bluuebunny/crossref_metadata_2025 huggingface dataset:
Phonetic Mastering of Arabic Words With Long Vowels in the Turkic Languages
Authors: Karataeva S.
Published: February 2021

The purpose of our article can be characterized as a scientific review of the vocal system of the Kyrgyz language against the background of Turkic phonology and the patterns of development of the vocal paradigm, the transformation and evolution of long vowels in the historical context (influence of the Arabic language) of Central Asia. Analyzing all data related to the long vowels’ changes in the above-mentioned language and the transformations based on Arabic borrowings. Also, subjected to a detailed analysis of the graphic influences from the side of Arabic graphics in relation to Kyrgyz phonology and linguistic facts about the transformation of Arabic tokens during adaptation in a foreign language context. Nevertheless, to explain the areal features of the Kyrgyz language on the scale of Central Asia. To demonstrate (on the example of archaic words, religious lexicon terms) the stages and patterns of the historical development of the vocal system of a given language in a comparative and cognitive plan. The purpose of this study is, therefore, to identify and describe the patterns of development of quantum phonetics, phonosemantic features of long vowels of Kyrgyz lexemes and phonemes on the one hand, and Arabic guttural and posterolinguistic connectives on the other hand. Kyrgyz and Arabic are multisystem languages. The Arabic language, in a typological sense, is inflectional and belongs to the Semitic group, at the same time, according to some scholars, the Kyrgyz is an agglutinative language and has Altai origin. It is well known that the phonetic spectrum and their variable language palette of the Arabic language is very diverse. In phonetic terms, the Arabic language has a widely developed system of consonant phonemes, on the other hand, the likelihood of the phonomorphological and phonosemantic function of vowels in the Kyrgyz language is quite high too. As part of our research, we tried to identify the seven positions of long vowels in the Arabic language, and in parallel to this show the transformations of Arabic sounds based on the internal phonetic laws of the Kyrgyz language. Consequently, the Arabic long vowels in the process of adaptation in the Kyrgyz language environment, to a certain extent, retained their quantitative character (quantum coefficient) in comparison with other Turkic languages of Central Asia.
The Characteristics of the Genre and Style in the Works of Yassawi
Authors: Nosirov Sh.
Published: February 2021

In the form of hikmet Ahmed Yassawi is a historical document that reads the life of the Yassawi sheikh himself, divided by him into two periods: sixty-three years on earth and sixty-three years under the earth. The results of the study of the Hikmet Corps convince that Ahmed Yassavi, despite the presence of phantasms in his texts, lived and served his faith as a sane person who organized an authoritative Sufi organization in Turkestan and effectively led it for decades.
Humanisme, biopolitique et civilité: les cas d'Albert Camus et Malika Mokeddem
Authors: Vallury Raji
Published: February 2021

Mon article analyse la relation entre humanisme et biopolitique chez Albert Camus et Malika Mokeddem. Faisant appel au concept de la civilité, je suggère que Mokeddem rapièce l’écart creusé par Camus entre vie humaine et vie politique. Proposée par Étienne Balibar, la civilité présuppose l'inséparabilité de l'appartenance à l'humanité et l'appartenance à la vie politique; l'impossibilité de diviser l'existence humaine entre la vie nue et la vie politique. Camus et Mokeddem désignent l'espace de la politique comme la sphère d'une apparence, où un sujet se rend visible et audible par la parole. Mokeddem trace une civilité capable d'intégrer le droit de cité des femmes, dessinant une communauté égalitaire soustraite à la logique des régimes biopolitiques. « Féminisant » l'humanisme, Mokeddem démontre qu'une capacité politique partagée en commun fait l'humanité, et pas le contraire. Camus et Mokeddem offrent des alternatives au « nécro-pouvoir » identifié par Achille Mbembe comme constitutif des régimes coloniaux et postcoloniaux.
Derrida's Missing Woman
Authors: Thevenet Charlotte
Published: February 2021

Since Sarah Kofman's death in 1994, many critics have investigated her friendship with Jacques Derrida, and have tried to make sense of its striking dissymmetry. Contrary to those merely deeming Kofman ‘an orthodox Derridean’ (Alice Jardine), thus ascribing to her the unrewarding role of the disciple, Penelope Deutscher and more recently Ginette Michaud, among others, have endeavoured to interpret Derrida's odd silences and omissions regarding Kofman's work in a more subtle manner. Drawing on these readings, this article questions the erasure of ‘Sarah Kofman’ from Derrida's oeuvre by comparing it to the paradoxical effacement of ‘woman’ in the philosopher's texts, arguing that ‘Sarah Kofman’ both as a proper name and as a corpus figures the ‘woman’ missing from Derrida's work. Drawing on the work of feminist critics like Jardine, Miller and Spivak, the article retraces the ambiguous function of ‘woman’ in Derrida's writing, before stressing parallels between ‘Sarah Kofman’ and the Derridean ‘woman’.
And Yet It Quakes! (Nietzsche and Voltaire)
Authors: Kofman Sarah
Published: February 2021

One of a handful of texts written by Sarah Kofman in the interim between the publication of her Explosion (1992, 1993), a 700-page analysis of Ecce Homo, and her sudden death in 1994, ‘And Yet It Quakes!’ is an unflinching contribution to her perennial analysis of Nietzsche's legacy. The essay opens with a presentation of the responses of Voltaire and Nietzsche to natural catastrophe: an earthquake in Lisbon in the case of the former, an earthquake in Ischia for the latter. Drawing on a metaphoric architecture of quaking or shakenness to draw together a variety of themes and problematics, the essay elaborates a rich comparative study of these two thinkers on the basis of their hasty passing-on from the ‘“humanitarian” considerations’ which such catastrophes might evoke. After analysing the influence of Voltaire on Nietzsche and the rich synergies between the two, with particular reference to irony and laughter, to aristocratism, and to the function of a polemical hostility to Rousseau within their various projects, Kofman's essay closes with a complex — and somewhat ambivalent — affirmation of the radicality of the Nietzschean project. (This text, first published in Furor shortly before Kofman's death, is collected in the posthumous Imposture de la beauté et autres textes (Galilée, 1995) and in Tributs à Voltaire (Furor, 2017). The ayant-droit is favourable to publication.)
Iron Age domestic activity at Dornoch, Sutherland
Authors: Johnstone Nicholas
Published: February 2021

Archaeological works in 2015 within an agricultural area to the north of Dornoch have provided evidence for the prehistoric occupation of the area. The 2015 excavation uncovered evidence of Iron Age settlement, including a palisade enclosure within which was a post-built structure as well as a collection of hearth pits and large stone-lined pits. The recovery of a pivot stone from one later Iron Age feature is evidence for the former presence of a domestic structure. While the artefactual evidence and a programme of radiocarbon dating strongly indicates an Iron Age origin for the majority of the remains identified, a single calibrated date recovered from a shell midden indicates the likely reworking of Neolithic material, and one hearth structure may potentially overlie a large Neolithic pit feature. An artefact assemblage of worked coarse stone, worked antler, and Iron Age pottery was recovered.
When Birnam Wood rises: prehistoric activity at Birnam Crescent, Bearsden, Glasgow
Authors: Kilpatrick Maureen C.
Published: February 2021

An archaeological evaluation and subsequent strip, map and sample excavation were carried out by GUARD Archaeology Ltd for CALA Homes (West) between 2017 and early 2018 on a site proposed for residential development in Bearsden, East Dunbartonshire. During the work a series of archaeological features comprising pits and postholes and several small drystone structures were uncovered across the site and were subsequently excavated.
The End Has (Not Yet) Come: The 1918 Spanish Flu and the COVID-19 Pandemic in a Brazilian Seventh-day Adventist Bulletin
Authors: Novaes Allan
Published: February 2021

This is a comparative analysis of similarities and differences between the Brazilian Adventist discourse on the 1918 Influenza pandemic – also known as the Spanish Flu – and the current Brazilian Adventist discourse on the COVID-19 pandemic. It focuses on how Adventists articulate the distinctive eschatological and sanitary elements of their narrative tradition in order to explain the two crises and to situate themselves in relation to them. The analysis corpus contains select texts published in Revista Adventista, the official bulletin of Brazilian Seventh-day Adventists, pertaining to two time periods: 1918–1920 and the first quarter of 2020. Both materials present pandemic crises as opportunities for evangelism since they display the understanding that societal values and paradigms become less impervious to religion in such conditions. But they differ in the fact that the 1918–1920 material concentrates on religious expansion and doctrine, especially emphasising the message of impending judgement of a Great Controversy metanarrative, while the 2020 material explores the medical and humanitarian aspects connected to the pandemic, transcending a purely eschatological emphasis and accommodating a concerted effort to give the readers emotional support to face the pandemic.
‘It is the antichrist. Can't you see?’ Perceptions of COVID-19 among Nigeria's Christians and the Religion—Health Debate
Authors: Ossai Emmanuel Chiwetalu
Published: February 2021

How does religion influence health? Responses to this question have shown that religious beliefs could have positive and negative effects on people's health. This paper focuses on religion's influence on how believers perceive and deal with diseases, and it aims to contribute to the debate by considering how COVID-19 was interpreted in Sub-Saharan Africa's Nigeria, which has been regarded as very religious, partly because the majority of her citizens identify as Christians or Muslims. It explores perceptions of COVID-19 in the country using data collected between March and May 2020, from (a) in-depth interviews with Christians in various states in the southern part of the country, (b) Facebook polls and (c) articles and readers' comments on the websites of Nigeria's Punch and Vanguard Newspapers. The findings corroborate the notion that (a) religion could have a negative influence on people's views about, and responses to, diseases, and that (b) religious organisations could serve as helpful partners in the fight against diseases. However, the data also demonstrate how the religious responses occurred within a context of political failure, which, in turn, is a major threat to public health in Nigeria. This suggests that to understand and successfully deal with the negative religious and cultural views about diseases in societies where such unhelpful relationships exist, it may be useful to consider how wider political and socio-economic realities help to shape those perceptions or the preference for religious sources of interpretation and healing.
Resonant scattering of electromagnetic waves by small metal particles: a new insight into the old problem
Authors: Tribelsky M I , Miroshnichenko A E
Published: February 2021

This review is devoted to a discussion of new (and often unexpected) aspects of the old problem of elastic light scattering by small metal particles, whose size is comparable to or smaller than the thickness of the skin layer. The main focus is on elucidating the physical grounds for these new aspects. It is shown that, in many practically important cases, the scattering of light by such particles, despite their smallness, may have almost nothing in common with the Rayleigh scattering. So-called anomalous scattering and absorption, as well as Fano resonances, including unconventional (associated with the excitation of longitudinal electromagnetic oscillations) and directional Fano resonances, observed only at a small solid angle, are discussed in detail. The review contains a Mathematical Supplement, which includes a summary of the main results of the Mie theory and a discussion of some general properties of scattering coefficients. In addition to being of purely academic interest, the phenomena considered in this review can find wide applications in biology, medicine, pharmacology, genetic engineering, imaging of ultra-small objects, ultra-high-resolution spectroscopy, information transmission, recording, and processing, as well as many other applications and technologies.
Simposio Abdomen Agudo
Authors: Barboza Besada Eduardo
Published: February 2021

El abdomen agudo es un síndrome muy frecuente en la práctica médica, cuyo principal síntoma es el dolor abdominal, el que puede responder a una enfermedad no específica.
Enfermedad de Coronavirus 2019 (COVID-19). Segunda parte
Authors: Sjogren María H.
Published: February 2021

La crisis por la infección con el SARS-CoV-2 demandó nuevos métodos de tratamiento y prevención. Inicialmente la prevención se limitó a recomendar máscaras faciales, distanciamiento social y cierre de instituciones. Con la descripción del genoma viral, se pudo elaborar posibles vacunas contra este nuevo virus. Entre las inmunizaciones mas promisorias están dos productos mRNA, uno es de Moderna y el Instituto Nacional de Salud en Estados Unidos y otro el de Pfizer y BioNTech. Estas vacunas, usan un análogo sintético de la altamente antigénica espiga viral, quien, al ser inoculado en humanos, ordenan producir proteínas virales, estimuladoras de anticuerpos y funciones inmunológicas que eliminan el virus. Tienen 95% de eficacia en estudios de Fase 3 y se pueden producir en corto tiempo. Ambos laboratorios han aplicado para una autorización de emergencia del Food and Drug Administration en USA y fueron aprobadas para uso en humanos en diciembre de 2020. Otra plataforma es la inserción de análogos sintéticos de la espiga viral en un adenovirus inerte Astra Zeneca y la Universidad de Oxford reportaron una eficacia de aproximadamente 70%, sin embargo, ha habido ciertas irregularidades y el resultado final necesita aclaración.  Vectores virales se usaron en Rusia y en China, las vacunas están autorizadas en sus países de origen. Otros productos con virus atenuado, virus inerte y partículas subvirales están en estudio y contribuirán a la prevención de esta enfermedad que ha infectado mas de 60 millones de personas y ha ocasionado la muerte de cerca de dos millones.
Abdomen Agudo. Primera parte
Authors: Del Castillo-Yrigoyen Mario
Published: February 2021

La enfermedad de la vesícula por presencia de cálculos es muy frecuente en el mundo, su incidencia puede diferir de un país a otro, pero lo que sí se puede afirmar es que es más frecuente entre los 30 a 69 años y con una incidencia general de la enfermedad de cálculos biliares promedio de 19% en mujeres y 10% en hombres.
Estimating Dependence Among Lumber Strength Properties With Copula Models
Authors: Cai Yanling , Joe Harry , Pan Shenyi
Published: February 2021

A copula-based approach is used to estimate the dependence among three lumber strength properties: modulus of elasticity (MOE), modulus of rupture (MOR), and ultimate tensile strength (UTS). MOR and UTS are destructive measurements so they cannot be obtained simultaneously for lumber specimens. The dependence modeling is possible under an appropriate experimental design with i) a shoulder group for rupture, ii) a shoulder group for tension, and iii) other groups proof loaded in either the rupture or tension mode with survivors tested to failure in the mode that was not initially tested. With a fitted copula model based on an assumption of no damage due to the proof loading procedure, we conclude that there is a strong dependence between MOR and UTS conditioning on MOE. To assess the “no damage assumption,” a graphical method with simulated data from the fitted copula model is used. It suggests that there may be some damage to the lumber specimens due to proof loading, especially for weaker lumber specimens. Information from the dependence model can potentially help reduce monitoring costs in the lumber industry.
A LCMS Metabolomic Workflow to Investigate Metabolic Patterns in Human Intestinal Cells Exposed to Hydrolyzed Crab Waste Materials
Authors: Ó Fearghail Fionn , Behan Patrice , Engström Niklas , Scheers Nathalie
Published: February 2021

We have developed a LCMS metabolomic workflow to investigate metabolic patterns from human intestinal cells treated with simulated gastrointestinal-digested hydrolyzed crab waste materials. This workflow facilitates smart and reproducible comparisons of cell cultures exposed to different treatments. In this case the variable was the hydrolysis methods, also accounting for the GI digestion giving an output of direct correlation between cellular metabolic patterns caused by the treatments. In addition, we used the output from this workflow to select treatments for further evaluation of the Caco-2 cell response in terms of tentative anti-inflammatory activity in the hopes to find value in the crab waste materials to be used for food products. As hypothesized, the treatment identified to change the cellular metabolomic pattern most readily, was also found to cause the greatest effect in the cells, although the response was pro-inflammatory rather than anti-inflammatory, it proves that changes in cellular metabolic patterns are useful predictors of bioactivity. We conclude that the developed workflow allows for cost effective, rapid sample preparation as well as accurate and repeatable LCMS analysis and introduces a data pipeline specifically for probe the novel metabolite patterns created as a means to assess the performing treatments.
Zoledronic Acid-Loaded Hybrid Hyaluronic Acid/Polyethylene Glycol/Nano-Hydroxyapatite Nanoparticle: Novel Fabrication and Safety Verification
Authors: Xu Yan , Zhang Zheng , Wang Hehui , Zhong Wu , Sun Chengmei , Sun Wei , Wu Hongwei
Published: February 2021

Osteosarcoma is a malignant tumor that often occurs in adolescents and children. Zoledronic acid, a new-generation bisphosphonate, has been widely used as an antitumor drug to inhibit bone metastasis. However, the rapid renal elimination results in low effective concentrations. Meanwhile, high-dose intravenous zoledronic acid administration leads to severe side effects. The present study fabricated an organic–inorganic hybrid nanoparticle as the carrier of zoledronic acid. The rod-like nanoparticle, which had 150-nm length and 40-nm cross-sectional diameter, consisted of a hyaluronic acid/polyethylene glycol (HA-PEG) polymer shell and a nano-hydroxyapatite (nHA) core, with zoledronic acid molecules loading on the surface of nHA and clearance of HA-PEG shell. The nanoparticle was characterized by microscopic analysis, in vitro release study, cytotoxicity analysis, and in vivo immune response examination. Results showed that the compact and stable structure could achieve high drug loading efficiency, sustained drug release, and great biocompatibility. In vitro and in vivo experiments revealed the low cytotoxicity and acceptable immune response under low-dose nanoparticle treatment, indicating its potential application for future osteosarcoma therapeutic strategies.
Toward Patient Specific Models of Pediatric IVDs: A Parametric Study of IVD Mechanical Properties
Authors: Pickering Edmund , Pivonka Peter , Little J. Paige
Published: February 2021

Patient specific finite element (FE) modeling of the pediatric spine is an important challenge which offers to revolutionize the treatment of pediatric spinal pathologies, for example adolescent idiopathic scoliosis (AIS). In particular, modeling of the intervertebral disc (IVD) is a unique challenge due to its structural and mechanical complexity. This is compounded by limited ability to non-invasively interrogate key mechanical parameters of a patient's IVD. In this work, we seek to better understand the link between mechanical properties and mechanical behavior of patient specific FE models of the pediatric lumbar spine. A parametric study of IVD parameter was conducted, coupled with insights from current knowledge of the pediatric IVD. In particular, the combined effects of parameters was investigated. Recommendations are made toward areas of importance in patient specific FE modeling of the pediatric IVD. In particular, collagen fiber bundles of the IVD are found to dominate IVD mechanical behavior and are thus recommended as an area of primary focus for patient specific FE models. In addition, areas requiring further experimental research are identified. This work provides a valuable building block toward the development of patient specific models of the pediatric spine.
Meeting Changing Customer Requirements in Food and Agriculture Through the Application of Blockchain Technology
Authors: Sengupta Ushnish , Kim Henry Michael
Published: February 2021

This research summarizes the implementation of blockchain technology in the food and agriculture industry in Canada. Our research indicates that blockchain solutions are an existing and proven set of technologies. We also describe how blockchain based supply chain traceability information has many more benefits than its current use for food safety and product recalls. We recommend that costs for development of blockchain based solutions should also be distributed across stakeholders, and apportioned by the relevant industry associations. Our research indicates that adoption of blockchain technology in agriculture will achieve critical mass earlier when the industry applies a consortium approach, in a regulatory environment that is supported by government. This report also makes recommendations relevant to the integration of blockchain for end consumers of food.
Mrc1-Dependent Chromatin Compaction Represses DNA Double-Stranded Break Repair by Homologous Recombination Upon Replication Stress
Authors: Xing Poyuan , Dong Yang , Zhao Jingyu , Zhou Zhou , Li Zhao , Wang Yu , Li Mengfei , Zhang Xinghua , Chen Xuefeng
Published: February 2021

The coordination of DNA replication and repair is critical for the maintenance of genome stability. It has been shown that the Mrc1-mediated S phase checkpoint inhibits DNA double-stranded break (DSB) repair through homologous recombination (HR). How the replication checkpoint inhibits HR remains only partially understood. Here we show that replication stress induces the suppression of both Sgs1/Dna2- and Exo1-mediated resection pathways in an Mrc1-dependent manner. As a result, the loading of the single-stranded DNA binding factor replication protein A (RPA) and Rad51 and DSB repair by HR were severely impaired under replication stress. Notably, the deletion of MRC1 partially restored the recruitment of resection enzymes, DSB end resection, and the loading of RPA and Rad51. The role of Mrc1 in inhibiting DSB end resection is independent of Csm3, Tof1, or Ctf4. Mechanistically, we reveal that replication stress induces global chromatin compaction in a manner partially dependent on Mrc1, and this chromatin compaction limits the access of chromatin remodeling factors and HR proteins, leading to the suppression of HR. Our study reveals a critical role of the Mrc1-dependent chromatin structure change in coordinating DNA replication and recombination under replication stress.
Cardiac Gq Receptors and Calcineurin Activation Are Not Required for the Hypertrophic Response to Mechanical Left Ventricular Pressure Overload
Authors: Yu Ze-Yan , Gong Hutao , Wu Jianxin , Dai Yun , Kesteven Scott H. , Fatkin Diane , Martinac Boris , Graham Robert M. , Feneley Michael P.
Published: February 2021

Rationale

Gq-coupled receptors are thought to play a critical role in the induction of left ventricular hypertrophy (LVH) secondary to pressure overload, although mechano-sensitive channel activation by a variety of mechanisms has also been proposed, and the relative importance of calcineurin- and calmodulin kinase II (CaMKII)-dependent hypertrophic pathways remains controversial.

Objective

To determine the mechanisms regulating the induction of LVH in response to mechanical pressure overload.

Methods and Results

Transgenic mice with cardiac-targeted inhibition of Gq-coupled receptors (GqI mice) and their non-transgenic littermates (NTL) were subjected to neurohumoral stimulation (continuous, subcutaneous angiotensin II (AngII) infusion for 14 days) or mechanical pressure overload (transverse aortic arch constriction (TAC) for 21 days) to induce LVH. Candidate signaling pathway activation was examined. As expected, LVH observed in NTL mice with AngII infusion was attenuated in heterozygous (GqI+/–) mice and absent in homozygous (GqI–/–) mice. In contrast, LVH due to TAC was unaltered by either heterozygous or homozygous Gq inhibition. Gene expression of atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and α-skeletal actin (α-SA) was increased 48 h after AngII infusion or TAC in NTL mice; in GqI mice, the increases in ANP, BNP and α-SA in response to AngII were completely absent, as expected, but all three increased after TAC. Increased nuclear translocation of nuclear factor of activated T-cells c4 (NFATc4), indicating calcineurin pathway activation, occurred in NTL mice with AngII infusion but not TAC, and was prevented in GqI mice infused with AngII. Nuclear and cytoplasmic CaMKIIδ levels increased in both NTL and GqI mice after TAC but not AngII infusion, with increased cytoplasmic phospho- and total histone deacetylase 4 (HDAC4) and increased nuclear myocyte enhancer factor 2 (MEF2) levels.

Conclusion

Cardiac Gq receptors and calcineurin activation are required for neurohumorally mediated LVH but not for LVH induced by mechanical pressure overload (TAC). Rather, TAC-induced LVH is associated with activation of the CaMKII-HDAC4-MEF2 pathway.
Extracellular Pneumococcal Serine Proteases Affect Nasopharyngeal Colonization
Authors: Ali Murtadha Q. , Kohler Thomas P. , Burchhardt Gerhard , Wüst Andreas , Henck Nadin , Bolsmann Robert , Voß Franziska , Hammerschmidt Sven
Published: February 2021

Streptococcus pneumoniae has evolved versatile strategies to colonize the nasopharynx of humans. Colonization is facilitated by direct interactions with host cell receptors or via binding to components of the extracellular matrix. In addition, pneumococci hijack host-derived extracellular proteases such as the serine protease plasmin(ogen) for ECM and mucus degradation as well as colonization. S. pneumoniae expresses strain-dependent up to four serine proteases. In this study, we assessed the role of secreted or cell-bound serine proteases HtrA, PrtA, SFP, and CbpG, in adherence assays and in a mouse colonization model. We hypothesized that the redundancy of serine proteases compensates for the deficiency of a single enzyme. Therefore, double and triple mutants were generated in serotype 19F strain EF3030 and serotype 4 strain TIGR4. Strain EF3030 produces only three serine proteases and lacks the SFP encoding gene. In adherence studies using Detroit-562 epithelial cells, we demonstrated that both TIGR4Δcps and 19F mutants without serine proteases or expressing only CbpG, HtrA, or PrtA have a reduced ability to adhere to Detroit-562 cells. Consistent with these results, we show that the mutants of strain 19F, which preferentially colonizes mice, abrogate nasopharyngeal colonization in CD-1 mice after intranasal infection. The bacterial load in the nasopharynx was monitored for 14 days. Importantly, mutants showed significantly lower bacterial numbers in the nasopharynx two days after infection. Similarly, we detected a significantly reduced pneumococcal colonization on days 3, 7, and 14 post-inoculations. To assess the impact of pneumococcal serine proteases on acute infection, we infected mice intranasally with bioluminescent and invasive TIGR4 or isogenic triple mutants expressing only CbpG, HtrA, PrtA, or SFP. We imaged the acute lung infection in real-time and determined the survival of the mice. The TIGR4lux mutant expressing only PrtA showed a significant attenuation and was less virulent in the acute pneumonia model. In conclusion, our results showed that pneumococcal serine proteases contributed significantly to pneumococcal colonization but played only a minor role in pneumonia and invasive diseases. Because colonization is a prerequisite for invasive diseases and transmission, these enzymes could be promising candidates for the development of antimicrobials to reduce pneumococcal transmission.
Learning From Limited Data: Towards Best Practice Techniques for Antimicrobial Resistance Prediction From Whole Genome Sequencing Data
Authors: Lüftinger Lukas , Májek Peter , Beisken Stephan , Rattei Thomas , Posch Andreas E.
Published: February 2021

Antimicrobial resistance prediction from whole genome sequencing data (WGS) is an emerging application of machine learning, promising to improve antimicrobial resistance surveillance and outbreak monitoring. Despite significant reductions in sequencing cost, the availability and sampling diversity of WGS data with matched antimicrobial susceptibility testing (AST) profiles required for training of WGS-AST prediction models remains limited. Best practice machine learning techniques are required to ensure trained models generalize to independent data for optimal predictive performance. Limited data restricts the choice of machine learning training and evaluation methods and can result in overestimation of model performance. We demonstrate that the widely used random k-fold cross-validation method is ill-suited for application to small bacterial genomics datasets and offer an alternative cross-validation method based on genomic distance. We benchmarked three machine learning architectures previously applied to the WGS-AST problem on a set of 8,704 genome assemblies from five clinically relevant pathogens across 77 species-compound combinations collated from public databases. We show that individual models can be effectively ensembled to improve model performance. By combining models via stacked generalization with cross-validation, a model ensembling technique suitable for small datasets, we improved average sensitivity and specificity of individual models by 1.77% and 3.20%, respectively. Furthermore, stacked models exhibited improved robustness and were thus less prone to outlier performance drops than individual component models. In this study, we highlight best practice techniques for antimicrobial resistance prediction from WGS data and introduce the combination of genome distance aware cross-validation and stacked generalization for robust and accurate WGS-AST.
Individualized Experience With Percutaneous Transcatheter Closure of Multiple Atrial Septal Defects: A Single-Center Study
Authors: Wang Zhenquan , Zhan Yi , Jin Jiahui , Wu Tingting , Zhang Songyue , Qiu Huixian , Wang Qiaoyu , Wu Rongzhou
Published: February 2021

Multiple atrial septal defects (ASDs) are one type of secundum ASD, most of which have an atrial septal aneurysm or long interdefect distance. In our retrospective single-center study, we reviewed different closure strategies for multiple ASDs. We analyzed 50 patients who underwent percutaneous transcatheter closure from May 2011 to July 2019. Information on the patients' characteristics, operation procedure, occluder selection, and complications was collected. According to the feature of the defects and device choice, multiple ASDs were divided into five groups. A successful operation was achieved in every patient. A total of 50 patients were implanted with 58 devices, with 26 patients implanted with a single standard ASD occluder (ASDO); six patients were implanted with double standard ASDOs, and only one patient was implanted with three standard ASDOs. There were 17 patients whose closure was made using the small-waist–big-edge ASDO. Seventy-six percent of the patients (38/50) had an immediate residual shunt. During the mean follow-up of 25.76 ± 22.53 months, the complete closure rate was 92%. Except for two patients with a transient atrioventricular block, individualized experience with percutaneous transcatheter closure for multiple ASDs was effective in a single-center study. After a mid- to long-term follow-up, the multiple ASDOs and small-waist–big-edge ASDO had no serious adverse events or complications.
Mitochondrial Dysfunction Increases Arrhythmic Triggers and Substrates; Potential Anti-arrhythmic Pharmacological Targets
Authors: Saadeh Khalil , Fazmin Ibrahim Talal
Published: February 2021

Incidence of cardiac arrhythmias increases significantly with age. In order to effectively stratify arrhythmic risk in the aging population it is crucial to elucidate the relevant underlying molecular mechanisms. The changes underlying age-related electrophysiological disruption appear to be closely associated with mitochondrial dysfunction. Thus, the present review examines the mechanisms by which age-related mitochondrial dysfunction promotes arrhythmic triggers and substrate. Namely, via alterations in plasmalemmal ionic currents (both sodium and potassium), gap junctions, cellular Ca2+homeostasis, and cardiac fibrosis. Stratification of patients' mitochondrial function status permits application of appropriate anti-arrhythmic therapies. Here, we discuss novel potential anti-arrhythmic pharmacological interventions that specifically target upstream mitochondrial function and hence ameliorates the need for therapies targeting downstream changes which have constituted traditional antiarrhythmic therapy.
Fault Instability and Its Relation to Static Coulomb Failure Stress Change in the 2016 Mw 6.5 Pidie Jaya Earthquake, Aceh, Indonesia
Authors: Kusumawati Dian , Sahara David P. , Widiyantoro Sri , Nugraha Andri Dian , Muzli Muzli , Imran Iswandi , Puspito Nanang T. , Zulfakriza Zulfakriza
Published: February 2021

Herein, we applied the fault instability criterion and integrated it with the static Coulomb stress change (ΔCFS) to infer the mechanism of the 2016 Mw 6.5 Pidie Jaya earthquake and its aftershock distribution. Several possible causative faults have been proposed; however, the existence of a nearby occurrence, the 1967 mb 6.1 event, created obscurity. Hence, we applied the fault instability analysis to the Pidie Jaya earthquake 1) to corroborate the Pidie Jaya causative fault analysis and 2) to analyze the correlation between ΔCFS distribution imparted by the mainshock and the fault instability of the reactivated fault planes derived from the focal solution of the Pidie Jaya aftershocks. We performed the fault instability analysis for two possible source faults: the Samalanga-Sipopok Fault and the newly inferred Panteraja Fault. Although the maximum instability value of the Samalanga-Sipopok Fault is higher, the dip value of the Panteraja Fault coincides with its optimum instability. Therefore, we concluded that Panteraja was the causative fault plane. Furthermore, a link between the 1967 mb 6.1 event and the 2016 Mw 6.5 earthquake is discussed. To analyze the correlation between the fault instability and the ΔCFS, we resolved the ΔCFS of the Pidie Jaya mainshock on its aftershock planes and compared the ΔCFS results with the fault instability calculation on each aftershock plane. We discussed the possibility of conjugate failure as shown by the aftershock fault instability. Related to the ΔCFS and fault instability comparison, we found that not all the aftershocks have positive ΔCFSs, but their instability value is high. Thus, we suggest that the fault plane instability plays a role in events that do not occur in positive ΔCFS areas. Apart from these, we also showed that the off-Great Sumatran Fault (Panteraja and Samalanga-Sipopok Faults) are unstable in the Sumatra regional stress setting, thereby making it more susceptible to slip movement.
Megathrust Slip Behavior for Great Earthquakes Along the Sumatra-Andaman Subduction Zone Mapped From Satellite GOCE Gravity Field Derivatives
Authors: Álvarez Orlando , Pechuan Canet Stefanie , Gimenez Mario , Folguera Andrés
Published: February 2021

During the last two decades, space geodesy allowed mapping accurately rupture areas, slip distribution, and seismic coupling by obtaining refined inversion models and greatly improving the study of great megathrust earthquakes. A better understanding of these phenomena involving large areas of hundreds of square kilometers came from the last gravity satellite mission that allowed detecting mass transfer through the Earth interior. In this work, we performed direct modeling of satellite GOCE (Gravity Field and Steady-State Ocean Circulation Explorer) derived gravity gradients up to degree/order N = 200 of the harmonic expansion and then corrected this by the effect of topography. Cutting off the model up to this degree/order allows inferring mass heterogeneities located at an approximate depth of 31 km, just along the plate interface where most (but not all) significant slip occurs. Then, we compared the vertical gravity gradient to well-constrained coseismic slip models for three of the last major earthquakes along the Sunda interface. We analyzed seismic rupture behavior for recent and for historical earthquakes along this subduction margin and the relationship of the degree of interseismic coupling using the gravity signal. From this, we found that strong slip patches occurred along minima gravity gradient lobes and that the maximum vertical displacements were related quantitatively to the gravity-derived signal. The degree of interseismic coupling also presents a good correspondence to the vertical gravity gradient, showing an inverse relationship, with low degrees of coupling over regions of relatively higher density. This along-strike segmentation of the gravity signal agrees with the along-strike seismic segmentation observed from recent and historical earthquakes. The thermally controlled down-dip ending of the locked fault zone along central Sumatra also presented an inverse relationship with the density structure along the forearc inferred using our modeling. From this work, we inferred different mass heterogeneities related to persistent tectonic features along the megathrust and along the marine forearc, which may control strain accumulation and release along the megathrust. Combining these data with geodetical and seismological data could possibly delimit and monitor areas with a higher potential seismic hazard around the world.
Opportunities and Challenges in Functional Genomics Research in Osteoporosis: Report From a Workshop Held by the Causes Working Group of the Osteoporosis and Bone Research Academy of the Royal Osteoporosis Society on October 5th 2020
Authors: Tobias Jonathan H. , Duncan Emma L. , Kague Erika , Hammond Chrissy L. , Gregson Celia L. , Bassett Duncan , Williams Graham R. , Min Josine L. , Gaunt Tom R. , Karasik David , Ohlsson Claes , Rivadeneira Fernando , Edwards James R. , Hannan Fadil M. , Kemp John P. , Gilbert Sophie J. , Alonso Nerea , Hassan Neelam , Compston Juliet E. , Ralston Stuart H.
Published: February 2021

The discovery that sclerostin is the defective protein underlying the rare heritable bone mass disorder, sclerosteosis, ultimately led to development of anti-sclerostin antibodies as a new treatment for osteoporosis. In the era of large scale GWAS, many additional genetic signals associated with bone mass and related traits have since been reported. However, how best to interrogate these signals in order to identify the underlying gene responsible for these genetic associations, a prerequisite for identifying drug targets for further treatments, remains a challenge. The resources available for supporting functional genomics research continues to expand, exemplified by “multi-omics” database resources, with improved availability of datasets derived from bone tissues. These databases provide information about potential molecular mediators such as mRNA expression, protein expression, and DNA methylation levels, which can be interrogated to map genetic signals to specific genes based on identification of causal pathways between the genetic signal and the phenotype being studied. Functional evaluation of potential causative genes has been facilitated by characterization of the “osteocyte signature”, by broad phenotyping of knockout mice with deletions of over 7,000 genes, in which more detailed skeletal phenotyping is currently being undertaken, and by development of zebrafish as a highly efficient additional in vivo model for functional studies of the skeleton. Looking to the future, this expanding repertoire of tools offers the hope of accurately defining the major genetic signals which contribute to osteoporosis. This may in turn lead to the identification of additional therapeutic targets, and ultimately new treatments for osteoporosis.
Global Perspective on the Development of Genetically Modified Immune Cells for Cancer Therapy
Authors: Pinte Laetitia , Cunningham Amy , Trébéden-Negre Helene , Nikiforow Sarah , Ritz Jerome
Published: February 2021

Since the first genetically-engineered clinical trial was posted toclinicaltrials.govin 2003 (NCT00019136), chimeric antigen receptor (CAR) and T-cell receptor (TCR) therapies have exhibited unprecedented growth. USA, China, and Europe have emerged as major sites of investigation as many new biotechnology and established pharmaceutical companies invest in this rapidly evolving field. Although initial studies focused primarily on CD19 as a target antigen, many novel targets are now being evaluated. Next-generation genetic constructs, starting materials, and manufacturing strategies are also being applied to enhance efficacy and safety and to treat solid tumors as well as hematologic malignancies. Fueled by dramatic clinical efficacy and recent regulatory approvals of CD19-targeted CAR cell therapies, the field of engineered cell therapeutics continues to expand. Here, we review all 745 genetically modified CAR and TCR clinical trials with anticipated accrual of over 28,000 patients posted toclinicaltrials.govuntil 31stof December 2019. We analyze projected patient enrollment, geographic distribution and phase of studies, target antigens and diseases, current strategies for optimizing efficacy and safety, and trials expected to yield important clinical data in the coming 6–12 months.
Pharaoh Cuttlefish, Sepia pharaonis, Genome Reveals Unique Reflectin Camouflage Gene Set
Authors: Song Weiwei , Li Ronghua , Zhao Yun , Migaud Herve , Wang Chunlin , Bekaert Michaël
Published: February 2021

Sepia pharaonis, the pharaoh cuttlefish, is a commercially valuable cuttlefish species across the southeast coast of China and an important marine resource for the world fisheries. Research efforts to develop linkage mapping, or marker-assisted selection have been hampered by the absence of a high-quality reference genome. To address this need, we produced a hybrid reference genome of S. pharaonis using a long-read platform (Oxford Nanopore Technologies PromethION) to assemble the genome and short-read, high quality technology (Illumina HiSeq X Ten) to correct for sequencing errors. The genome was assembled into 5,642 scaffolds with a total length of 4.79 Gb and a scaffold N50 of 1.93 Mb. Annotation of the S. pharaonis genome assembly identified a total of 51,541 genes, including 12 copies of the reflectin gene, that enable cuttlefish to control their body coloration. This new reference genome for S. pharaonis provides an essential resource for future studies into the biology, domestication and selective breeding of the species.
Population Bottlenecks and Intra-host Evolution During Human-to-Human Transmission of SARS-CoV-2
Authors: Wang Daxi , Wang Yanqun , Sun Wanying , Zhang Lu , Ji Jingkai , Zhang Zhaoyong , Cheng Xinyi , Li Yimin , Xiao Fei , Zhu Airu , Zhong Bei , Ruan Shicong , Li Jiandong , Ren Peidi , Ou Zhihua , Xiao Minfeng , Li Min , Deng Ziqing , Zhong Huanzi , Li Fuqiang , Wang Wen-jing , Zhang Yongwei , Chen Weijun , Zhu Shida , Xu Xun , Jin Xin , Zhao Jingxian , Zhong Nanshan , Zhang Wenwei , Zhao Jincun , Li Junhua , Xu Yonghao
Published: February 2021

The emergence of the novel human coronavirus, SARS-CoV-2, causes a global COVID-19 (coronavirus disease 2019) pandemic. Here, we have characterized and compared viral populations of SARS-CoV-2 among COVID-19 patients within and across households. Our work showed an active viral replication activity in the human respiratory tract and the co-existence of genetically distinct viruses within the same host. The inter-host comparison among viral populations further revealed a narrow transmission bottleneck between patients from the same households, suggesting a dominated role of stochastic dynamics in both inter-host and intra-host evolutions.
Silencing Heat Shock Protein 47 (HSP47) in Fibrogenic Precision-Cut Lung Slices: A Surprising Lack of Effects on Fibrogenesis?
Authors: Ruigrok Mitchel J. R. , El Amasi Khaled E. M. , Leeming Diana J. , Sand Jannie M. B. , Frijlink Henderik W. , Hinrichs Wouter L. J. , Olinga Peter
Published: February 2021

Idiopathic pulmonary fibrosis (IPF) is a chronic disease that is characterized by the excessive deposition of scar tissue in the lungs. As currently available treatments are unable to restore lung function in patients, there is an urgent medical need for more effective drugs. Developing such drugs, however, is challenging because IPF has a complex pathogenesis. Emerging evidence indicates that heat shock protein 47 (HSP47), which is encoded by the gene Serpinh1, may be a suitable therapeutic target as it is required for collagen synthesis. Pharmacological inhibition or knockdown of HSP47 could therefore be a promising approach to treat fibrosis. The objective of this study was to assess the therapeutic potential of Serpinh1-targeting small interfering RNA (siRNA) in fibrogenic precision-cut lung slices prepared from murine tissue. To enhance fibrogenesis, slices were cultured for up to 144 h with transforming growth factor β1. Self-deliverable siRNA was used to knockdown mRNA and protein expression, without affecting the viability and morphology of slices. After silencing HSP47, only the secretion of fibronectin was reduced while other aspects of fibrogenesis remained unaffected (e.g., myofibroblast differentiation as well as collagen secretion and deposition). These observations are surprising as others have shown that Serpinh1-targeting siRNA suppressed collagen deposition in animals. Further studies are therefore warranted to elucidate downstream effects on fibrosis upon silencing HSP47.