bluuebunny/crossref_metadata_2025 huggingface dataset:
Chemical–protein interaction extraction via Gaussian probability distribution and external biomedical knowledge
Authors: Sun Cong , Yang Zhihao , Su Leilei , Wang Lei , Zhang Yin , Lin Hongfei , Wang Jian
Published: May 2020

Motivation

The biomedical literature contains a wealth of chemical–protein interactions (CPIs). Automatically extracting CPIs described in biomedical literature is essential for drug discovery, precision medicine, as well as basic biomedical research. Most existing methods focus only on the sentence sequence to identify these CPIs. However, the local structure of sentences and external biomedical knowledge also contain valuable information. Effective use of such information may improve the performance of CPI extraction.

Results

In this article, we propose a novel neural network-based approach to improve CPI extraction. Specifically, the approach first employs BERT to generate high-quality contextual representations of the title sequence, instance sequence and knowledge sequence. Then, the Gaussian probability distribution is introduced to capture the local structure of the instance. Meanwhile, the attention mechanism is applied to fuse the title information and biomedical knowledge, respectively. Finally, the related representations are concatenated and fed into the softmax function to extract CPIs. We evaluate our proposed model on the CHEMPROT corpus. Our proposed model is superior in performance as compared with other state-of-the-art models. The experimental results show that the Gaussian probability distribution and external knowledge are complementary to each other. Integrating them can effectively improve the CPI extraction performance. Furthermore, the Gaussian probability distribution can effectively improve the extraction performance of sentences with overlapping relations in biomedical relation extraction tasks.

Availability and implementation

Data and code are available at https://github.com/CongSun-dlut/CPI_extraction.

Supplementary information

Supplementary data are available at Bioinformatics online.
Ventricular fibrillation mechanism and global fibrillatory organization are determined by gap junction coupling and fibrosis pattern
Authors: Handa Balvinder S , Li Xinyang , Baxan Nicoleta , Roney Caroline H , Shchendrygina Anastasia , Mansfield Catherine A , Jabbour Richard J , Pitcher David S , Chowdhury Rasheda A , Peters Nicholas S , Ng Fu Siong
Published: May 2020

Aims

Conflicting data exist supporting differing mechanisms for sustaining ventricular fibrillation (VF), ranging from disorganized multiple-wavelet activation to organized rotational activities (RAs). Abnormal gap junction (GJ) coupling and fibrosis are important in initiation and maintenance of VF. We investigated whether differing ventricular fibrosis patterns and the degree of GJ coupling affected the underlying VF mechanism.

Methods and results

Optical mapping of 65 Langendorff-perfused rat hearts was performed to study VF mechanisms in control hearts with acute GJ modulation, and separately in three differing chronic ventricular fibrosis models; compact fibrosis (CF), diffuse fibrosis (DiF), and patchy fibrosis (PF). VF dynamics were quantified with phase mapping and frequency dominance index (FDI) analysis, a power ratio of the highest amplitude dominant frequency in the cardiac frequency spectrum. Enhanced GJ coupling with rotigaptide (n = 10) progressively organized fibrillation in a concentration-dependent manner; increasing FDI (0 nM: 0.53 ± 0.04, 80 nM: 0.78 ± 0.03, P < 0.001), increasing RA-sustained VF time (0 nM: 44 ± 6%, 80 nM: 94 ± 2%, P < 0.001), and stabilized RAs (maximum rotations for an RA; 0 nM: 5.4 ± 0.5, 80 nM: 48.2 ± 12.3, P < 0.001). GJ uncoupling with carbenoxolone progressively disorganized VF; the FDI decreased (0 µM: 0.60 ± 0.05, 50 µM: 0.17 ± 0.03, P < 0.001) and RA-sustained VF time decreased (0 µM: 61 ± 9%, 50 µM: 3 ± 2%, P < 0.001). In CF, VF activity was disorganized and the RA-sustained VF time was the lowest (CF: 27 ± 7% vs. PF: 75 ± 5%, P < 0.001). Global fibrillatory organization measured by FDI was highest in PF (PF: 0.67 ± 0.05 vs. CF: 0.33 ± 0.03, P < 0.001). PF harboured the longest duration and most spatially stable RAs (patchy: 1411 ± 266 ms vs. compact: 354 ± 38 ms, P < 0.001). DiF (n = 11) exhibited an intermediately organized VF pattern, sustained by a combination of multiple-wavelets and short-lived RAs.

Conclusion

The degree of GJ coupling and pattern of fibrosis influences the mechanism sustaining VF. There is a continuous spectrum of organization in VF, ranging between globally organized fibrillation sustained by stable RAs and disorganized, possibly multiple-wavelet driven fibrillation with no RAs.
Exploring the Ecology and Indicator Value of Some Larvae of Odonata Genera in Colombia
Authors: Garzón-Salamanca Laura L , Rivera-Rondón Carlos A , Aristizabal Hernán , Forero Dimitri
Published: May 2020

Bioindication is a method to assess environmental conditions using indicator organisms. In Colombia, water quality evaluation is mostly performed following the Biological Monitoring Working Party/Colombia method (BMWP/Col), which uses aquatic macroinvertebrates at the taxonomic family level. Studies on potential bioindicators are important to produce comprehensive information on the requirements of macroinvertebrates and their value for water quality bioindication. We studied the larval ecology of several common genera of Odonata from Colombian freshwater ecosystems and assigned an indicator value to each genus. The physical and chemical water characteristics of 1,022 sites surveyed in Colombia from 2005 to 2016 were analyzed using a principal component analysis (PCA). The relationship between environmental conditions and Odonata genera found was studied using multiple logistic regressions between sample coordinates of the first three axes of the PCA and occurrence of the respective genus. We assigned an indicator value for each genus using the logistic regression and the water quality of samples. The highest indicator values were assigned to genera, which were mainly explained by the PCA axis associated with water quality, showed a high odds ratio to this axis, and were found in ecosystems with excellent water quality. The indicator values suggested for each taxon are, Brechmorhoga Kirby, 1894, 8; Macrothemis Hagen, 1868, 4; Micrathyria Kirby, 1889, 4 (Libellulidae); Progomphus Selys, 1854, 7 (Gomphidae); Acanthagrion Selys, 1876, 4; and Argia Rambur, 1842, 7 (Coenagrionidae). Differences in water quality preferences in genera of the same family suggest that higher taxonomic resolution may allow more detailed environmental assessments.
Symposium summary: Epigenetic inheritance—impact for biology and society 26–28 August 2019, Zurich, Switzerland
Authors: Lazar-Contes Irina , Roszkowski Martin , Tanwar Deepak K , Mansuy Isabelle M
Published: May 2020

The concept of epigenetic inheritance proposes a new and unconventional way to think about heredity in health and disease, at the interface between genetics and the environment. Epigenetic inheritance is a form of biological inheritance not encoded in the DNA sequence itself but mediated by epigenetic factors. Because epigenetic factors can be modulated by the environment, they can relay this information to the genome and modify its activity consequentially. If epigenetic changes induced by environmental exposure are present in the germline and persist in germ cells during development until conception, they have the potential to transfer the traces of ancestral exposure to the progeny.

This form of heredity relates to the extremely important question of nature versus nurture and how much of our own make-up is genetically or epigenetically determined, a question that remains largely unresolved. Because it questions the dominant dogma of genetics and brings a paradigm shift in sciences, it has to creating strong bridges between disciplines and provide solid causal evidence to be firmly established.

The second edition of a conference fully dedicated to epigenetic inheritance was held in August 2019 in Zurich, Switzerland. This symposium titled ‘Epigenetic inheritance: impact for biology and society’ (http://www.epigenetic-inheritance-zurich.ethz.ch), gathered experts in the field of epigenetic inheritance to discuss the concept and pertinent findings, exchange views and expertise about models and methods, and address challenges raised by this new discipline. The symposium offered a mix of invited lectures and short talks selected from abstracts, poster sessions and a workshop ‘Meet the experts: Q&A’. A tour of a local omics facility the Functional Genomics Center Zurich was also offered to interested participants. Additional comments and impressions were shared by attendees on Twitter #eisz19 during and after the symposium. This summary provides an overview of the different sessions and talks and describes the main findings presented.
Prognostic implications of left ventricular myocardial work indices in cardiac amyloidosis
Authors: Clemmensen Tor Skibsted , Eiskjær Hans , Ladefoged Bertil , Mikkelsen Fabian , Sørensen Jens , Granstam Sven-Olof , Rosengren Sara , Flachskampf Frank A , Poulsen Steen Hvitfeldt
Published: May 2020

Aims

Left ventricular (LV) myocardial work index (LVMWI) derived from pressure–strain analysis resembles a novel non-invasive method for LV function evaluation. LV global longitudinal strain (LVGLS) has proven beneficial for risk stratification in cardiac amyloidosis (CA) patients. This study aimed to evaluate the potential additive value of LVMWI for outcome prediction in CA patients.

Methods and results

We enrolled 100 CA patients in the period 2014–19 from Aarhus University Hospital, Denmark and Uppsala University Hospital, Sweden. All patients underwent comprehensive echocardiographic evaluation and were prospectively followed until censuring date on 31 March 2019 or death. During follow-up, we registered major adverse cardiac events (MACE) comprising heart failure requiring hospitalization and all-cause mortality. The median follow-up was 490 (228–895) days. During follow-up, a total of 42% of patients experienced MACE and 29% died. Patients with LVMWI <1043 mmHg% had higher MACE risk than patients with LVMWI >1043 mmHg% [hazard ratio (HR) 2.3, 95% confidence interval (CI) 1.2–4.3; P = 0.01]. Furthermore, patients with LVMWI <1039 mmHg% also had higher all-cause mortality risk than patients with LVMWI >1039 mmHg% (HR 2.6, 95% CI 1.2–5.5; P < 0.05). Moreover, the apical-to-basal segmental work ratio was a significant MACE and all-cause mortality predictor. By combining LVMWI and apical-to-basal segmental work ratio, we obtained an independent model for all-cause mortality prediction (high vs. low risk: HR 6.4, 95% CI 2.4–17.1; P < 0.0001). In contrast, LVGLS did not predict all-cause mortality.

Conclusion

LV myocardial work may be of prognostic value in CA patients by predicting both MACE and all-cause mortality.
The interplay between cardiology and diabetology: a renewed collaboration to optimize cardiovascular prevention and heart failure management
Authors: Sabouret Pierre , Galati Giuseppe , Angoulvant Denis , Germanova Olga , Castelletti Silvia , Pathak Atul , Metra Marco , Margonato Alberto
Published: May 2020

Type 2 diabetes mellitus (T2DM) portends high risk of atherosclerotic cardiovascular (CV) events and of CV mortality; moreover, this group of patients has a very high probability of developing heart failure (HF). In this review, we discuss new advances in pharmacological treatment both in CV prevention and in HF management with a special focus on T2DM patients. A large number of randomized clinical trials and meta-analyses provided strong evidence about therapeutic strategies acting on glucose metabolism, such as GLP-1 RA and SGLT2i and about lipid-lowering treatment, such as PCSK9i and icosapent ethyl. Moreover, SGLT2i demonstrated strong evidence of benefit particularly in HF management both in diabetic and non-diabetic patients. The pathophysiological bases of multiple mechanisms of benefit of this class of drug explain the unexpected and remarkable results demonstrated both by prevention trials and by trials dedicated only to HF (like DAPA-HF). These, new drugs in the CV therapeutic armamentarium are establishing a new comprehensive approach from prevention to therapy of HF, giving more emphasis on HF classification in four stages (A→D). New therapies, which are on the horizon, promise to further reduce CV mortality and morbidity in HF patients irrespective of diabetic status.
Grazing effect of flagellates on bacteria in response to phosphate addition in the oligotrophic Cretan Sea, NE Mediterranean
Authors: Oikonomou Andreas , Livanou Eleni , Mandalakis Manolis , Lagaria Anna , Psarra Stella
Published: May 2020

The planktonic food web in the oligotrophic Mediterranean Sea is dominated by small-sized (<20 μm) microbes, with nanoflagellates being the major bacterial grazers and the main participants in nutrient cycling. Phosphate is a key nutrient in the P-limited Cretan Sea (NE Mediterranean) and P-availability can affect its trophic dynamics. Here, we examined the grazing potential of heterotrophic (HF) and pigmented (PF) nanoflagellates as a response mechanism to phosphate amendment. Flagellate grazing effect on bacteria was quantified in P-amended nutrient-depleted water from the Cretan Sea over the course of 4 days using microcosm experiments. P-addition positively affected HF abundance, while PF abundance remained unchanged. At the community level, P-addition had a negative effect on PF bacterial removal rates. In the control, PF-grazing rate was significantly higher than that of HF throughout the experiment. Pigment analysis showed no changes in phytoplankton community composition as a result of P-addition, indicating that PF grazing rate declined as a physiological response of the cells. The present study emphasizes the dominant grazing role of PF under P-depleted conditions and reveals that during the late stratified season PF respond to P-addition by lowering their grazing rates, enhancing the relative importance of bacterial removal by HF.
Upregulated insulin receptor tyrosine kinase substrate promotes the proliferation of colorectal cancer cells via the bFGF/AKT signaling pathway
Authors: Wang Song , Liu Zheng , Ma Yi-Ming , Guan Xu , Jiang Zheng , Sun Peng , Liu En-Rui , Zhang Yu-Kun , Wang Hong-Ying , Wang Xi-Shan
Published: May 2020

Background

Some recent studies on insulin receptor tyrosine kinase substrate (IRTKS) have focused more on its functions in diseases. However, there is a lack of research on the role of IRTKS in carcinomas and its mechanism remains ambiguous. In this study, we aimed to clarify the role and mechanism of IRTKS in the carcinogenesis of colorectal cancer (CRC).

Methods

We analysed the expression of IRTKS in CRC tissues and normal tissues by researching public databases. Cancer tissues and adjacent tissues of 67 CRC patients who had undergone radical resection were collected from our center. Quantitative real-time polymerase chain reaction and immunohistochemistry were performed in 52 and 15 pairs of samples, respectively. In vitro and in vivo experiments were conducted to observe the effect of IRTKS on CRC cells. Gene Set Enrichment Analysis and Metascape platforms were used for functional annotation and enrichment analysis. We detected the protein kinase B (AKT) phosphorylation and cell viability of SW480 transfected with small interfering RNAs (siRNAs) with or without basic fibroblast growth factor (bFGF) through immunoblotting and proliferation assays.

Results

The expression of IRTKS in CRC tissues was higher than that in adjacent tissues and normal tissues (all P < 0.05). Disease-free survival of patients with high expression was shorter. Overexpression of IRTKS significantly increased the proliferation rate of CRC cells in vitro and the number of tumor xenografts in vivo. The phosphorylation level of AKT in CRC cells transfected with pLVX-IRTKS was higher than that in the control group. Furthermore, siRNA-IRTKS significantly decreased the proliferation rate of tumor cells and the phosphorylation level of AKT induced by bFGF.

Conclusion

IRTKS mediated the bFGF-induced cell proliferation through the phosphorylation of AKT in CRC cells, which may contribute to tumorigenicity in vivo.
Measuring Self-Perceptions of Aging: Differences Between Measures When Predicting Health Outcomes
Authors: Boeder Jordan , Tse Dwight C K
Published: May 2020

Objectives

The majority of self-perceptions of aging (SPA) research uses either a combination of the Aging-related Cognitions (AgeCog) scales of Ongoing Development and Physical Loss, or the Attitudes Towards Own Aging (ATOA) subscale to assess views on aging. Although these scales are used interchangeably, the valence (positive/negative) and the specificity of the view on aging (domain-based/general) being assessed are not consistent. This study investigates how different measures of SPA relate to one another and whether they differentially predict various types of health outcomes (psychological/physiological; well-being/ill-being).

Method

Data from the 2008 and 2014 waves of the German Aging Survey (DEAS; N = 3,745), a population-based representative survey of adults aged 40–95, was used to examine the relationship between the AgeCog scales and the ATOA subscale, as well as the differences in the types of health outcomes each predicts.

Results

The correlations between the AgeCog scales and the ATOA were higher than the correlation between the AgeCog scales (p < .001). The AgeCog scale of Ongoing Development significantly predicted psychological health outcomes across a 6-year period, while the AgeCog scale of Physical Loss and the ATOA subscale predicted both physiological and psychological health outcomes.

Discussion

Evidence supports using the AgeCog scale of Ongoing Development to predict domain-relevant, psychological health outcomes. However, the multidimensionality of SPA is best measured by the ATOA subscale or a combination of the two AgeCog scales. Both forms of measurement were found to maximize the amount of explained variance for psychological and physiological indicators of well-being and ill-being.
Evaluation of the in vitro activity of new polymyxin B analogue SPR206 against clinical MDR, colistin-resistant and tigecycline-resistant Gram-negative bacilli
Authors: Zhang Yawei , Zhao Chunjiang , Wang Qi , Wang Xiaojuan , Chen Hongbin , Li Henan , Zhang Feifei , Wang Hui
Published: May 2020

Background

SPR206 is a novel polymyxin analogue. Activity against clinical isolates is little documented.

Methods

A collection of 200 MDR, carbapenem-resistant, tigecycline-resistant, colistin-resistant and non-MDR clinical isolates of Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Enterobacter cloacae and Stenotrophomonas maltophilia was obtained from 50 centres across China (2016–17). All isolates were derived from respiratory tract, urine and blood samples. Strains were purposely selected on the basis of phenotypes, genotypes and specimen origins. MICs of SPR206 and other antimicrobials were determined.

Results

SPR206 was active against all bacteria tested except colistin-resistant isolates. The MIC50/90 values of SPR206 for colistin-resistant strains were comparable to known polymyxins (16/128 versus 8/128 mg/L). SPR206 exhibited potent activity against colistin-susceptible OXA-producing A. baumannii (MIC50/90 = 0.064/0.125 mg/L), NDM-producing Enterobacteriaceae (MIC50/90 = 0.125/0.25 mg/L) and KPC-2-producing Enterobacteriaceae (MIC50/90 = 0.125/0.5 mg/L). In fact, SPR206 was the most potent agent tested, with 2- to 4-fold lower MICs than colistin and polymyxin B for A. baumannii, P. aeruginosa and Enterobacteriaceae. Additionally, MIC values of SPR206 (MIC50/90 = 0.064/0.125 mg/L) were 16- to 32-fold lower than those of tigecycline (MIC50/90 = 2/2 mg/L) for tigecycline-susceptible carbapenem-resistant A. baumannii.

Conclusions

SPR206 showed good in vitro activity against MDR, tigecycline-resistant and non-MDR clinical isolates of Gram-negative pathogens. SPR206 also exhibited superior potency to colistin and polymyxin B, with 2- to 4-fold lower MIC50/90 values.
Modeling consent in the time of COVID-19
Authors: Knoppers Bartha Maria , Beauvais Michael J S , Joly Yann , Zawati Ma'n H , Rousseau Simon , Chassé Michaël , Mooser Vincent
Published: May 2020

Effective responses to the COVID-19 pandemic require novel solutions for research and responsible data sharing. Biobanking presents itself as a key priority in furthering our understanding of COVID-19. In this article, we propose a tripartite approach to consent to create resources for research relating to COVID-19. The approach aims to link three levels of participation: COVID-19 patients, respiratory/infectious disease patients, and longitudinal study participants. We explore the potential approaches that can be taken to consent processes with these three participant groups. We furthermore describe an access model for both single-site and multi-site data and sample storage. Through dealing with these topics at a high level, the model may be adapted to local legal and ethical requirements while still pursuing its ultimate goal: the creation of a research infrastructure that supports transparent, strong, and open science.
Underperformed and Underreported Testing for Persistent Oropharyngeal Poliovirus Infections in Primary Immune Deficient Patients—Risk for Reemergence of Polioviruses
Authors: Shulman Lester M , Weil Merav , Somech Raz , Stauber Tali , Indenbaum Victoria , Rahav Galia , Mendelson Ella , Sofer Danit
Published: May 2020

Background

Individuals with primary immune deficiencies (PIDs) may excrete poliovirus for extended periods and remain a major reservoir for polio after eradication. Poliovirus can spread by fecal–oral or oral–oral transmission. In middle- and high-income countries, oral–oral transmission may be more prevalent than fecal–oral transmission of polioviruses where PIDs patients survive longer. Our aim was to determine the prevalence of prolonged or persistent oropharyngeal poliovirus infections in PIDs.

Methods

We performed a literature search for reports of prolonged (excreting poliovirus for ≥6 months and ≤5 years) or persistent (excreting poliovirus for >5 years) poliovirus infections in PIDs.

Results

There were 140 PID cases with prolonged or persistent poliovirus infections. All had poliovirus-positive stools. Testing of oropharyngeal mucosa was only reported for 6 cases, 4 of which were positive. Molecular analyses demonstrated independent evolution of poliovirus in the gut and oropharyngeal mucosa in 2 cases. Seven PIDs had multiple lineages of the same poliovirus serotype in stools without information about polioviruses in oropharyngeal mucosa.

Conclusions

Testing for persistence of poliovirus in oropharyngeal mucosa of PID patients is rare, with virus recovered in 4 of 5 cases in whom stools were positive. Multiple lineages or serotypes in 7 additional PID cases may indicate separate foci of infection, some of which might be in oropharyngeal mucosa. We recommend screening throat swabs in addition to stools for poliovirus in PID patients. Containment protocols for reducing both oral–oral and fecal–oral transmission from PID patients must be formulated for hospitals and community settings.
Similar yet critically different: the distribution, dynamics and function of histone variants
Authors: Probst Aline V , Desvoyes Bénédicte , Gutierrez Crisanto
Published: May 2020

Organization of the genetic information into chromatin plays an important role in the regulation of all DNA template-based reactions. The incorporation of different variant versions of the core histones H3, H2A, and H2B, or the linker histone H1 results in nucleosomes with unique properties. Histone variants can differ by only a few amino acids or larger protein domains and their incorporation may directly affect nucleosome stability and higher order chromatin organization or indirectly influence chromatin function through histone variant-specific binding partners. Histone variants employ dedicated histone deposition machinery for their timely and locus-specific incorporation into chromatin. Plants have evolved specific histone variants with unique expression patterns and features. In this review, we discuss our current knowledge on histone variants in Arabidopsis, their mode of deposition, variant-specific post-translational modifications, and genome-wide distribution, as well as their role in defining different chromatin states.
Insurance
Authors: Benatar Martin , Hussain Munib
Published: May 2020

This chapter discusses the importance of project insurance. Financiers take an onerous approach to insurance in project finance transactions, requiring a comparably more robust insurance programme than would be adopted in a project that is financed on balance sheet alone. This reflects the fact that until the project company has established a reliable revenue stream, it will have a low level of capitalization and be highly leveraged. The primary function of insurance is to act as a risk transfer mechanism. In return for a known cost (the premium) the uncertainty associated with both the frequency and severity of loss is transferred to the insurer. The discussions cover insurance programme design, project company control, the breadth and scope of the insurance programme, legal and commercial influences on procurement, and insurance risk itself and lenders’ clauses.
The IPO Process, IPO Disclosure, and the Prospectus Regulation
Authors: Teerink Han
Published: May 2020

This chapter offers insight into a typical initial public offering (IPO) process, highlighting key practical and legal considerations around disclosure, through the IPO prospectus and otherwise. The prospectus plays a key role in the preparations for, and execution of, an IPO. As an IPO prospectus typically constitutes a company's first public dissemination of financial and business information, the company and other parties involved in the IPO process must carefully consider the right balance between, on the one hand, drafting the IPO prospectus as a marketing document introducing the company and its business to potential investors, whilst, on the other hand, being able to use the prospectus as a disclosure document that protects the company against liability arising from claims from investors or others after the IPO. Here, the chapter summarizes the different phases in an IPO process and the most important documents and parties involved, focusing on the central role of the IPO prospectus. In addition, a number of changes resulting from the enactment of the Prospectus Regulation are likely to be of particular relevance to IPO processes. The expected impact of these changes is therefore also discussed.
Stabilization and Underpricing in IPOs
Authors: Lombardo Stefano
Published: May 2020

This chapter zooms in on stabilization and underpricing in IPOs. The Market Abuse Regulation (MAR) provides an exemption from the prohibitions of insider dealing and of market manipulation for the stabilisation of securities. This is usually realised in the case of an initial public offering (IPO) and is regulated in detail by Commission Delegated Regulation 2016/1052. The chapter thus introduces the economic theory of IPOs, analysing in particular the underpricing phenomenon (and its opposite, the overpricing). After a comparative and useful description of the US system of IPO stabilization activity, the chapter focuses on a detailed analysis of the European regime under MAR and Regulation 2016/1052.
The Obligation to Publish a Prospectus and Exemptions
Authors: Lieverse Kitty
Published: May 2020

This chapter offers a comprehensive treatment of the obligation to publish a prospectus, including the available exemptions. The Prospectus Regulation provides for an update of the prospectus obligation and the exemptions thereto. However, the provisions that determine the requirement to publish an approved prospectus have remained unaltered. In addition, the exemptions to have a prospectus available compliant with the Prospectus Regulation have largely remained the same. The chapter shows, however, that there have been some changes when it comes to exemptions. Notably, the regime for small size offerings has changed. The chapter concludes that the goal of the European legislator to enhance harmonisation between the member states by including the prospectus regime in a regulation, has not been achieved for these small-size offerings. In addition, some exemptions for the prospectus requirement in the event of a listing have either been extended or restricted. Finally, the chapter notes that the disclosure regime as such, as is provided by a prospectus under the Prospectus Regulation, has not been truly reconsidered, in the context also of concurrence with other disclosure regimes.
‘Light’ Disclosure Regimes
Authors: Perrone Andrea
Published: May 2020

This chapter zooms in on the ‘light’ disclosure regime for small and medium-sized enterprises (SMEs). It shows that SME financing through capital markets is no easy task. On the supply side, adverse selection and lack of liquid secondary markets hamper the access of both retail and professional investors. On the demand side, lack of financial literacy, costs of compliance, and the possibility for the owners to lose control of the firm discourage SMEs from turning to capital markets for funds. For both reasons, it is therefore understandable why SMEs are typically financed through banking and banks maintain a ‘monopolistic’ power over SMEs. In this context, the chapter argues that the light disclosure regime introduced by the Prospectus Regulation is mostly toothless. Still shaped by the ‘myth of the informed layman’ and of little use to institutional investors, the EU Growth prospectus does reduce compliance costs for issuers but suffers the lack of a EU-based ‘eco-system’ fully supporting SMEs seeking finance.
‘Light’ Disclosure Regimes
Authors: Horsten Pim
Published: May 2020

This chapter analyses and discusses the ‘light’ disclosure regime available for secondary issuances. Here, it remains to be seen whether this new simplified regime will be used much in practice. The proportionate disclosure regime for statutory rights issues introduced by the 2010 amendment of the Prospectus Directive was little used. Moreover, at a conceptual level the chapter submits that not many would disagree that for investors at some stage more disclosure makes a prospectus difficult to understand, as it may be difficult to discern important facts in a mass of less important detail. The chapter asserts that the ideal disclosure document is short, clear, and comprehensive in including all information an investor needs to make an informed investment decision. The tension, however, is between short and comprehensive, in the sense of including all necessary information. The chapter concludes that time will tell whether in case of secondary issuances one will see simplified prospectuses with reduced disclosure only.
Luxembourg
Authors: Hoffeld Veronique
Published: May 2020

This chapter focuses on the Luxembourg civil liability regime which applies to information given in a prospectus. Luxembourg has implemented certain specific provisions on prospectus liability; however, these do not constitute an entirely autonomous civil liability regime on prospectus liability as such. Most aspects with regards to a person's liability must be determined in accordance with the general Luxembourg provisions on civil liability from the Luxembourg Civil Code. No questions have yet arisen before the Luxembourg courts on the liability regime which applies to those persons responsible for the information given in a prospectus. There is therefore no established Luxembourg case law complementing the provisions currently in place. This chapter thus concerns those situations where a prospectus contains misleading information or omits to include material information infringing the requirements of the Luxembourg legal provisions on prospectuses.
Reevaluating the Risk of Smallpox Reemergence
Authors: MacIntyre C Raina
Published: May 2020

Introduction

Smallpox, caused by variola virus, was eradicated in 1980, but remains a category A bioterrorism agent. A decade ago, smallpox ranked second after anthrax in a multifactorial risk priority scoring analysis of category A bioterrorism agents. However, advances in genetic engineering and synthetic biology, including published methods for synthesizing an Orthopoxvirus, require the assumptions of this scoring for smallpox and other category A agents to be reviewed.

Materials and Methods

The risk priority framework was reviewed and revised to account for the capability for creation of synthetic or engineered smallpox and other category A agents.

Results

The absolute score for all agents increased because of gene editing and synthetic biology capability, which was not present when the framework was developed more than a decade ago, although new treatments revised scores downward for smallpox, Ebola, and botulism. In the original framework, smallpox scored 0 for global availability, given the high security around known seed stocks of variola in two laboratories in the United States and Russia. Now, smallpox can be created using synthetic biology, raising the score for this criterion to 2. Other agents too, such as Ebola, score higher for availability, based on synthetic biology capability. When advances in synthetic biology and genetic engineering are considered, smallpox and anthrax are now equally ranked the highest category A bioterrorism agents for planning and preparedness.

Conclusions

Revision of a risk priority framework for category A bioterrorism agents shows that smallpox should be elevated in priority for preparedness planning, and that gene editing and synthetic biology raises the overall risk for all agents. The ranking of categories A, B, and C agents should also be revisited, as there is an endless possibility of engineered threats that may be more severe than any agent on the category A list.
Implementing Evidence-Based Practice Facilitators: A Case Series
Authors: Augustino Leslie R , Braun Lisa , Heyne Rebecca E , Shinn Antoinette , Lovett-Floom LeAnne , King Heather , Brackett Ceferina , Migliore Laurie , Hatzfeld Jennifer
Published: May 2020

Background

In 2017, the TriService Nursing Research Program completed a strategic planning session, which identified key barriers to implementing evidence-based practice (EBP) within the U.S. Military Health System (MHS) including a focus on readiness training and deployments, frequent staff moves for military members, and relatively junior nurses in clinical roles. To facilitate EBP at individual military treatment facilities (MTFs), an EPB Facilitator role was developed using an evidence-based model and based on validated EBP competencies.

Methods

This new role was implemented at four MTFs in 2018: Naval Medical Center Portsmouth, 59th Medical Wing at Joint Base San Antonio Lackland, Naval Medical Center San Diego, and David Grant USAF Medical Center at Travis Air Force Base. This case series provides a description of the initial implementation of this role.

Results

Common enablers and challenges were identified from the experiences at all four sites. These included the importance of incorporating efforts into existing organizational efforts and infrastructure; the value of nurse leaders inviting EBP facilitators to participate and engage in scheduled meetings and committees; the significance of engaging with existing quality, process improvement, and training initiatives; and the benefit of collaborating with advanced practice nurses within the organization. The common challenges for all EBP facilitators were the frequent staff turnover at all levels and a lack of standardization to review and approve EBP initiatives, which makes it difficult to navigate the complete process of project implementation and collaboration across sites. Another challenge has been the difficulty to measure the impact of this role at the MTF and MHS levels.

Conclusions

As EBP efforts continue and the program matures, it is anticipated that the outcomes from the individually completed projects, to include decreases in safety events, fiscal savings, and other improvements in organizational metrics, can be compiled to demonstrate the collective impact of these roles within the MHS.
Determination of magnetic field strength on the event horizon of supermassive black holes in active galactic nuclei
Authors: Piotrovich M Yu , Mikhailov A G , Buliga S D , Natsvlishvili T M
Published: May 2020

We estimated the magnetic field strength at the event horizon for a sample of supermassive black holes (SMBHs) in active galactic nuclei (AGNs). Our estimates were made using the values of the inclination angles of the accretion disc to the line of sight, which we obtained previously from spectropolarimetric observations in the visible spectrum. We also used published values of full width at half-maximum of spectral line Hβ from broad-line region, masses of SMBHs, and luminosity of AGNs at 5100 $\mathring{\rm A}$. In addition, we used the literature data on the spins of SMBHs obtained from their X-ray spectra. Our estimates showed that the magnetic field strength at the event horizon of the majority of SMBHs in AGNs range from several to tens of kG and have mean values of about 104 G. At the same time, for individual objects, the fields are significantly larger – of the order of hundreds kG or even 1 MG.
Increasing accuracy of HLA imputation by a population-specific reference panel in a FinnGen biobank cohort
Authors: Ritari Jarmo , Hyvärinen Kati , Clancy Jonna ,   FinnGen, Partanen Jukka , Koskela Satu
Published: May 2020

The HLA genes, the most polymorphic genes in the human genome, constitute the strongest single genetic susceptibility factor for autoimmune diseases, transplantation alloimmunity and infections. HLA imputation via statistical inference of alleles based on single-nucleotide polymorphisms (SNPs) in linkage disequilibrium (LD) with alleles is a powerful first-step screening tool. Due to different LD structures between populations, the accuracy of HLA imputation may benefit from matching the imputation reference with the study population. To evaluate the potential advantage of using population-specific reference in HLA imputation, we constructed an HLA reference panel consisting of 1150 Finns with 5365 major histocompatibility complex region SNPs consistent between genome builds. We evaluated the accuracy of the panel against a European panel in an independent test set of 213 Finnish subjects. We show that the Finnish panel yields a lower imputation error rate (1.24% versus 1.79%). More than 30% of imputation errors occurred in haplotypes enriched in Finland. The frequencies of imputed HLA alleles were highly correlated with clinical-grade HLA allele frequencies and allowed accurate replication of established HLA–disease associations in ∼102 000 biobank participants. The results show that a population-specific reference increases imputation accuracy in a relatively isolated population within Europe and can be successfully applied to biobank-scale genome data collections.
Identification and analysis of consensus RNA motifs binding to the genome regulator CTCF
Authors: Kuang Shuzhen , Wang Liangjiang
Published: May 2020

CCCTC-binding factor (CTCF) is a key regulator of 3D genome organization and gene expression. Recent studies suggest that RNA transcripts, mostly long non-coding RNAs (lncRNAs), can serve as locus-specific factors to bind and recruit CTCF to the chromatin. However, it remains unclear whether specific sequence patterns are shared by the CTCF-binding RNA sites, and no RNA motif has been reported so far for CTCF binding. In this study, we have developed DeepLncCTCF, a new deep learning model based on a convolutional neural network and a bidirectional long short-term memory network, to discover the RNA recognition patterns of CTCF and identify candidate lncRNAs binding to CTCF. When evaluated on two different datasets, human U2OS dataset and mouse ESC dataset, DeepLncCTCF was shown to be able to accurately predict CTCF-binding RNA sites from nucleotide sequence. By examining the sequence features learned by DeepLncCTCF, we discovered a novel RNA motif with the consensus sequence, AGAUNGGA, for potential CTCF binding in humans. Furthermore, the applicability of DeepLncCTCF was demonstrated by identifying nearly 5000 candidate lncRNAs that might bind to CTCF in the nucleus. Our results provide useful information for understanding the molecular mechanisms of CTCF function in 3D genome organization.
Phase II study of peginterferon alpha-2b for patients with unresectable or recurrent craniopharyngiomas: a Pediatric Brain Tumor Consortium report
Authors: Goldman Stewart , Pollack Ian F , Jakacki Regina I , Billups Catherine A , Poussaint Tina Y , Adesina Adekunle M , Panigrahy Ashok , Parsons Donald W , Broniscer Alberto , Robinson Giles W , Robison Nathan J , Partap Sonia , Kilburn Lindsay B , Onar-Thomas Arzu , Dunkel Ira J , Fouladi Maryam
Published: May 2020

Background

Craniopharyngiomas account for approximately 1.2–4% of all CNS tumors. They are typically treated with a combination of surgical resection and focal radiotherapy. Unfortunately, treatment can lead to permanent deleterious effects on behavior, learning, and endocrine function.

Methods

The Pediatric Brain Tumor Consortium performed a multicenter phase 2 study in children and young adults with unresectable or recurrent craniopharyngioma (PBTC-039). Between December 2013 and November 2017, nineteen patients (median age at enrollment, 13.1 y; range, 2–25 y) were enrolled in one of 2 strata: patients previously treated with surgery alone (stratum 1) or who received radiation (stratum 2).

Results

Eighteen eligible patients (8 male, 10 female) were treated with weekly subcutaneous pegylated interferon alpha-2b for up to 18 courses (108 wk). Therapy was well tolerated with no grade 4 or 5 toxicities. 2 of the 7 eligible patients (28.6%) in stratum 1 had a partial response, but only one response was sustained for more than 3 months. None of the 11 stratum 2 patients had an objective radiographic response, although median progression-free survival was 19.5 months.

Conclusions

Pegylated interferon alpha-2b treatment, in lieu of or following radiotherapy, was well tolerated in children and young adults with recurrent craniopharyngiomas. Although objective responses were limited, progression-free survival results are encouraging, warranting further studies.
Validation of diffusion MRI phenotypes for predicting response to bevacizumab in recurrent glioblastoma: post-hoc analysis of the EORTC-26101 trial
Authors: Schell Marianne , Pflüger Irada , Brugnara Gianluca , Isensee Fabian , Neuberger Ulf , Foltyn Martha , Kessler Tobias , Sahm Felix , Wick Antje , Nowosielski Martha , Heiland Sabine , Weller Michael , Platten Michael , Maier-Hein Klaus H , Von Deimling Andreas , Van Den Bent Martin J , Gorlia Thierry , Wick Wolfgang , Bendszus Martin , Kickingereder Philipp
Published: May 2020

Background

This study validated a previously described diffusion MRI phenotype as a potential predictive imaging biomarker in patients with recurrent glioblastoma receiving bevacizumab (BEV).

Methods

A total of 396/596 patients (66%) from the prospective randomized phase II/III EORTC-26101 trial (with n = 242 in the BEV and n = 154 in the non-BEV arm) met the inclusion criteria with availability of anatomical and diffusion MRI sequences at baseline prior treatment. Apparent diffusion coefficient (ADC) histograms from the contrast-enhancing tumor volume were fitted to a double Gaussian distribution and the mean of the lower curve (ADClow) was used for further analysis. The predictive ability of ADClow was assessed with biomarker threshold models and multivariable Cox regression for overall survival (OS) and progression-free survival (PFS).

Results

ADClow was associated with PFS (hazard ratio [HR] = 0.625, P = 0.007) and OS (HR = 0.656, P = 0.031). However, no (predictive) interaction between ADClow and the treatment arm was present (P = 0.865 for PFS, P = 0.722 for OS). Independent (prognostic) significance of ADClow was retained after adjusting for epidemiological, clinical, and molecular characteristics (P ≤ 0.02 for OS, P ≤ 0.01 PFS). The biomarker threshold model revealed an optimal ADClow cutoff of 1241*10–6 mm2/s for OS. Thereby, median OS for BEV-patients with ADClow ≥ 1241 was 10.39 months versus 8.09 months for those with ADClow < 1241 (P = 0.004). Similarly, median OS for non-BEV patients with ADClow ≥ 1241 was 9.80 months versus 7.79 months for those with ADClow < 1241 (P = 0.054).

Conclusions

ADClow is an independent prognostic parameter for stratifying OS and PFS in patients with recurrent glioblastoma. Consequently, the previously suggested role of ADClow as predictive imaging biomarker could not be confirmed within this phase II/III trial.
A constructive model for collective intelligence
Authors: Zhang Wei , Mei Hong
Published: May 2020

Natural phenomena of collective intelligence (CI) occurring in physical space show a potential approach to effective large-scale human collaboration in cyberspace. Based on existing explanatory understanding of CI, this perspective proposes a constructive model for building artificial CI systems, i.e., problem-oriented CI phenomena with AI-powered information integration and feedback.
Successful intervention for overwhelming postsplenectomy infection caused by non-vaccine pneumococcal serotype 23A
Authors: Kojima Yuichi , Ikeda Kazuna , Matsumura Akihiro , Shimohama Shun , Chang Bin , Yoshida Takayuki , Hamada Kunio , Ito Akihide , Ito Toshiki
Published: May 2020

The spleen plays an important role in the body’s immune defense against invasive infections, particularly those caused by encapsulated bacteria. Encapsulated bacterial infection in asplenic patients is a medical emergency called overwhelming postsplenectomy infection (OPSI) and has a mortality rate of 50–70%. Here, we report the case of a 51-year-old Asian man who complained of emesis and diarrhea as primary symptoms. He rapidly progressed to coma and was eventually diagnosed with OPSI (pyogenic ventriculitis/spondylitis) caused by non-vaccine pneumococcal serotype 23A. Aggressive management, including empiric antibiotic therapy, a staircase approach for intracranial pressure-targeted therapy and laminectomy/laminoplasty, resulted in a good recovery. Our report highlights that non-vaccine pneumococcal serotypes can cause disease in vaccinated patients.
High-mass star formation in Orion B triggered by cloud–cloud collision: Merging molecular clouds in NGC 2024
Authors: Enokiya Rei , Ohama Akio , Yamada Rin , Sano Hidetoshi , Fujita Shinji , Hayashi Katsuhiro , Tsutsumi Daichi , Torii Kazufumi , Nishimura Atsushi , Konishi Ryotaro , Yamamoto Hiroaki , Tachihara Kengo , Hasegawa Yutaka , Kimura Kimihiro , Ogawa Hideo , Fukui Yasuo
Published: May 2020

We performed new comprehensive 13CO(J = 2–1) observations toward NGC 2024, the most active star-forming region in Orion B, with an angular resolution of ∼100″ obtained with Nanten2. We found that the associated cloud consists of two independent velocity components. The components are physically connected to the H ii region as evidenced by their close correlation with the dark lanes and the emission nebulosity. The two components show complementary distribution with a displacement of ∼0.6 pc. Such complementary distribution is typical to colliding clouds discovered in regions of high-mass star formation. We hypothesize that a cloud–cloud collision between the two components triggered the formation of the late O-type stars and early B stars localized within 0.3 pc of the cloud peak. The duration time of the collision is estimated to be 0.3 million years from a ratio of the displacement and the relative velocity ∼3 km s−1 corrected for probable projection. The high column density of the colliding cloud ∼1023 cm−2 is similar to those in the other high-mass star clusters in RCW 38, Westerlund 2, NGC 3603, and M 42, which are likely formed under trigger by cloud–cloud collision. The present results provide an additional piece of evidence favorable to high-mass star formation by a major cloud–cloud collision in Orion.