bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiovascular and pregnancy outcomes in women with coronary microvascular dysfunction: a case series
Authors: Pacheco Christine , Wei Janet , Minissian Margo , Shufelt Chrisandra L , Kilpatrick Sarah J , Quesada Odayme , Bairey Merz C Noel
Published: May 2019

Background

Coronary microvascular dysfunction (CMD) is associated with adverse cardiovascular outcomes. Coronary microvascular dysfunction is observed in women of childbearing age, however, the frequency of adverse pregnancy outcomes (APO) is unknown.

Case summary

Women previously enrolled in a single centre prospective CMD registry diagnosed using invasive coronary reactivity testing were included. Among 279 women enrolled, 5 of 47 (10.6%) of childbearing age (18–44 years) subsequently became pregnant, representing a fertility rate of 36.8 births per 1000 women-years. None had history of hypertension, diabetes, or smoking. Four (80%) had a history of prior spontaneous miscarriage. Median age at CMD diagnosis was 32 years (IQR: 32–35). During pregnancy, most reported stable or improved angina, while one reported increased angina frequency, an emergency room visit and accelerated anti-anginal therapy. None experienced gestational hypertension, diabetes, pre-eclampsia, myocardial infarction, or death. Two (40%) experienced APO of preterm delivery and small neonate for gestational age. Following pregnancy, angina severity scores, and/or functional capacity decreased in three women (60%).

Discussion

In this first case-series of five women with CMD who became pregnant, increased angina and accelerated care during pregnancy and post-partum was not commonly observed. Fertility rates were lower than the national average, while prior spontaneous miscarriage and subsequent APO were higher. Further studies are warranted to understand and manage pregnancy in women with CMD, as well as the impact of pregnancy on longer term angina, functional capacity, and outcomes.
Pleiotropic effects of laminar flow and statins depend on the Krüppel-like factor-induced lncRNA MANTIS
Authors: Leisegang Matthias S , Bibli Sofia-Iris , Günther Stefan , Pflüger-Müller Beatrice , Oo James A , Höper Cindy , Seredinski Sandra , Yekelchyk Michail , Schmitz-Rixen Thomas , Schürmann Christoph , Hu Jiong , Looso Mario , Sigala Fragiska , Boon Reinier A , Fleming Ingrid , Brandes Ralf P
Published: May 2019

Aims

To assess the functional relevance and therapeutic potential of the pro-angiogenic long non-coding RNA MANTIS in vascular disease development.

Methods and results

RNA sequencing, CRISPR activation, overexpression, and RNAi demonstrated that MANTIS, especially its Alu-element, limits endothelial ICAM-1 expression in different types of endothelial cells. Loss of MANTIS increased endothelial monocyte adhesion in an ICAM-1-dependent manner. MANTIS reduced the binding of the SWI/SNF chromatin remodelling factor BRG1 at the ICAM-1 promoter. The expression of MANTIS was induced by laminar flow and HMG-CoA-reductase inhibitors (statins) through mechanisms involving epigenetic rearrangements and the transcription factors KLF2 and KLF4. Mutation of the KLF binding motifs in the MANTIS promoter blocked the flow-induced MANTIS expression. Importantly, the expression of MANTIS in human carotid artery endarterectomy material was lower compared with healthy vessels and this effect was prevented by statin therapy. Interestingly, the protective effects of statins were mediated in part through MANTIS, which was required to facilitate the atorvastatin-induced changes in endothelial gene expression. Moreover, the beneficial endothelial effects of statins in culture models (spheroid outgrowth, proliferation, telomerase activity, and vascular organ culture) were lost upon knockdown of MANTIS.

Conclusion

MANTIS is tightly regulated by the transcription factors KLF2 and KLF4 and limits the ICAM-1 mediated monocyte adhesion to endothelial cells and thus potentially atherosclerosis development in humans. The beneficial effects of statin treatment and laminar flow are dependent on MANTIS.
Antiaging Therapies, Cognitive Impairment, and Dementia
Authors: Wahl Devin , Anderson Rozalyn M , Le Couteur David G
Published: May 2019

Aging is a powerful risk factor for the development of many chronic diseases including dementia. Research based on disease models of dementia have yet to yield effective treatments, therefore it is opportune to consider whether the aging process itself might be a potential therapeutic target for the treatment and prevention of dementia. Numerous cellular and molecular pathways have been implicated in the aging process and compounds that target these processes are being developed to slow aging and delay the onset of age-associated conditions. A few particularly promising therapeutic agents have been shown to influence many of the main hallmarks of aging and increase life span in rodents. Here we discuss the evidence that some of these antiaging compounds may beneficially affect brain aging and thereby lower the risk for dementia.
Association Between Muscle Strength, Mobility, and the Progression of Hyperkyphosis in the Elderly: The Kurabuchi Cohort Study
Authors: Sugai Keiko , Michikawa Takehiro , Takebayashi Toru , Nishiwaki Yuji
Published: May 2019

Background

The progression of hyperkyphosis is a significant factor in declining general health. The purpose of this study was to investigate whether muscle strength and/or mobility is associated with the progression of hyperkyphosis in elderly people.

Methods

As part of a cohort study of community-dwelling elderly people, handgrip strength and mobility (evaluated with the Timed Up and Go Test: TUG) were assessed at baseline (2005–2006). Kyphosis was also evaluated at baseline and in follow-up examinations 4 years later, with the block method. To exclude the measurement error, the progression of kyphosis was defined as increase of 2 or more blocks. The association of kyphosis progression in each group with handgrip strength and/or mobility was assessed using Poisson regression analysis.

Results

Results on 403 participants were available for the final analysis, and kyphosis progression was observed in 53 (13.1%) of them. Multivariable analysis adjusted for sex, age, baseline block number, bone stiffness, TUG performance, or handgrip strength simultaneously revealed that low handgrip strength (<26 kg in men, <18 kg in women) and low mobility (>13.5 seconds) at baseline were both independently associated with kyphosis progression (adjusted risk ratio [95% confidence interval]: 2.11 [1.06–4.20] and 2.48 [1.26–4.89], respectively).

Conclusions

Our study showed that low handgrip strength and low mobility are clearly associated with the progression of kyphosis. Further study is needed on the applicability of these results to preventive measures.
The Ethics of Socially Assistive Robots in Aged Care. A Focus Group Study With Older Adults in Flanders, Belgium
Authors: Vandemeulebroucke Tijs , Dierckx de Casterlé Bernadette , Welbergen Laura , Massart Michiel , Gastmans Chris
Published: May 2019

Objectives

Socially assistive robots (SARs) need to be studied from older adults’ perspective, given their predicted future ubiquity in aged-care settings. Current ethical discourses on SARs in aged care are uninformed by primary stakeholders’ ethical perceptions. This study reports on what community-dwelling older adults in Flanders, Belgium, perceive as ethical issues of SARs in aged care.

Methods

Constructivist grounded theory guided the study of 9 focus groups of 59 community-dwelling older adults (70+ years) in Flanders, Belgium. An open-ended topic guide and a modified Alice Cares documentary focused discussions. The Qualitative Analysis Guide of Leuven (QUAGOL) guided data analysis.

Results

Data revealed older adults’ multidimensional perceptions on the ethics of SARs which were structured along three sections: (a) SARs as components of a techno-societal evolution, (b) SARs’ embeddedness in aged-care dynamics, (c) SARs as embodiments of ethical considerations.

Discussion

Perceptions sociohistorically contextualize the ethics of SAR use by older adults’ views on societal, organizational, and relational contexts in which aged care takes place. These contexts need to inform the ethical criteria for the design, development, and use of SARs. Focusing on older adults’ ethical perceptions creates “normativity in place,” viewing participants as moral subjects.
Glycan diversity in the course of vertebrate evolution
Authors: Suzuki Noriko
Published: May 2019

Vertebrates are estimated to have arisen over 500 million years ago in the Cambrian Period. Species that survived the Big Five extinction events at a global scale underwent repeated adaptive radiations along with habitat expansions from the sea to the land and sky. The development of the endoskeleton and neural tube enabled more complex body shapes. At the same time, vertebrates became suitable for the invasion and proliferation of foreign organisms. Adaptive immune systems were acquired for responses to a wide variety of pathogens, and more sophisticated systems developed during the evolution of mammals and birds. Vertebrate glycans consist of common core structures and various elongated structures, such as Neu5Gc, Galα1–3Gal, Galα1–4Gal, and Galβ1–4Gal epitopes, depending on the species. During species diversification, complex glycan structures were generated, maintained or lost. Whole-genome sequencing has revealed that vertebrates harbor numerous and even redundant glycosyltransferase genes. The production of various glycan structures is controlled at the genetic level in a species-specific manner. Because cell surface glycans are often targets of bacterial and viral infections, glycan structural diversity is presumed to be protective against infections. However, the maintenance of apparently redundant glycosyltransferase genes and investment in species-specific glycan structures, even in higher vertebrates with highly developed immune systems, are not well explained. This fact suggests that glycans play important roles in unknown biological processes.
The role of the angle of the ascending aortic curvature on the development of type A aortic dissection: ascending aortic angulation and dissection
Authors: Gode Safa , Akinci Okan , Ustunısık Cigdem Tel , Sen Onur , Kadirogulları Ersin , Aksu Timucin , Ersoy Burak , Gurbak Ismail , Duman Zihni Mert , Erentug Vedat
Published: May 2019

OBJECTIVES

Type A aortic dissection (TAD), which consists of an intimal tear in the aorta, necessitates emergency surgery. Various risk factors related to aortic dissection have been defined in the literature. According to our hypothesis, a narrower angle of ascending aortic curvature (AAAC) may be an additional risk factor in relation to aortic dissection due to the increased force applied to the aortic wall.

METHODS

Patients undergoing ascending aortic surgery due to an ascending aortic aneurysm (AsAA) (n = 105) and patients undergoing such surgery because of the occurrence of TAD (n = 101) were enrolled in this study. The AAAC was measured using Cobb’s method; the measurements were made on all patients by just 1 cardiovascular radiologist using 3-dimensional computerized tomographic imaging. This measurement was made indirectly by using the aortic valve and brachiocephalic artery to avoid obtaining misleading data as a result of distortions due to dissection. A statistical comparison was also performed relating the traditional risk factors for TAD to other clinical and echocardiographic parameters: the diameter of the ascending aorta and the AAAC.

RESULTS

The AAAC was found to be narrower statistically in the TAD group (α = 76.2° ± 17.5°) than it was in the AsAA group (α = 92.9° ± 13°) (P < 0.001). Furthermore, mean ascending aortic diameter (P = 0.019), the presence of a bicuspid aorta (P = 0.007) and aortic valve stenosis (P = 0.005) were higher in the AsAA group. According to multivariable analyses, a narrower AAAC is a significant predictor for the development of TAD (odds ratio 0.93, 95% confidence interval 0.91–0.95; P < 0.001). Overall hospital mortality from various causes including stroke, myocardial infarction, bleeding or renal failure was 13% in the TAD group and 7% in the AsAA group.

CONCLUSIONS

According to this study, the AAAC was significantly smaller in aortic dissection patients than in aortic aneurysm patients. This may be related to higher shear stress and elevated pressure on the ascending aorta in patients with a narrower AAAC. Thus, a narrower AAAC may be an additional risk factor in the development of TAD. Therefore, we may need to be more careful in terms of looking for the development of aortic dissection in patients with narrower AAAC.
Microfluidic platform for studying osteocyte mechanoregulation of breast cancer bone metastasis
Authors: Mei Xueting , Middleton Kevin , Shim Dongsub , Wan Qianqian , Xu Liangcheng , Ma Yu-Heng Vivian , Devadas Deepika , Walji Noosheen , Wang Liyun , Young Edmond W K , You Lidan
Published: May 2019

Bone metastasis is a common, yet serious, complication of breast cancer. Breast cancer cells that extravasate from blood vessels to the bone devastate bone quality by interacting with bone cells and disrupting the bone remodeling balance. Although exercise is often suggested as a cancer intervention strategy and mechanical loading during exercise is known to regulate bone remodeling, its role in preventing bone metastasis remains unknown. We developed a novel in vitro microfluidic tissue model to investigate the role of osteocytes in the mechanical regulation of breast cancer bone metastasis. Metastatic MDA-MB-231 breast cancer cells were cultured inside a 3D microfluidic lumen lined with human umbilical vein endothelial cells (HUVECs), which is adjacent to a channel seeded with osteocyte-like MLO-Y4 cells. Physiologically relevant oscillatory fluid flow (OFF) (1 Pa, 1 Hz) was applied to mechanically stimulate the osteocytes. Hydrogel-filled side channels in-between the two channels allowed real-time, bi-directional cellular signaling and cancer cell extravasation over 3 days. The applied OFF was capable of inducing intracellular calcium responses in osteocytes (82.3% cells responding with a 3.71 fold increase average magnitude). Both extravasation distance and percentage of extravasated side-channels were significantly reduced with mechanically stimulated osteocytes (32.4% and 53.5% of control, respectively) compared to static osteocytes (102.1% and 107.3% of control, respectively). This is the first microfluidic device that has successfully integrated stimulatory bone fluid flow, and demonstrated that mechanically stimulated osteocytes reduced breast cancer extravasation. Future work with this platform will determine the specific mechanisms involved in osteocyte mechanoregulation of breast cancer bone metastasis, as well as other types of cancer metastasis and diseases.
Enhancing clinical concept extraction with contextual embeddings
Authors: Si Yuqi , Wang Jingqi , Xu Hua , Roberts Kirk
Published: May 2019

Objective

Neural network–based representations (“embeddings”) have dramatically advanced natural language processing (NLP) tasks, including clinical NLP tasks such as concept extraction. Recently, however, more advanced embedding methods and representations (eg, ELMo, BERT) have further pushed the state of the art in NLP, yet there are no common best practices for how to integrate these representations into clinical tasks. The purpose of this study, then, is to explore the space of possible options in utilizing these new models for clinical concept extraction, including comparing these to traditional word embedding methods (word2vec, GloVe, fastText).

Materials and Methods

Both off-the-shelf, open-domain embeddings and pretrained clinical embeddings from MIMIC-III (Medical Information Mart for Intensive Care III) are evaluated. We explore a battery of embedding methods consisting of traditional word embeddings and contextual embeddings and compare these on 4 concept extraction corpora: i2b2 2010, i2b2 2012, SemEval 2014, and SemEval 2015. We also analyze the impact of the pretraining time of a large language model like ELMo or BERT on the extraction performance. Last, we present an intuitive way to understand the semantic information encoded by contextual embeddings.

Results

Contextual embeddings pretrained on a large clinical corpus achieves new state-of-the-art performances across all concept extraction tasks. The best-performing model outperforms all state-of-the-art methods with respective F1-measures of 90.25, 93.18 (partial), 80.74, and 81.65.

Conclusions

We demonstrate the potential of contextual embeddings through the state-of-the-art performance these methods achieve on clinical concept extraction. Additionally, we demonstrate that contextual embeddings encode valuable semantic information not accounted for in traditional word representations.
Effects of Host Age and Density on the Performance of Apanteles hemara (Hymenoptera: Braconidae), a Larval Endoparasitoid of Spoladea recurvalis (Lepidoptera: Crambidae)
Authors: Othim S T O , Ramasamy S , Kahuthia-Gathu R , Dubois T , Ekesi S , Fiaboe K K M
Published: May 2019

The amaranth leaf-webber, Spoladea recurvalis (Fabricius; Lepidoptera: Crambidae), is a serious pest of Amaranthus sp. in Africa and Asia. Apanteles hemara (Nixon; Hymenoptera: Braconidae) is by far the most important larval endoparasitoid of the amaranth leaf-webber. We examined the effects of host density and age on the biological characteristics of A. hemara. The regression model of the number of hosts supplied to A. hemara against the number of larvae parasitized resulted in a curve corresponding to type II functional response, with a significant increase in the number of hosts parasitized up to the density of 30 hosts before being constant up to 40 hosts. In contrast, the parasitism rate decreased linearly with increasing host densities. Development time, sex ratio, and adult longevity were not significantly affected by host density. The immature parasitoid mortality was significantly higher at higher host densities. Apanteles hemara did not parasitize 7-d-old larvae and beyond, while parasitism was significantly higher among 1- to 2-d-old compared with 3- to 4-d-old larvae. Immature parasitoid mortality was 2.6 times higher in 1- to 2-d-old larvae compared with 5- to 6-d-old larvae. The developmental period of the parasitoid from egg to adult was longest among 1- to 2-d-old larvae and least among 5- to 6-d-old larvae. Nonreproductive mortality was markedly higher among 1- to 2-d-old larvae compared with the older larvae. Adult female A. hemara were significantly larger on 3- to 4-d-old larvae compared with either 1- to 2-d-old or 5- to 6-d-old larvae. We discuss the implications of our results for the interpretation of functional response in parasitoids, mass rearing, conservation, and augmentative biological control of S. recurvalis.
ESTIMATING DIVERSION RATIOS IN HOSPITAL MERGERS
Authors: Rossi Cecilia , Whitehouse Russell , Moore Alex
Published: May 2019

Understanding patient choice is vital in assessing the closeness of competition between hospitals. The standard technique used in the UK is to estimate substitution patterns based on historical general practitioner (GP) referrals. In this paper we compare the results of the ‘GP referral’ methodology to a demand estimation approach. Using patient-level data over a 3-year period (2012/13–2014/15) we apply both methodologies to every hypothetical merger between hospitals in England, for three specialties. We find a high degree of consistency between the two approaches, suggesting that GP referral analysis is a useful and reliable filter in merger cases. There are a small number of cases, however, in which the GP referral approach filters out potentially problematic mergers. This is particularly true for ‘borderline’ cases. Filtering should therefore be done with caution and in conjunction with additional evidence.
‘The Only Thing “Womanish” is the Composer’: Music at Nineteenth-Century Exhibitions of Women’s Work
Authors: Kirby Sarah
Published: May 2019

The 1880s saw a burgeoning of exhibitions of ‘Women’s Work’ across the world. These events focused on the artistic and industrial abilities of women, signifying an unprecedented shift away from the emphasis usually placed on maleness and masculinized technology in contemporary exhibition culture. The first Exhibition, held in Bristol in 1885, included a musical novelty: a concert entirely of works composed by women. The next, in Sydney in 1888, included a whole series of such concerts. These concerts—containing works by Kate Loder, Clara Wieck, Fanny Hensel, Agnes Zimmermann, and Maude Valérie White—were extraordinarily well received, applauded in both concept and execution. Yet, their reception appears paradoxical against the contemporary critical climate. In both Britain and Australia, the ‘question’ of women composers was widely debated, and works met with condescension or hostility. By exploring the expectations surrounding displays of ‘women’s work’, I argue that it was the exhibition context itself that influenced the reception of this music. While Exhibitions were conventionally seen as male-gendered events, ‘Women’s’ Exhibitions allowed organizers to blur the distinctions between private and public space. Similarly, while women composers were criticized for their encroachment in the male concert sphere, these Exhibitions also blurred these boundaries and gave critics an appropriate ‘feminine’ framework through which to view and critique the works.
A CRISPR/Cas9 screen identifies the histone demethylase MINA53 as a novel HIV-1 latency-promoting gene (LPG)
Authors: Huang Huachao , Kong Weili , Jean Maxime , Fiches Guillaume , Zhou Dawei , Hayashi Tsuyoshi , Que Jianwen , Santoso Netty , Zhu Jian
Published: May 2019

Although combination antiretroviral therapy is potent to block active replication of HIV-1 in AIDS patients, HIV-1 persists as transcriptionally inactive proviruses in infected cells. These HIV-1 latent reservoirs remain a major obstacle for clearance of HIV-1. Investigation of host factors regulating HIV-1 latency is critical for developing novel antiretroviral reagents to eliminate HIV-1 latent reservoirs. From our recently accomplished CRISPR/Cas9 sgRNA screens, we identified that the histone demethylase, MINA53, is potentially a novel HIV-1 latency-promoting gene (LPG). We next validated MINA53’s function in maintenance of HIV-1 latency by depleting MINA53 using the alternative RNAi approach. We further identified that in vitro MINA53 preferentially demethylates the histone substrate, H3K36me3 and that in cells MINA53 depletion by RNAi also increases the local level of H3K36me3 at LTR. The effort to map the downstream effectors unraveled that H3K36me3 has the cross-talk with another epigenetic mark H4K16ac, mediated by KAT8 that recognizes the methylated H3K36 and acetylated H4K16. Removing the MINA53-mediated latency mechanisms could benefit the reversal of post-integrated latent HIV-1 proviruses for purging of reservoir cells. We further demonstrated that a pan jumonji histone demethylase inhibitor, JIB-04, inhibits MINA53-mediated demethylation of H3K36me3, and JIB-04 synergizes with other latency-reversing agents (LRAs) to reactivate latent HIV-1.
Efficient HIV-1 Trans Infection of CD4+ T Cells Occurs in the Presence of Antiretroviral Therapy
Authors: Rappocciolo Giovanna , Sluis-Cremer Nicolas , Rinaldo Charles R
Published: May 2019

Background

Antiretroviral therapy (ART) has dramatically improved the quality of life of people with HIV-1 infection (PWH). However, it is not curative, and interruption of ART results in rapid viral rebound. Cell-to-cell transfer of HIV-1, or trans infection, is a highly efficient mechanism of virus infection of CD4+ T cells by professional antigen-presenting cells (APCs), that is, dendritic cells (DCs), macrophages, and B lymphocytes.

Methods

APC from HIV seronegative donors treated with ART in vitro (CCR5 agonist, NRTI, PI and NNRTI, alone or in combination), were loaded with HIV R5-tropic HIVBal and mixed with autologous or heterologous CD4+ T lymphocytes to assess trans infection. Ex vivo APC from chronic HIV-infected MACS participants before and after initiation of ART, were also loaded with HIV R5-tropic HIVBal and tested for trans infection against autologous or heterologous CD4+ T lymphocytes. Virus replication was measured by p24 ELISA.

Results

Here we show in vitro that antiretroviral drugs did not block the ability of DCs and B cells to trans-infect CD4+ T cells, although they were effective in blocking direct cis infection of CD4+ T cells. Moreover, ex vivo DCs and B cells from ART-suppressed PWH mediated efficient HIV-1 trans infection of CD4+ T cells, which were resistant to direct cis infection.

Conclusions

Our study supports a role for HIV-1 trans infection in maintenance of the HIV-1 reservoir during ART.
Internal and External Objects of Cognition
Authors: Ayers Michael
Published: May 2019

Detailed analysis is conducted of the different constructions in which ‘know’, ‘believe’, ‘see’, and cognate verbs appear in ordinary or natural language, of their functions and of the relations and differences between them: e.g. noun-clauses of the form ‘that P’ serve different purposes after each of these classes of verb, partly reflected in the proposition–fact distinction—although ‘facts’ are ontologically unsuited to be what it is in the world we know. Some relevant views of Timothy Williamson (e.g. ‘e=k’) are discussed. The emphasis in current epistemology on the ‘know/see that P’ construction is criticized—no construction, and no use of the term ‘evidence’, is philosophically best, since it is no accident that we have them all. The philosophical task is to understand how they work together—the footprints in language of our cognitive relation to reality, manifestations of what knowledge, belief, and perception are.
A Macroeconomic Model with Financial Panics
Authors: Gertler Mark , Kiyotaki Nobuhiro , Prestipino Andrea
Published: May 2019

This article incorporates banks and banking panics within a conventional macroeconomic framework to analyse the dynamics of a financial crisis of the kind recently experienced. We are particularly interested in characterizing the sudden and discrete nature of banking panics as well as the circumstances that make an economy vulnerable to such panics in some instances but not in others. Having a conventional macroeconomic model allows us to study the channels by which the crisis affects real activity both qualitatively and quantitatively. In addition to modelling the financial collapse, we also introduce a belief driven credit boom that increases the susceptibility of the economy to a disruptive banking panic.
A Sequence Resource of Autosomes and Additional Chromosomes in the Peach Pathotype of Alternaria alternata
Authors: Ushijima Koichiro , Yamamoto Mikihiro
Published: May 2019

Alternaria alternata is a generally saprophytic fungus. Its genome consists of 10 autosomes, while some strains have one or two additional chromosomes, called a conditionally dispensable chromosome (CDC). A CDC is not required for reproduction but confers host-specific pathogenicity. We sequenced the genome of the peach pathotype of A. alternata using Nanopore and assembled it into 20 sequences. The 10 largest sequences corresponded to 10 gapless sequences of A. solani autosomes, and 1 sequence was a mitochondrial genome. Nine other sequences may be derived from CDCs because of lack of similarity with autosomes of other Alternaria spp. The sequence information could provide novel insights into genomes of Alternaria spp. and on the biosynthesis of a novel host-specific toxin in the peach pathotype of A. alternata.
Novel Rhabdovirus and an almost complete drain fly transcriptome recovered from two independent contaminations of clinical samples
Authors: Brito Francisco , Manni Mosè , Laubscher Florian , Schibler Manuel , Hartley Mary-Anne , Keitel Kristina , Mlaganile Tarsis , d’Acremont Valerie , Cordey Samuel , Kaiser Laurent , Zdobnov Evgeny M
Published: May 2019

Metagenomic approaches enable an open exploration of microbial communities without requiring a priori knowledge of a sample’s composition by shotgun sequencing the total RNA or DNA of the sample. Such an approach is valuable for exploratory diagnostics of novel pathogens in clinical practice. Yet, one may also identify surprising off-target findings. Here we report a mostly complete transcriptome from a drain fly (likely Psychoda alternata) as well as a novel Rhabdovirus-like virus recovered from two independent contaminations of RNA sequencing libraries from clinical samples of cerebral spinal fluid (CSF) and serum, out of a total of 724 libraries sequenced at the same laboratory during a 2-year time span. This drain fly genome shows a considerable divergence from previously sequenced insects, which may obscure common clinical metagenomic analyses not expecting such contaminations. The classification of these contaminant sequences allowed us to identify infected drain flies as the likely origin of the novel Rhabdovirus-like sequence, which could have been erroneously linked to human pathology, had they been ignored.
Risk assessment of Ebola virus disease spreading in Uganda using a multilayer temporal network
Authors: Riad Mahbubul H , Sekamatte Musa , Ocom Felix , Makumbi Issa , Scoglio Caterina M
Published: May 2019

Network-based modelling of infectious diseases apply compartmental models on a contact network, which makes the epidemic process crucially dependent on the network structure. For highly contagious diseases such as Ebola virus disease (EVD), the inter-personal contact plays the most vital role in the human to human transmission. Therefore, for accurate representation of the EVD spreading, the contact network needs to resemble the reality. Prior research work has mainly focused on static networks (only permanent contacts) or activity driven networks (only temporal contacts) for Ebola spreading. A comprehensive network for EVD spreading should include both these network structures, as there are always some permanent contacts together with temporal contacts. Therefore, we propose a multilayer temporal network for Uganda, which is at risk of Ebola outbreak from the neighboring Democratic Republic of Congo (DRC) epidemic. The network has a permanent layer representing permanent contacts among individuals within family level, and a data driven temporal network for human movements motivated by cattle trade, fish trade, or general communications. We propose a Gillespie algorithm with the susceptible-infected-recovered (SIR) compartmental model to simulate the evolution of the EVD spreading as well as to evaluate the risk throughout our network. As an example, we applied our method to a multilayer network consisting of 23 districts along different movement routes in Uganda starting from bordering districts of DRC to Kampala. Simulation results shows that some regions are at higher risk of infection, suggesting some focal points for Ebola preparedness and providing direction to inform interventions in the field. Simulation results also shows that decreasing physical contacts as well as increasing preventive measures result in a reduction of chances to develop an outbreak. Overall, the main contribution of this paper lies in the novel method for risk assessment, the accuracy of which can be increased by increasing the amount and the accuracy of the data used to build the network and the model.
APEC: an accesson-based method for single-cell chromatin accessibility analysis
Authors: Li Bin , Li Young , Li Kun , Zhu Lianbang , Yu Qiaoni , Cai Pengfei , Fang Jingwen , Zhang Wen , Du Pengcheng , Jiang Chen , Qu Kun
Published: May 2019

The development of sequencing technologies has promoted the survey of genome-wide chromatin accessibility at single-cell resolution; however, comprehensive analysis of single-cell epigenomic profiles remains a challenge. Here, we introduce an accessibility pattern-based epigenomic clustering (APEC) method, which classifies each individual cell by groups of accessible regions with synergistic signal patterns termed “accessons”. By integrating with other analytical tools, this python-based APEC package greatly improves the accuracy of unsupervised single-cell clustering for many different public data sets. APEC also predicts gene expressions, identifies significant differential enriched motifs, discovers super enhancers, and projects pseudotime trajectories. Furthermore, we adopted a fluorescent tagmentation-based single-cell ATAC-seq technique (ftATAC-seq) to investigated the per cell regulome dynamics of mouse thymocytes. Associated with ftATAC-seq, APEC revealed a detailed epigenomic heterogeneity of thymocytes, characterized the developmental trajectory and predicted the regulators that control the stages of maturation process. Overall, this work illustrates a powerful approach to study single-cell epigenomic heterogeneity and regulome dynamics.
Interruption of Continuous Opioid Exposure Exacerbates Drug-Evoked Adaptations in the Mesolimbic Dopamine System
Authors: Lefevre Emilia M. , Pisansky Marc T. , Toddes Carlee , Baruffaldi Federico , Pravetoni Marco , Tian Lin , Kono Thomas J. Y. , Rothwell Patrick E.
Published: May 2019

Drug-evoked adaptations in the mesolimbic dopamine system are postulated to drive opioid abuse and addiction. These adaptations vary in magnitude and direction following different patterns of opioid exposure, but few studies have systematically manipulated the pattern of opioid administration while measuring neurobiological and behavioral impact. We exposed male and female mice to morphine for one week, with administration patterns that were either intermittent (daily injections) or continuous (osmotic minipump infusion). We then interrupted continuous morphine exposure with either naloxone-precipitated or spontaneous withdrawal. Continuous morphine exposure caused tolerance to the psychomotor-activating effects of morphine, whereas both intermittent and interrupted morphine exposure caused long-lasting psychomotor sensitization. Given links between locomotor sensitization and mesolimbic dopamine signaling, we used fiber photometry and a genetically encoded dopamine sensor to conduct longitudinal measurements of dopamine dynamics in the nucleus accumbens. Locomotor sensitization caused by interrupted morphine exposure was accompanied by enhanced dopamine signaling in the nucleus accumbens. To further assess downstream consequences on striatal gene expression, we used next-generation RNA sequencing to perform genome-wide transcriptional profiling in the nucleus accumbens and dorsal striatum. The interruption of continuous morphine exposure exacerbated drug-evoked transcriptional changes in both nucleus accumbens and dorsal striatum, dramatically increasing differential gene expression and engaging unique signaling pathways. Our study indicates that opioid-evoked adaptations in brain function and behavior are critically dependent on the pattern of drug administration, and exacerbated by interruption of continuous exposure. Maintaining continuity of chronic opioid administration may therefore represent a strategy to minimize iatrogenic effects on brain reward circuits.
The Effect of Aging, Parkinson’s Disease, and Exogenous Dopamine on the Neural Response Associated with Auditory Regularity Processing
Authors: Jaja Abdullah Al , Grahn Jessica A. , Herrmann Björn , MacDonald Penny A.
Published: May 2019

Processing regular patterns in auditory scenes is important for navigating complex environments. Electroencephalography (EEG) studies find enhancement of sustained brain activity, correlating with the emergence of a regular pattern in sounds. How aging, aging-related diseases such as Parkinson’s disease (PD), and treatment of PD affect this fundamental function remain unknown. We addressed this knowledge gap. Healthy younger and older adults, and PD patients listened to sounds that contained or were devoid of regular patterns. Healthy older adults and PD patients were tested twice—on and off dopaminergic medication in counterbalanced order. Regularity-evoked, sustained EEG activity was reduced in older, compared to younger adults. PD patients and older controls had comparable attenuation of the sustained response. Dopaminergic therapy further weakened the sustained response in both groups. These findings suggest that fundamental regularity processing is impacted by aging-related neural changes but not those underlying PD. The finding that dopaminergic therapy attenuates rather than improves the sustained response coheres with the dopamine overdose response and implicates brain regions receiving dopamine from the ventral tegmental area in regularity processing.
Circulating bacterial DNA as a tool towards non-invasive biomarkers for colorectal cancer and adenoma
Authors: Xiao Qian , Lu Wei , Kong Xiangxing , Shao Yang W. , Hu Yeting , Wang Ao , Bao Hua , Liu Kaihua , Wang Xiaonan , Wu Xue , Zheng Shu , Yuan Ying , Ding Kefeng
Published: May 2019

Objective

The gut microbiota is closely associated with colorectal neoplasia. While most metagenomics studies utilized fecal samples, circulating microbial DNA in colorectal neoplasia patients remained unexplored. This study aimed to characterize microbial DNA in plasma samples and build a machine learning model for colorectal neoplasia early detection.

Design

We performed whole genome sequencing of plasma samples from 25 colorectal cancer (CRC) patients, 10 colorectal adenoma (CRA) patients and 22 healthy controls (HC). Microbial DNA was obtained by removing the host genome and relative abundance was measured by mapping reads into microbial genomes. Significant biomarker species were identified in the discovery cohort and built into a random forest model, which was tested in the validation cohort.

Results

In the discovery cohort, there were 127 significant species between CRC patients and HC. Based on the random forest model, 28 species were selected from the discovery cohort (AUC=0.944) and yielded an AUC of 1 in the validation cohort. Interestingly, relative abundance of most biomarker species in CRA patients were between CRC patients and HC with a trend towards CRC patients. Furthermore, pathway enrichment analysis also showed similar pattern where CRA patients had intermediate relative abundance of significant pathways compared to CRC patients and HC. Finally, species network analysis revealed that CRC and HC displayed distinct patterns of species association.

Conclusions

We demonstrated characteristic alteration of circulating bacterial DNA in colorectal neoplasia patients. The predictive model accurately distinguished CRC and CRA from HC, suggesting the utility of circulating bacterial biomarkers as a non-invasive tool for colorectal neoplasia screening and early diagnosis.
Is it reasonable to account for population structure in genome-wide association studies?
Authors: Kim Bongsong
Published: May 2019

Population structure is widely perceived as a noise factor that undermines the quality of association between an SNP variable and a phenotypic variable in genome-wide association studies (GWAS). The linear model for GWAS generally accounts for population-structure variables to obtain the adjusted phenotype which has less noise. Its result is known to amplify the contrast between significant SNPs and insignificant SNPs in a resultant Manhattan plot. In fact, however, conventional GWAS practice often implements the linear model in an unusual way in that the population-structure variables are incorporated into the linear model in the form of continuous variables rather than factor variables. If the coefficients for population-structure variables change across all SNPs, then each SNP variable will be regressed against a differently adjusted phenotypic variable, making the GWAS process unreliable. Focusing on this concern, this study investigated whether accounting for population-structure variables in the linear model for GWAS can assure the adjusted phenotypes to be consistent across all SNPs. The result showed that the adjusted phenotypes resulting across all SNPs were not consistent, which is alarming considering conventional GWAS practice that accounts for population structure.
Three differently coloured polymorphs of 3,6-bis(4-chlorophenyl)-2,5-dipropyl-2,5-dihydropyrrolo[3,4-c]pyrrole-1,4-dione
Authors: So Hee-Soo , Matsumoto Shinya
Published: May 2019

In this paper, the conformational polymorphism of a chlorinated diketopyrrolopyrrole (DPP) dye having flexible substituents in a non-hydrogen-bonding system is reported. The propyl-substituted DPP derivative (PR3C) has three polymorphic forms, each showing a different colour (red, orange and yellow). All polymorphs could be obtained concomitantly under various crystallization conditions. The results of the crystal structure analysis indicate that PR3C adopts different conformations in each polymorph. The packing effect caused by the difference in the arrangement of neighbouring molecules was found to play an important role in the occurrence of the observed polymorphism. The thermodynamic stability relationship between the three polymorphs was identified by thermal analysis and indicates that the yellow polymorph is the thermally stable form. The results indicate that the yellow form and orange form are enantiotropically related, and the other polymorph is monotropically related to the others.
Accurate and efficient representation of intramolecular energy in ab initio generation of crystal structures. II. Smoothed intramolecular potentials
Authors: Sugden Isaac J. , Adjiman Claire S. , Pantelides Constantinos C.
Published: May 2019

The application of crystal structure prediction (CSP) to industrially relevant molecules requires the handling of increasingly large and flexible compounds. A revised model for the effect of molecular flexibility on the lattice energy that removes the discontinuities and non-differentiabilities present in earlier models (Sugden et al., 2016), with a view to improving the performance of CSP is presented. The approach is based on the concept of computing a weighted average of local models, and has been implemented within the CrystalPredictor code. Through the comparative investigation of several compounds studied in earlier literature, it is shown that this new model results in large reductions in computational effort (of up to 65%) and in significant increases in reliability. The approach is further applied to investigate, for the first time, the computational polymorphic landscape of flufenamic acid for Z′ = 1 structures, resulting in the successful identification of all three experimentally resolved polymorphs within reasonable computational time.
Crystal structures and Hirshfeld surface analyses of 4,4′-{[1,3-phenylenebis(methylene)]bis(oxy)}bis(3-methoxybenzaldehyde) and 4,4′-{[(1,4-phenylenebis(methylene)]bis(oxy)}bis(3-methoxybenzaldehyde)
Authors: Iqbal Saleem , Viswanathan Vijayan , Velmurugan Devadasan , Abiraman Tamilselvan , Balasubramanian Sengottuvelan , Gunasekaran Krishnasamy
Published: May 2019

The title compounds, C24H22O6 (I) and C24H22O6 (II), each crystallize with half a molecule in the asymmetric unit. The whole molecule of compound (I) is generated by twofold rotation symmetry, the twofold axis bisecting the central benzene ring. The whole molecule of compound (II) is generated by inversion symmetry, the central benzene ring being located on an inversion center. In (I), the outer benzene rings are inclined to each other by 59.96 (10)° and by 36.74 (9)° to the central benzene ring. The corresponding dihedral angles in (II) are 0.0 and 89.87 (12)°. In the crystal of (I), molecules are linked by C—H...O hydrogen bonds and C—H...π interactions, forming ribbons propagating along the [10\overline{1}] direction. In the crystal of (II), molecules are linked by C—H...O hydrogen bonds, forming a supramolecular framework. The Hirshfeld surface analyses indicate that for both compounds the H...H contacts are the most significant, followed by O...H/H...O and C...H/H...C contacts.
Is motorcycle tourism ready to rev up in Pennsylvania? An exploratory study of suppliers’ business attitudes of motorcycle tourism
Authors: Quadri-Felitti Donna , Sykes Diane , Chen Feier (Faye)
Published: May 2019

Purpose

Motorcycle tourism, as an emerging segment of travelers, has steadily increased in the USA and UK. While previous literature reveals that the attributes of both the journey and the destination are motivations for motorcycle tourists, the extent to which supply-side stakeholders are aware of those motivators is not clear. This study aims to explore the perceived value of motorcycle tourism between differing tourism suppliers in the US state of Pennsylvania and investigates whether they exhibit sufficient agreement to satisfy the cooperation and collaboration identified as necessary in stakeholder theory.

Design/methodology/approach

For this exploratory study, an electronic survey captured data from different tourism suppliers (N = 123) in the US state of Pennsylvania. A series of analysis of variance and equality of means tests assessed differences and agreements between types of suppliers perceptions of the value of motorcycle tourism and issues associated with successful development of the niche segment.

Findings

Results reveal alignment among tourism suppliers, as well as between identified motorcyclists’ motivations. While negative perceptions about riders within popular culture appear to continue among some tourism operators, the economic value of the segment is growing in its appeal among the respondents.

Research limitations/implications

The unique characteristics of Pennsylvania’s substantial rural areas and the sample being drawn from tourism organizations suggest generalizing the results with caution.

Practical implications

Practitioners can capture more of these tourists by highlighting amenities that attract motorcyclists, collaborating together on events and welcoming messages for motorcyclists, as well as educating their communities and policymakers about their interest in the segment’s economic value.

Social implications

Overall the study’s findings suggest that while a cultural stereotype of the “outlaw” motorcyclist remains, this negative image may be waning among tourism operators. Additionally, these results indicate a possible consistency among the state’s tourism supply-side stakeholders desire to host this segment because of potential positive benefits of these tourists.

Originality/value

There is scant academic research on this visible and growing tourism niche. There is none that these authors found that examined the tourism suppliers’ sentiments regarding the segment’s contribution to tourism, nor explored stakeholder theory relative to tourism suppliers and this niche segment.
Conference report: second UNWTO/UNESCO world conference on tourism and culture: fostering sustainable development
Authors: Almuhrzi Hamed Mohammed , Al-Azri Hamed Ibrahim
Published: May 2019

Purpose

The purpose of this conference report is to provide an overview of the Second UNWTO/UNESCO World Conference on Tourism and Culture: Fostering Sustainable Development.

Design/methodology/approach

This is a conference report that provides an overview of the Second UNWTO/UNESCO World Conference on Tourism and Culture: Fostering Sustainable Development. Based on the authors’ involvement in setting the scene for the conference and their attendance, they follow a thematic content analysis procedure to extract and synthesize the most important issues and concerns being discussed during the discussions and commentaries of the conference.

Findings

The report presents an overview of the conference, the main outcomes of its sessions and the main reoccurring themes during the conference’s sessions.

Originality/value

This is the first conference report on the Second UNWTO/UNESCO World Conference on Tourism and Culture: Fostering Sustainable Development.