and opioid utilization in the first 6 weeks following surgery and (ii) evaluate the effectiveness of postoperative communication using a robotic mobile messaging platform. Subjects indicated for PAO were enrolled from a young adult hip clinic. For the first 2 weeks after surgery, subjects received daily mobile messages inquiring about pain level on a 0–10 scale and the number of opioid pain medication tablets they consumed in the previous 24 h. Messaging frequency decreased to 3 per week in Weeks 3–6. Pain scores, opioid utilization and response rates with our mobile messaging platform were quantified for the 6-week postoperative period. Twenty-nine subjects underwent PAO. Twenty-one had concurrent hip arthroscopy. Average daily pain scores decreased over the first four postoperative days. Average pain scores reported were 5.9 ± 1.9, 4.1 ± 3.3 and 3.0 ± 3.5 on Day 1, Day 14 and Week 6, respectively. Reported opioid tablet utilization was 5.0 ± 3.2, 2.2 ± 2.0 and 0.0 ± 0.0 on Days 1 and 14 and at 6 weeks. Response rate for participants completing the 6-week messaging protocol was 84.1%. Patient-reported pain scores decreased over the first two postoperative weeks following PAO before plateauing in weeks 3–6. Opioid pain medication utilization increased in the first postoperative week before gradually declining to no tabs consumed at 6 weeks after PAO. Automated mobile messaging is an effective method of perioperative communication for the collection of pain scores and opioid utilization in patients undergoing PAO.
Factors Associated With Use of High-Cost Agents for the Treatment of Metastatic Non–Small Cell Lung Cancer
Authors: Bradley Cathy J , Eguchi Megan , Perraillon Marcelo C
Published: November 2019

Background

Antineoplastic agents approved in recent decades are a marked advancement in cancer treatment, but they come at considerable cost. These drugs may widen survival disparities between patients who receive these agents and those who do not. We examine factors associated with the use of high-cost antineoplastic agents for the treatment of metastatic non–small cell lung cancer.

Methods

We conducted a retrospective observational study using 2007–2015 Surveillance, Epidemiology, and End-Results–Medicare data supplemented with the Area Health Resource File. Patients were aged 66 years and older, were enrolled in fee-for-service Medicare Part D, were diagnosed with a first primary diagnosis of metastatic non–small cell lung cancer, and had received an antineoplastic agent. “High-cost agents” were defined as agents costing $5000 or more per month. Independent variables include race/ethnicity, urban or rural residency, census tract poverty, and treatment facility type (eg, National Cancer Institute designation).

Results

Patients who lived in areas of high poverty were 4 percentage points less likely to receive high-cost agents (two-sided P < .001). Patients who were not treated at a National Cancer Institute–designated center were 10 percentage points less likely to receive these agents (two-sided P < .001). A 27 percentage-point increase in the likelihood of receiving a high-cost agent was observed in 2015, as compared to 2007, highlighting the rapid change in practice patterns (two-sided P < .001).

Conclusion

Potential policy and care delivery solutions involve outreach and support to community physicians who treat patients in remote areas. We estimate that widespread use of these agents conservatively cost approximately $3 billion per year for the treatment of metastatic non–small cell lung cancer alone.
Abdominal cocoon: an unexpected cause of ascites in a healthy patient
Authors: Kappauf Catharine , Rahaman Jamal , Popowich Daniel
Published: November 2019

Abdominal cocoon is the idiopathic fibrotic encasement of abdominal organs. It classically presents as small bowel obstruction in young women. In this case report, we present a rare example of a patient presenting solely with massive ascites of presumed gynecologic origin, who upon surgical exploration was found to have abdominal cocoon. We discuss the patient’s unique disease presentation, unrevealing work-up and the treatment strategy pursued, and provide a review of the literature.
Theatrical Marginalia: Pierre Baillot and the Prototype of the Modern Performer
Authors: Morabito Fabio
Published: November 2019

In Western art music, the idea of the professional performer as a versatile interpreter of someone else’s music consolidated around the turn of the nineteenth century. The institutionalization of instrumental training in dedicated schools (such as the Paris Conservatoire, established in 1795) favoured an increasing specialization of composers and performers in their respective tasks. Scholars have often traced the development of these modern professional identities to fundamental innovations in the fabric and conceptions of musical notation. The newly detailed scores by Haydn, Mozart, and Beethoven specify articulation, phrasing, and even fingerings, suggesting a growing authority of the composer over the performer’s moves, and the score itself as an increasingly important focus of the musical event (scripting both what performers should do and what listeners, ideally, should discern). Rather than focusing on how music was notated by composers, this article proposes to explore the perspective of the performers handling it: how they understood their role in bringing the score to life, and the realms of commentary they inspired in Parisian debates about the progress of the art and the mechanization of performance in the early nineteenth century. At the core of the Paris Conservatoire’s universal pedagogical project, the violinist Pierre Baillot (1771–1842) devised a prototype professional figure for the future of instrumental performance across genres: not a puppet-musician controlled via invisible strings, but an architect of musical impersonations, able to stimulate images or stories in the listeners’ minds and leave them theatrically spellbound.
Susceptibility of uncommon Candida species to systemic antifungals by the EUCAST methodology
Authors: Díaz-García Judith , Alcalá Luis , Martín-Rabadán Pablo , Mesquida Aina , Sánchez-Carrillo Carlos , Reigadas Elena , Muñoz Patricia , Escribano Pilar , Guinea Jesús
Published: November 2019

The incidence of infections by uncommon Candida species has increased in recent years, however, in vitro susceptibility data are scarce. Here we assess the susceptibility of C. krusei, C. dubliniensis, C. lusitaniae, and C. guilliermondii complex isolates (n = 120) to antifungal agents by the EUCAST methodology. C. dubliniensis proved to be the most susceptible species, similar to that of C. albicans (P < .05), whereas C. guilliermondii was the least susceptible. Two C. krusei isolates were echinocandin-resistant and harbored a point mutation (L701M) in the FKS1. Some isolates were either fluconazole-resistant (C. lusitaniae, n = 2) or fluconazole non-wild type (C. guilliermondii, n = 3).
Rotation measure synthesis applied to synthetic SKA images of galaxy clusters
Authors: Loi F , Murgia M , Govoni F , Vacca V , Bonafede A , Ferrari C , Prandoni I , Feretti L , Giovannini G , Li H
Published: November 2019

Future observations with next-generation radio telescopes will help us to understand the presence and evolution of magnetic fields in galaxy clusters through determination of the so-called rotation measure (RM). In this work, we applied the RM synthesis technique to synthetic first phase Square Kilometre Array mid frequency element (i.e. the SKA1-MID) radio images of a pair of merging galaxy clusters, measured between 950 and 1750 MHz with a resolution of 10 arcsec and thermal noise of 0.1μJy beam−1. The results of our RM synthesis analysis are compared with the simulation input parameters. We study two cases: one with radio haloes at the cluster centres and another without. We found that the information obtained with RM synthesis is in general agreement with the input information; however, some discrepancies are present. We characterize them in this work, with the final goal of determining the potential impact of SKA1-MID on the study of cluster magnetic fields.
Phylogenomics Identifies an Ancestral Burst of Gene Duplications Predating the Diversification of Aphidomorpha
Authors: Julca Irene , Marcet-Houben Marina , Cruz Fernando , Vargas-Chavez Carlos , Johnston John Spencer , Gómez-Garrido Jèssica , Frias Leonor , Corvelo André , Loska Damian , Cámara Francisco , Gut Marta , Alioto Tyler , Latorre Amparo , Gabaldón Toni
Published: November 2019

Aphids (Aphidoidea) are a diverse group of hemipteran insects that feed on plant phloem sap. A common finding in studies of aphid genomes is the presence of a large number of duplicated genes. However, when these duplications occurred remains unclear, partly due to the high relatedness of sequenced species. To better understand the origin of aphid duplications we sequenced and assembled the genome of Cinara cedri, an early branching lineage (Lachninae) of the Aphididae family. We performed a phylogenomic comparison of this genome with 20 other sequenced genomes, including the available genomes of five other aphids, along with the transcriptomes of two species belonging to Adelgidae (a closely related clade to the aphids) and Coccoidea. We found that gene duplication has been pervasive throughout the evolution of aphids, including many parallel waves of recent, species-specific duplications. Most notably, we identified a consistent set of very ancestral duplications, originating from a large-scale gene duplication predating the diversification of Aphidomorpha (comprising aphids, phylloxerids, and adelgids). Genes duplicated in this ancestral wave are enriched in functions related to traits shared by Aphidomorpha, such as association with endosymbionts, and adaptation to plant defenses and phloem-sap-based diet. The ancestral nature of this duplication wave (106–227 Ma) and the lack of sufficiently conserved synteny make it difficult to conclude whether it originated from a whole-genome duplication event or, alternatively, from a burst of large-scale segmental duplications. Genome sequencing of other aphid species belonging to different Aphidomorpha and related lineages may clarify these findings.
Allele frequency net database (AFND) 2020 update: gold-standard data classification, open access genotype data and new query tools
Authors: Gonzalez-Galarza Faviel F , McCabe Antony , Santos Eduardo J Melo dos , Jones James , Takeshita Louise , Ortega-Rivera Nestor D , Cid-Pavon Glenda M Del , Ramsbottom Kerry , Ghattaoraya Gurpreet , Alfirevic Ana , Middleton Derek , Jones Andrew R
Published: November 2019

The Allele Frequency Net Database (AFND, www.allelefrequencies.net) provides the scientific community with a freely available repository for the storage of frequency data (alleles, genes, haplotypes and genotypes) related to human leukocyte antigens (HLA), killer-cell immunoglobulin-like receptors (KIR), major histocompatibility complex Class I chain related genes (MIC) and a number of cytokine gene polymorphisms in worldwide populations. In the last five years, AFND has become more popular in terms of clinical and scientific usage, with a recent increase in genotyping data as a necessary component of Short Population Report article submissions to another scientific journal. In addition, we have developed a user-friendly desktop application for HLA and KIR genotype/population data submissions. We have also focused on classification of existing and new data into ‘gold–silver–bronze’ criteria, allowing users to filter and query depending on their needs. Moreover, we have also continued to expand other features, for example focussed on HLA associations with adverse drug reactions. At present, AFND contains >1600 populations from >10 million healthy individuals, making AFND a valuable resource for the analysis of some of the most polymorphic regions in the human genome.
Sensitive CometChip assay for screening potentially carcinogenic DNA adducts by trapping DNA repair intermediates
Authors: Ngo Le P , Owiti Norah A , Swartz Carol , Winters John , Su Yang , Ge Jing , Xiong Aoli , Han Jongyoon , Recio Leslie , Samson Leona D , Engelward Bevin P
Published: November 2019

Genotoxicity testing is critical for predicting adverse effects of pharmaceutical, industrial, and environmental chemicals. The alkaline comet assay is an established method for detecting DNA strand breaks, however, the assay does not detect potentially carcinogenic bulky adducts that can arise when metabolic enzymes convert pro-carcinogens into a highly DNA reactive products. To overcome this, we use DNA synthesis inhibitors (hydroxyurea and 1-β-d-arabinofuranosyl cytosine) to trap single strand breaks that are formed during nucleotide excision repair, which primarily removes bulky lesions. In this way, comet-undetectable bulky lesions are converted into comet-detectable single strand breaks. Moreover, we use HepaRG™ cells to recapitulate in vivo metabolic capacity, and leverage the CometChip platform (a higher throughput more sensitive comet assay) to create the ‘HepaCometChip’, enabling the detection of bulky genotoxic lesions that are missed by current genotoxicity screens. The HepaCometChip thus provides a broadly effective approach for detection of bulky DNA adducts.
In vitro and in vivo properties of therapeutic oligonucleotides containing non-chiral 3′ and 5′ thiophosphate linkages
Authors: Duschmalé Jörg , Hansen Henrik Frydenlund , Duschmalé Martina , Koller Erich , Albaek Nanna , Møller Marianne Ravn , Jensen Klaus , Koch Troels , Wengel Jesper , Bleicher Konrad
Published: November 2019

The introduction of non-bridging phosphorothioate (PS) linkages in oligonucleotides has been instrumental for the development of RNA therapeutics and antisense oligonucleotides. This modification offers significantly increased metabolic stability as well as improved pharmacokinetic properties. However, due to the chiral nature of the phosphorothioate, every PS group doubles the amount of possible stereoisomers. Thus PS oligonucleotides are generally obtained as an inseparable mixture of a multitude of diastereoisomeric compounds. Herein, we describe the introduction of non-chiral 3′ thiophosphate linkages into antisense oligonucleotides and report their in vitro as well as in vivo activity. The obtained results are carefully investigated for the individual parameters contributing to antisense activity of 3′ and 5′ thiophosphate modified oligonucleotides (target binding, RNase H recruitment, nuclease stability). We conclude that nuclease stability is the major challenge for this approach. These results highlight the importance of selecting meaningful in vitro experiments particularly when examining hitherto unexplored chemical modifications.
Genome3D: integrating a collaborative data pipeline to expand the depth and breadth of consensus protein structure annotation
Authors: Sillitoe Ian , Andreeva Antonina , Blundell Tom L , Buchan Daniel W A , Finn Robert D , Gough Julian , Jones David , Kelley Lawrence A , Paysan-Lafosse Typhaine , Lam Su Datt , Murzin Alexey G , Pandurangan Arun Prasad , Salazar Gustavo A , Skwark Marcin J , Sternberg Michael J E , Velankar Sameer , Orengo Christine
Published: November 2019

Genome3D (https://www.genome3d.eu) is a freely available resource that provides consensus structural annotations for representative protein sequences taken from a selection of model organisms. Since the last NAR update in 2015, the method of data submission has been overhauled, with annotations now being ‘pushed’ to the database via an API. As a result, contributing groups are now able to manage their own structural annotations, making the resource more flexible and maintainable. The new submission protocol brings a number of additional benefits including: providing instant validation of data and avoiding the requirement to synchronise releases between resources. It also makes it possible to implement the submission of these structural annotations as an automated part of existing internal workflows. In turn, these improvements facilitate Genome3D being opened up to new prediction algorithms and groups. For the latest release of Genome3D (v2.1), the underlying dataset of sequences used as prediction targets has been updated using the latest reference proteomes available in UniProtKB. A number of new reference proteomes have also been added of particular interest to the wider scientific community: cow, pig, wheat and mycobacterium tuberculosis. These additions, along with improvements to the underlying predictions from contributing resources, has ensured that the number of annotations in Genome3D has nearly doubled since the last NAR update article. The new API has also been used to facilitate the dissemination of Genome3D data into InterPro, thereby widening the visibility of both the annotation data and annotation algorithms.
Necroptotic astrocytes contribute to maintaining stemness of disseminated medulloblastoma through CCL2 secretion
Authors: Liu Hailong , Sun Youliang , O’Brien Jenny A , Franco-Barraza Janusz , Qi Xueling , Yuan Hongyu , Jin Wei , Zhang Junping , Gu Chunyu , Zhao Zhenyu , Yu Chunjiang , Feng Shiyu , Yu Xinguang
Published: November 2019

Background

Medulloblastoma (MB) with metastases at diagnosis and recurrence correlates with poor prognosis. Unfortunately, the molecular mechanism underlying metastases growth has received less attention than primary therapy-naïve MB. Though astrocytes have been frequently detected in brain tumors, their roles in regulating the stemness properties of MB stem-like cells (MBSCs) in disseminated lesions remain elusive.

Methods

Effects of tumor-associated astrocyte (TAA)–secreted chemokine C-C ligand 2 (CCL2) on MBSC self-renewal was determined by immunostaining analysis. Necroptosis of TAA was examined by measuring necrosome activity. Alterations in Notch signaling were examined after inhibition of CCL2. Progression of MBSC-derived tumors was evaluated after pharmaceutical blockage of necroptosis.

Results

TAA, as the essential components of disseminated tumor, produced high levels of CCL2 to shape the inflammation microenvironment, which stimulated the enrichment of MBSCs in disseminated MB. In particular, CCL2 played a pivotal role in maintaining stem-like properties via Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3)–mediated activation of Notch signaling. Loss of CCL2/C-C chemokine receptor 2 (CCR2) function repressed the JAK2/STAT3-Notch pathway and impaired MBSC proliferation, leading to a dramatic reduction of stemness, tumorigenicity, and metastasizing capability. Furthermore, necroptosis-induced CCL2 release depended on activation of receptor-interacting protein 1 (RIP1)/RIP3/mixed lineage kinase domain-like pseudokinase (MLKL) in TAA, which promoted the oncogenic phenotype. Blockade of necroptosis resulted in CCL2 deprivation and compromised MBSC self-proliferation, indicating MBSCs outsourced CCL2 from necroptotic TAA. Finally, CCL2 was upregulated in high-risk stages of MB, further supporting its value as a prognostic indicator.

Conclusion

These findings highlighted the critical role of CCL2/CCR2 in Notch signaling activation in MBSCs and revealed a necroptosis-associated glial cytokine microenvironment driving stemness maintenance in disseminations.

Key Points

1. TAA-derived CCL2 promoted stemness in disseminated MBSCs through Notch signaling activation via the JAK2/STAT3 pathway.

2. TAA released CCL2 in a RIP1/RIP3/MLKL-dependent manner leading to necroptosis.
Visually constructing the chemical structure of a single molecule by scanning Raman picoscopy
Authors: Zhang Yao , Yang Ben , Ghafoor Atif , Zhang Yang , Zhang Yu-Fan , Wang Rui-Pu , Yang Jin-Long , Luo Yi , Dong Zhen-Chao , Hou J G
Published: November 2019

The strong spatial confinement of a nanocavity plasmonic field has made it possible to visualize the inner structure of a single molecule and even to distinguish its vibrational modes in real space. With such ever-improved spatial resolution, it is anticipated that full vibrational imaging of a molecule could be achieved to reveal molecular structural details. Here we demonstrate full Raman images of individual vibrational modes at the ångström level for a single Mg-porphine molecule, revealing distinct characteristics of each vibrational mode in real space. Furthermore, by exploiting the underlying interference effect and Raman fingerprint database, we propose a new methodology for structural determination, which we have called ‘scanning Raman picoscopy’, to show how such ultrahigh-resolution spectromicroscopic vibrational images can be used to visually assemble the chemical structure of a single molecule through a simple Lego-like building process.
A Retrospective Multisite Case-Control Series of Concomitant Use of Daptomycin and Statins and the Effect on Creatine Phosphokinase
Authors: Lehman Bethany , Neuner Elizabeth A , Heh Victor , Isada Carlos
Published: November 2019

Objective

Daptomycin has been associated with increased creatine phosphokinase (CPK) due to muscle injury leading to myalgias and muscle weakness. Statins have been proven to cause the same effects and it is recommended to discontinue the use of statins while on daptomycin. Evidence regarding this drug interaction is mixed. This study evaluated the risk of CPK elevation in concomitant use of daptomycin and statins compared to daptomycin alone.

Method

This is a multisite retrospective case-control study of patients who received daptomycin therapy with monitoring of CPK. Rates of CPK elevations were compared in patients receiving daptomycin with a statin versus daptomycin alone. To estimate the association between CPK elevation and daptomycin therapy controlling for other risk factors, logistic regression was used to analyze data. Statistical significance was determined at ɑ of 0.05.

Results

A total of 3658 patients were included in the study, with 2787 on daptomycin therapy alone and 871 with concurrent statin use. The incidence of CPK elevation was 90 events (3.2%) in the daptomycin group and 26 events (3.0%) in the concurrent statin group. Patients who received daptomycin therapy in addition to statins had no statistically significant difference from patients on daptomycin alone (hazard ratio, 1.05; P = .85; 95% confidence interval, 0.61–1.84). After adjusting for potential risk factors, the hazards ratio remained almost the same.

Conclusions

Concomitant use of daptomycin and statin did not show an increase risk of CPK elevation. Clinicians may consider concomitant use of daptomycin and statin therapy with weekly CPK monitoring.
Incidence and Predictive Risk Factors of Infective Events in Patients With Multiple Sclerosis Treated With Agents Targeting CD20 and CD52 Surface Antigens
Authors: Zappulo Emanuela , Buonomo Antonio Riccardo , Saccà Francesco , Russo Cinzia Valeria , Scotto Riccardo , Scalia Giulia , Nozzolillo Agostino , Lanzillo Roberta , Tosone Grazia , Gentile Ivan
Published: November 2019

Objective

Monoclonal antibodies (MAbs) directed against the CD20 and CD52 antigens are used increasingly in patients with multiple sclerosis (MS). Several life-threatening opportunistic infections have been reported in postmarketing case series. The aim of this study was to investigate the incidence of infections and associated prognostic factors during the first year of treatment in patients receiving anti-CD20 (ocrelizumab or rituximab) or anti-CD52 MAbs (alemtuzumab).

Methods

A retrospective study was conducted in patients with MS referring to the Neurodegenerative Diseases Center at the University of Naples Federico II who received MAbs between November 2015 and June 2018.

Results

A total of 163 patients were enrolled. Approximately 40% of patients experienced lymphocytopenia during treatment. Eighty-six infective events were reported in 67 patients (41%). Bacterial infections were significantly more frequent with anti-CD20, whereas viral infections prevailed with alemtuzumab. Cytomegalovirus reactivation rates were significantly higher in the alemtuzumab group than in patients on anti-CD20 (51% vs 6%, P < .001). The overall annualized infection rate was 1.1 per patient-year, higher in patients on anti-CD52 versus those on anti-CD20 regimens (1.5 vs 0.8 per patient-year). Alemtuzumab treatment, prior exposure to ≥2 MS drugs, and iatrogenic immune impairment significantly and independently predicted an infection event (adjusted hazard ratio [aHR], 2.7; P = .013; aHR, 1.7; P = .052; and aHR, 2.9; P = .004; respectively).

Conclusions

Given their considerable infection risk, MS patients receiving MAbs should undergo timely follow up and tailored preventive interventions. Anti-CD52–based treatment, prior exposure to MS drugs, and on-treatment immune impairment are significant predictive factors of infection and their evaluation could help clinicians to stratify a patient’s risk of infection.
Factors Influencing the Delivery of Intensive Rehabilitation in Stroke: Patient Perceptions Versus Rehabilitation Therapist Perceptions
Authors: Janssen Jessie , Klassen Tara D , Connell Louise A , Eng Janice J
Published: November 2019

Background

Despite increasing evidence regarding the benefit of intensive task-specific practice and aerobic exercise in stroke rehabilitation, implementation remains difficult. The factors influencing implementation have been explored from therapists’ perspectives; however, despite an increased emphasis on patient involvement in research, patients’ perceptions have not yet been investigated.

Objective

The study aimed to investigate factors influencing implementation of higher intensity activity in people with stroke and to compare this with therapists’ perspectives.

Design

The design was a cross-sectional qualitative study.

Methods

The study used semistructured interviews with people with stroke who were part of a randomized clinical trial, the Determining Optimal post-Stroke Exercise study, which delivered a higher intensity intervention. An interview guide was developed and data analyzed using implementation frameworks. Factors emerging from interviews with people with stroke were compared and contrasted with factors perceived by rehabilitation therapists.

Results

Ten people with stroke were interviewed before data saturation was reached. Participants had a positive attitude regarding working hard and were satisfied with the graded exercise test, high intensity intervention, and the feedback-monitoring devices. Therapists and patients had contrasting perceptions about their beliefs regarding intensive exercise and the content of the intervention, with therapists more focused on the methods and patients more focused on the personal interactions stemming from the therapeutic relationship.

Conclusions

People with stroke perceived no barriers regarding the implementation of higher intensity rehabilitation in practice and were positive towards working at more intense levels. Contrastingly, from the therapists’ perspective, therapists’ beliefs about quality of movement and issues around staffing and resources were perceived to be barriers. In addition, therapists and people with stroke perceived the contents of the intervention differently, highlighting the importance of involving patients and clinicians in the development and evaluation of rehabilitation interventions.