bluuebunny/crossref_metadata_2025 huggingface dataset:
New inscriptions from rural Cyrenaica
Authors: Alshareef Hamid , Chevrollier François , Dobias-Lalou Catherine
Published: April 2021

This paper publishes four inscriptions recently discovered by chance in the Cyrenaican countryside. Nos 1, 2 and 3 are in Greek. No. 1, from a tomb near Mgarnes, is a funerary stele inscribed in verse for a woman whose family was of some importance in the city of Cyrene. No. 2, from the same tomb, is an anthropomorphic stele for another woman, which is discussed on the basis of the dead person's name and the vicinity of the stone to the preceding stele. No. 3, from the middle plateau below Cyrene, is a marble panel with the epitaph of two women namedCornelia, increasing our knowledge of theCorneliifamily in Cyrenaica. No. 4, from near Khawlan in the south-east, is a boundary stele in Latin mentioning the boundaries of the province; combining this with the evidence from another such stone from el-Khweimat, close to Gerdes el-Gerrari towards the south-east, also mentioning the provincial boundaries, we are now able to outline the Romanlimesin the central part of Djebel Akhdar.
Eemian and early Weichselian environmental changes at the Jałówka site, NE Poland, and their correlation with marine and ice records
Authors: Kupryjanowicz Mirosława , Fiłoc Magdalena , Woronko Barbara , Karasiewicz Tomasz Mirosław , Rychel Joanna , Adamczyk Aleksander , Jarosz Joanna
Published: April 2021

Vegetation changes were documented across the last interglacial period (MIS 5e, Eemian) and continuing through the older part of the last glacial period (MIS 5d–a, early Weichselian). This study was based on pollen data collected at the Jałówka site, NE Poland. Two cold oscillations appeared within warm periods during this stage of the upper Pleistocene. The older oscillation was the temporary intra–interglacial cooling at the end of the Eemian. The younger one was the intra–interstadial cooling that occurred within the oldest interstadial of the early Weichselian (MIS 5c, Brørup). This last event corresponds well to the stadial separating both the Amersfoort and Brørup sensu stricto interstadials in the Netherlands and to the Montaigu event as recognized in France. The development of a pollen sequence allows speculation as to potential correlations with Greenland ice cores and marine records. We suggest that the Eemian in NE Poland may comprise not only MIS 5e, but also a part of MIS 5d. This supposition could shed light on potential for non-synchrony in upper boundaries of the MIS 5e and terrestrial Eemian in Europe. We await the development of more precise independent dating controls to validate our theory more assiduously.
Ottoman Language Learning in Early Modern Germany
Authors: Hanß Stefan
Published: April 2021

This article presents new evidence on the authorship and readership of the earliest printed Ottoman language materials that details the extent to which sixteenth- and seventeenth-century inhabitants of the Holy Roman Empire actively engaged in learning Ottoman. Such findings open up a new field of inquiry evaluating the Ottoman impact on the German-speaking lands reaching beyond the so-called “Turkish menace.” Presenting the variety of Ottoman language students, teachers, and materials in central Europe, as well as their connections with the oral world(s) of linguistic fieldwork in the Habsburg-Ottoman contact zone, this article argues that Ottoman language learning is an important but thus far neglected element in understanding the cultural and intellectual landscape of early modern central Europe. What may appear to be experiments with linguistic riddles on first glimpse was in fact grounded in deep enthusiasm and fascination for Ottoman language learning shared among a community of Protestant semi-scholarly aficionados.
Synthesis, crystal structure, and X-ray diffraction data of lithium m-phenylenediamine sulfate Li2(C6H10N2)(SO4)2
Authors: Zhou Junyan , Chai Congcong , Hao Munan , Zhong Xin
Published: April 2021

A new organic–inorganic hybrid lithium m-phenylenediamine sulfate (LPS), Li2(C6H10N2)(SO4)2, was synthesized under aqueous solution conditions. The X-ray powder diffraction study determined that the title compound crystallized in a monoclinic system at 300 K, with unit-cell parameters a = 7.8689(6) Å, b = 6.6353(5) Å, c = 11.8322(10) Å, β = 109.385(3) °, V = 582.77(8) Å3. Indexing of the diffraction patterns collected from 100 to 600 K reveals that LPS has no structural phase transition within the measured temperature range, and the volume expansion coefficient is approximately 2.79 × 10−5 K−1. The crystal structure was solved based on the single-crystal diffraction data with space group P21/m. Lithium and SO42− are found to form quasi-two-dimensional anti-fluorite [LiSO4] layers stacking along the c-axis, with m-phenylenediamine molecules inserted in the anti-fluorite layers and forming hydrogen bonds to the SO42−. This explains a moderate anisotropic expansion in LPS.
Diffuse subjects and dispersed power: New materialist insights and cautionary lessons for international law
Authors: Hohmann Jessie
Published: April 2021

This article sets out the major tenets of new materialism and maps out its implications for international law. It considers what new materialism might offer for those of us working within international law in the way of new insights, resources, practices or politics. It first sets the contours of new materialism within the broader material turn. It then elaborates three main tenets of new materialism’s methodology, theory, and ontology: its attention to matter in its physicality; the embedded and entangled subject; and the vitality or agency of objects. The article focuses on how new materialist work might help us to understand, first, subjectivity and second, power and accountability in international law. It concludes that new materialist approaches offer important and compelling insights, working against entrenched categories and structures that continue to perpetuate or excuse violence and harm in international law’s doctrines and practices. These insights provide resources for rethinking power and subjectivity, and the role these play in international law. However, those of us working to consider how we can respond to pressing crises of justice and coexistence within international law may find new materialism most powerful when brought into relation, and deep conversation, with more structural methodologies. Notably ‘older’ (Marxist or historical) materialisms grasp embedded power relations and deep-rooted systemic harms in more concrete ways. This is, the article concludes, a conversation that international law scholars are well placed to contribute to, deepening both ‘old’ and ‘new’ materialist insights for international law.
Racial and ethnic differences in response to treatment for Marfan syndrome
Authors: Ayers Rachel , Kelleman Michael , Iannucci Glen , McCracken Courtney , Oster Matthew E.
Published: April 2021

Objective:

To determine whether racial/ethnic differences exist for the treatment of Marfan syndrome aortopathy. The 2014 Pediatric Heart Network randomised trial of losartan versus atenolol in Marfan syndrome paediatric and young adult patients showed no treatment differences in the rate of aortic root growth over 3 years; however, they did not examine racial/ethnic differences, and recent data suggest that angiotensin receptor blockers may have different pharmacologic effects in different racial/ethnic populations.

Methods:

We performed a secondary analysis of public-use data from the Pediatric Heart Network randomised trial comparing the differences by race/ethnicity (non-Hispanic White, non-Hispanic Black, and Hispanic patients) amongst the treatment groups for the primary outcome of rate of aortic root enlargement by z score and secondary outcome of rate of change of absolute diameter of aortic root, z score and absolute diameter of ascending aorta, and blood pressure changes.

Results:

For aortic root enlargement by z score amongst non-Hispanic White patients, patients on losartan exhibited an annual z score change of –0.090 ± 0.016, compared to –0.146 ± 0.015 for those on atenolol (p = 0.01), favouring atenolol. For Hispanic and non-Hispanic Black patients, there was no difference in primary or secondary outcomes between treatment groups.

Conclusion:

Non-Hispanic White patients had a small, but statistically significantly greater decrease in aortic root z score favouring atenolol over losartan. There were no significant differences amongst Hispanic or non-Hispanic Black patients, which may be due to relatively small size numbers. These findings may have important implications for medication selection by race/ethnicity in Marfan syndrome patients, which has not previously been evaluated in studies.
Mass-Casualty Training Exercise Using High-Fidelity Computerized Simulators and Involving Time and Resource Limitation
Authors: Jacobson Phillip A. , Severin Paul N. , Rumoro Dino P. , Shah Shital
Published: April 2021

Purpose:

Training emergency department (ED) personnel in the care of victims of mass-casualty incidents (MCIs) is a highly challenging task requiring unique and innovative approaches. The purpose of this study was to retrospectively explore the value of high-fidelity simulators in an exercise that incorporates time and resource limitation as an optimal method of training health care personnel in mass-casualty care.

Methods:

Mass-casualty injury patterns from an explosive blast event were simulated for 12 victims using high-fidelity computerized simulators (HFCS). Programmed outcomes, based on the nature of injuries and conduct of participants, ranged from successful resuscitation and survival to death. The training exercise was conducted five times with different teams of health care personnel (n = 42). The exercise involved limited time and resources such as blood, ventilators, and imaging capability. Medical team performance was observed and recorded. Following the exercise, participants completed a survey regarding their training satisfaction, quality of the exercise, and their prior experiences with MCI simulations. The Likert scale responses from the survey were evaluated using mean with 95% confidence interval, as well as median and inter-quartile range. For the categorical responses, the frequency, proportions, and associated 95% confidence interval were calculated.

Results:

The mean rating on the quality of experiences related trainee survey questions (n = 42) was between 4.1 and 4.6 on a scale of 5.0. The mean ratings on a scale of 10.0 for quality, usefulness, and pertinence of the program were 9.2, 9.5, and 9.5, respectfully. One hundred percent of respondents believed that this type of exercise should be required for MCI training and would recommend this exercise to colleagues. The five medical team (n = 5) performances resulted in the number of deaths ranging from two (including the expectant victims) to six. Eighty percent of medical teams attempted to resuscitate the “expectant” infant and exhausted the O- blood supply. Sixty percent of medical teams depleted the supply of ventilators. Forty percent of medical teams treated “delayed” victims too early.

Conclusion:

A training exercise using HFCS for mass casualties and employing limited time and resources is described. This exercise is a preferred method of training among participating health care personnel.
Insights into codeswitching from online communication: Effects of language preference and conditions arising from vocabulary richness
Authors: Feldman Laurie Beth , Srinivasan Vidhushini , Fernandes Rachel B. , Shaikh Samira
Published: April 2021

Twitter data from a crisis that impacted many English–Spanish bilinguals show that the direction of codeswitches is associated with the statistically documented tendency of single speakers to prefer one language over another in their tweets, as gleaned from their tweeting history. Further, lexical diversity, a measure of vocabulary richness derived from information-theoretic measures of uncertainty in communication, is greater in proximity to a codeswitch than in productions remote from a switch. The prospects of a role for lexical diversity in characterizing the conditions for a language switch suggest that communicative precision may induce conditions that attenuate constraints against language mixing.
Deserving the Right to Work? Immigration Officials and the Work Permit in Germany
Authors: Schultz Caroline
Published: April 2021

This article investigates the role of deservingness conceptions in the implementation of labour market access policies for migrants with precarious legal status. It explores how immigration officials frame the deservingness of work permit applicants, considering also the political, legal and societal context in which they work. The analysis takes account of the Control, Attitude, Reciprocity, Identity and Need (CARIN) criteria, and uses primary data of semi-structured interviews with senior officials in German municipal immigration offices. It finds that officials frequently employ deservingness frames inbuilt into the relevant parts of the law, but also behavioural norms that go beyond legal requirements. The article makes two main contributions. Providing empirical insight into the migration bureaucracy’s part in the implementation of labour market policy, it seeks to help advance understanding of the complex processes of differential in- and exclusion in countries of immigration. Furthermore, the research design allows putting the CARIN criteria to an empirical test.
Die Kapitän-Nemo-Geschichten
Authors: Petermann Ulrike
Published: April 2021

Bereits im Grundschulalter können Kinder unter Angst- und Stresssymptomen wie Anspannung, Konzentrations- oder Schlafschwierigkeiten leiden. Die Kapitän-Nemo-Geschichten helfen Kindern dabei, sich zu entspannen und so Angst und Unruhe abzubauen. Die Entspannungsgeschichten sind für Kinder im Alter von etwa fünf bis zwölf Jahren konzipiert und eignen sich sowohl zum Vorlesen als auch zum selbstständigen Lesen. Leitfigur ist Kapitän Nemo, der die Kinder zu Reisen durch die Weltmeere mit dem Unterwasserboot Nautilus einlädt. Bei abwechslungsreichen Ausflügen in die Unterwasserwelt besuchen sie u.a. einen Korallenwald, suchen eine Schatzkarte, reiten auf Riesenschildkröten oder erkunden die Unterwasserstadt Atlantis. Die Geschichten zielen darauf ab, den Kindern Strategien zur Selbstberuhigung und Entspannung zu vermitteln, die sie selbstständig in schwierigen Alltagssituationen anwenden können.
Constraining Suprathermal Electron Evolution in a Parker Spiral Field With Cassini Observations
Authors: Graham G. A. , Bakrania M. R. , Rae I. J. , Owen C. J. , Walsh A. P. , Owens M. J.
Published: April 2021

Suprathermal electrons in the solar wind consist of the “halo,” present at all pitch angles, and the “strahl” which is a field‐aligned, beam‐like population. Examining the heliospheric evolution of strahl beams is key to understanding the in‐transit processing of solar wind suprathermal electrons, in particular, to identify electron scattering mechanisms and to establish the origin of the halo population. Not only does this have significant implications with regard to the kinetic processes occurring within the solar wind but also its thermodynamic evolution, as the suprathermal electrons carry the majority of the solar wind heat flux. In this investigation, an established model for suprathermal electron evolution in a Parker spiral interplanetary magnetic field is adapted from its original use. The model is constrained using solar wind strahl observed by the Cassini mission on its interplanetary journey to Saturn. The effects of large scale IMF geometry due to different solar wind velocities and application of different electron scattering factors are examined. It is found that slow solar wind speeds provide the closest match to the strahl width observations, both in terms of radial distance and electron energy trends, and that predominantly slower solar wind speeds were therefore likely observed by the Cassini mission en‐route to Saturn. It is necessary to include a strahl scattering factor which increases with electron energy in order to match observations, indicating that the strahl scattering mechanism must have an inherent energy dependence.
An Evaluation of Spire Radio Occultation Data in Assimilative Ionospheric Model GPSII and Validation by Ionosonde Measurements
Authors: Kramer Kelsey K. , Fridman Sergey V. , Nickisch L. J.
Published: April 2021

This paper presents a comprehensive analysis of results obtained using NWRA’s assimilative ionospheric model GPSII when it is driven by Spire Global, Inc.’s global navigation satellite system ‐ radio occultation (GNSS‐RO) measurements. Results of the assimilative model are validated using the database of Digisonde and Dynasonde ionograms. A week’s worth of dual‐frequency phase data was collected from Spire’s constellation of low‐Earth orbiting micro‐satellites carrying GNSS receivers and assimilated into GPSII. A validation study of GNSS‐RO measurements was performed in four geographical regions. GPSII operation with the data was evaluated and the results were validated against independent ionospheric measurements. Ground‐based ionosondes were employed in diagnosing the accuracy of the derived models; we studied the differences between the F2 peak parameters (the F2 layer critical frequency, , and the peak height of the F2 layer, ) derived from ionograms and those computed with GPSII. For the 1,491 validation events used in this study, the magnitude of the deviation of the GPSII‐predicted at an ionosonde location from the corresponding ionosonde‐observed value was found on average to be 0.608 MHz (with a median of 0.461 MHz) and the magnitude of the deviation of the GPSII‐predicted at an ionosonde location from the corresponding ionosonde‐observed value was found to be on average 22.9 km (with a median value of 18.0 km). Median GPSII validation errors for are a factor of four smaller than corresponding errors for IRI, while GPSII errors are a factors of two smaller than those for IRI. The analysis showed that Spire’s TEC data was both compatible for ingestion into GPSII and that the assimilation of the data improved the comparison to ground‐based ionosondes.
Extreme Rainfall Statistics May Shift as U.S. Climate Warms
Authors: Stanley Sarah
Published: April 2021

Precipitation data and high-resolution modeling suggest that extreme rainfall events under a changing climate will be shorter, more intense, and more widely spread out.
Distinct uptake, amplification, and release of SARS-CoV-2 by M1 and M2 alveolar macrophages
Authors: Lv Jiadi , Wang Zhenfeng , Qu Yajin , Zhu Hua , Zhu Qiangqiang , Tong Wei , Bao Linlin , Lv Qi , Cong Ji , Li Dan , Deng Wei , Yu Pin , Song Jiangping , Tong Wei-Min , Liu Jiangning , Liu Yuying , Qin Chuan , Huang Bo
Published: April 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) invades the alveoli, where abundant alveolar macrophages (AMs) reside. How AMs respond to SARS-CoV-2 invasion remains elusive. Here, we show that classically activated M1 AMs facilitate viral spread; however, alternatively activated M2 AMs limit the spread. M1 AMs utilize cellular softness to efficiently take up SARS-CoV-2. Subsequently, the invaded viruses take over the endo-lysosomal system to escape. M1 AMs have a lower endosomal pH, favoring membrane fusion and allowing the entry of viral RNA from the endosomes into the cytoplasm, where the virus achieves replication and is packaged to be released. In contrast, M2 AMs have a higher endosomal pH but a lower lysosomal pH, thus delivering the virus to lysosomes for degradation. In hACE2 transgenic mouse model, M1 AMs are found to facilitate SARS-CoV-2 infection of the lungs. These findings provide insights into the complex roles of AMs during SARS-CoV-2 infection, along with potential therapeutic targets.
Genetic drift from the out-of-Africa bottleneck leads to biased estimation of genetic architecture and selection
Authors: Ashraf Bilal , Lawson Daniel John
Published: April 2021

Most complex traits evolved in the ancestors of all modern humans and have been under negative or balancing selection to maintain the distribution of phenotypes observed today. Yet all large studies mapping genomes to complex traits occur in populations that have experienced the Out-of-Africa bottleneck. Does this bottleneck affect the way we characterise complex traits? We demonstrate using the 1000 Genomes dataset and hypothetical complex traits that genetic drift can strongly affect the joint distribution of effect size and SNP frequency, and that the bias can be positive or negative depending on subtle details. Characterisations that rely on this distribution therefore conflate genetic drift and selection. We provide a model to identify the underlying selection parameter in the presence of drift, and demonstrate that a simple sensitivity analysis may be enough to validate existing characterisations. We conclude that biobanks characterising more worldwide diversity would benefit studies of complex traits.
Association of visual motor processing and social cognition in schizophrenia
Authors: Lu Pin-Yen , Huang Yu-Lien , Huang Pai-Chuan , Liu Yi-Chia , Wei Shyh-Yuh , Hsu Wei-Yun , Chen Kao Chin , Chen Po See , Wu Wen-Chen , Yang Yen Kuang , Tseng Huai-Hsuan
Published: April 2021

Patients with schizophrenia have difficulties in social cognitive domains including emotion recognition and mentalization, and in sensorimotor processing and learning. The relationship between social cognitive deficits and sensorimotor function in patients with schizophrenia remains largely unexplored. With the hypothesis that impaired visual motor processing may decelerate information processing and subsequently affects various domains of social cognition, we examined the association of nonverbal emotion recognition, mentalization, and visual motor processing in schizophrenia. The study examined mentalization using the verbal subset of the Chinese version of Theory of Mind (CToM) Task, an equivalent task of the Faux Pas Test; emotion recognition using the Diagnostic Analysis of Nonverbal Accuracy 2-Taiwan version (DANVA-2-TW), and visual motor processing using a joystick tracking task controlled for basic motor function in 34 individuals with chronic schizophrenia in the community and 42 healthy controls. Patients with schizophrenia had significantly worse performance than healthy controls in social cognition, including facial, prosodic emotion recognition, and mentalization. Visual motor processing was also significantly worse in patients with schizophrenia. Only in patients with schizophrenia, both emotion recognition (mainly in prosodic modality, happy, and sad emotions) and mentalization were positively associated with their learning capacity of visual motor processing. These findings suggest a prospective role of sensorimotor function in their social cognitive deficits. Despite that the underlying neural mechanism needs further research, our findings may provide a new direction for restoration of social cognitive function in schizophrenia by enhancing visual motor processing ability.
Database of Wannier tight-binding Hamiltonians using high-throughput density functional theory
Authors: Garrity Kevin F. , Choudhary Kamal
Published: April 2021

Wannier tight-binding Hamiltonians (WTBH) provide a computationally efficient way to predict electronic properties of materials. In this work, we develop a computational workflow for high-throughput Wannierization of density functional theory (DFT) based electronic band structure calculations. We apply this workflow to 1771 materials (1406 3D and 365 2D), and we create a database with the resulting WTBHs. We evaluate the accuracy of the WTBHs by comparing the Wannier band structures to directly calculated spin-orbit coupling DFT band structures. Our testing includes k-points outside the grid used in the Wannierization, providing an out-of-sample test of accuracy. We illustrate the use of WTBHs with a few example applications. We also develop a web-app that can be used to predict electronic properties on-the-fly using WTBH from our database. The tools to generate the Hamiltonian and the database of the WTB parameters are made publicly available through the websites https://github.com/usnistgov/jarvis and https://jarvis.nist.gov/jarviswtb.
Cromolyn inhibits the secretion of inflammatory cytokines by human microglia (HMC3)
Authors: Wang Yi-Jun , Monteagudo Alina , Downey Matthew A. , Ashton-Rickardt Philip G. , Elmaleh David R.
Published: April 2021

Cromolyn is a known mast cell stabilizer and is approved for treatment of asthma and for other allergic indications. Cromolyn, in a new redesigned dry powder formulation, is being tested in a pivotal clinical trial in combination with low dose ibuprofen to treat early Alzheimer’s Disease (AD) subjects. To better understand the mechanistic effect cromolyn has in slowing down or halting the neuroinflammatory response associated with AD progression, we tested the effect of cromolyn to dampen the inflammatory response in the human HMC3 microglia cell line. The direct effect of cromolyn on HMC3 microglia is on cytokines and chemokines production following their activation by the inflammatory cytokine TNF-α. Cromolyn and a new fluorinated analog dramatically reduced the secretion of a wide spectrum of inflammatory mediators, which included cytokines such as IL-1β, IL-6, IL-8 and IFN-γ, and chemokines such as CXCL10, CCL2, CCL3 and CCL4. These results bolster our understanding of how our cromolyn platform modulates toxic microglia behavior as a dynamic future treatment option for neurodegenerative disorders.
Digestive symptoms in daily life of chronic adrenal insufficiency patients are similar to irritable bowel syndrome symptoms
Authors: Quénéhervé L. , Drui D. , Blin J. , Péré M. , Coron E. , Barbara G. , Barbaro M. R. , Cariou B. , Neunlist M. , Masson D. , Bach-Ngohou K.
Published: April 2021

Gastrointestinal symptoms are frequent in acute adrenal insufficiency. Although digestive symptoms can significantly reduce quality of life, they are rarely described in patients with treated chronic adrenal insufficiency (CAI). We aimed to characterize digestive symptoms in CAI patients. We used the section pertaining functional bowel disorders of the Rome IV questionnaire. A questionnaire was published on the website of the non-profit patient association “Adrenals” (NPPA of CAI patients) for five months. Information on demographics, characteristics of adrenal insufficiency, digestive symptoms and quality of life was collected. The relatives of CAI patients served as a control group. We analyzed responses of 33 control subjects and 119 patients (68 primary adrenal insufficiency (PAI), 30 secondary adrenal insufficiency (SAI) and 21 congenital adrenal hyperplasia (CAH)). Abdominal pain at least once a week over the past 3 months was reported by 40%, 47% and 33% of patients with PAI, SAI and CAH respectively versus 15% for the controls (p = 0.01). Symptoms were consistent with the Rome IV criteria for irritable bowel syndrome in 27%, 33% and 33% of patients respectively versus 6% for the controls (p < 0.0001). Quality of life was described as poor or very poor in 35%, 57% and 24% of patients respectively versus 5% for the controls (p < 0.0001). In conclusion, digestive symptoms are frequent and incapacitating in CAI patients and similar to symptoms of irritable bowel syndrome in 30% of CAI patients. Assessment and management of digestive symptoms should be considered a priority for physicians treating patients with CAI.
In silico screening identifies a novel small molecule inhibitor that counteracts PARP inhibitor resistance in ovarian cancer
Authors: Lin Z. Ping , Al Zouabi Nour N. , Xu Mark L. , Bowen Nicole E. , Wu Terence L. , Lavi Ethan S. , Huang Pamela H. , Zhu Yong-Lian , Kim Baek , Ratner Elena S.
Published: April 2021

Poly ADP-ribose polymerase (PARP) inhibitors are promising targeted therapy for epithelial ovarian cancer (EOC) with BRCA mutations or defective homologous recombination (HR) repair. However, reversion of BRCA mutation and restoration of HR repair in EOC lead to PARP inhibitor resistance and reduced clinical efficacy of PARP inhibitors. We have previously shown that triapine, a small molecule inhibitor of ribonucleotide reductase (RNR), impaired HR repair and sensitized HR repair-proficient EOC to PARP inhibitors. In this study, we performed in silico screening of small molecule libraries to identify novel compounds that bind to the triapine-binding pocket on the R2 subunit of RNR and inhibit RNR in EOC cells. Following experimental validation of selected top-ranking in silico hits for inhibition of dNTP and DNA synthesis, we identified, DB4, a putative RNR pocket-binding inhibitor markedly abrogated HR repair and sensitized BRCA-wild-type EOC cells to the PARP inhibitor olaparib. Furthermore, we demonstrated that the combination of DB4 and olaparib deterred the progression of BRCA-wild type EOC xenografts and significantly prolonged the survival time of tumor-bearing mice. Herein we report the discovery of a putative small molecule inhibitor of RNR and HR repair for combination with PARP inhibitors to treat PARP inhibitor-resistant and HR repair-proficient EOC.
Optimizing hydroponic culture media and NO3−/NH4+ ratio for improving essential oil compositions of purple coneflower (Echinacea purpurea L.)
Authors: Ahmadi Fatemeh , Samadi Abbas , Sepehr Ebrahim , Rahimi Amir , Shabala Sergey
Published: April 2021

Medicinal plants represent a valuable commodity due to beneficial effects of their natural products on human health, prompting a need for finding a way to optimize/increase their production. In this study, a novel growing media with various perlite particle size and its mixture with peat moss was tested for hydroponic-based production of Echinacea purpurea medicinal plant under greenhouse conditions. The plant growth parameters such as plant height, total fresh leave weight, fresh root weight, total biomass, total chlorophyll, leaf area, and essential oil compositions were assessed. Perlite particle size in the growing media was varied from very coarse (more than 2 mm) to very fine (less than 0.5 mm), and the ratio between perlite and peat moss varied from 50:50 v/v to 30:70 v/v. In addition, two nitrate (NO3−) to ammonium (NH4+) ratios (90:10 and 70:30) were tested for each growing media. The medium containing very fine-grade perlite and 50:50 v/v perlite to peat moss ratio was found to be most optimal and beneficial for E. purpurea performance, resulting in maximal plant height, fresh and dry weight, leaf surface area, and chlorophyll content. It was also found that an increase in NO3−/NH4+ ratio caused a significant increase in plant growth parameters and increase the plant essential oil content. The major terpene hydrocarbons found in extract of E. purpurea with the best growth parameters were germacrene D (51%), myrcene (15%), α-pinene (12%), β-caryophyllene (11%), and 1-Pentadecene (4.4%), respectively. The percentages of these terpene hydrocarbons were increased by increasing of NO3−/NH4+ ratio. It can be concluded that decreasing the perlite particle size and increasing the NO3−/NH4+ ratio increased the plant growth parameters and essential oil compositions in E. purpurea.
Low biological fluctuation of mitochondrial CpG and non-CpG methylation at the single-molecule level
Authors: Goldsmith Chloe , Rodríguez-Aguilera Jesús Rafael , El-Rifai Ines , Jarretier-Yuste Adrien , Hervieu Valérie , Raineteau Olivier , Saintigny Pierre , Chagoya de Sánchez Victoria , Dante Robert , Ichim Gabriel , Hernandez-Vargas Hector
Published: April 2021

Mammalian cytosine DNA methylation (5mC) is associated with the integrity of the genome and the transcriptional status of nuclear DNA. Due to technical limitations, it has been less clear if mitochondrial DNA (mtDNA) is methylated and whether 5mC has a regulatory role in this context. Here, we used bisulfite-independent single-molecule sequencing of native human and mouse DNA to study mitochondrial 5mC across different biological conditions. We first validated the ability of long-read nanopore sequencing to detect 5mC in CpG (5mCpG) and non-CpG (5mCpH) context in nuclear DNA at expected genomic locations (i.e. promoters, gene bodies, enhancers, and cell type-specific transcription factor binding sites). Next, using high coverage nanopore sequencing we found low levels of mtDNA CpG and CpH methylation (with several exceptions) and little variation across biological processes: differentiation, oxidative stress, and cancer. 5mCpG and 5mCpH were overall higher in tissues compared to cell lines, with small additional variation between cell lines of different origin. Despite general low levels, global and single-base differences were found in cancer tissues compared to their adjacent counterparts, in particular for 5mCpG. In conclusion, nanopore sequencing is a useful tool for the detection of modified DNA bases on mitochondria that avoid the biases introduced by bisulfite and PCR amplification. Enhanced nanopore basecalling models will provide further resolution on the small size effects detected here, as well as rule out the presence of other DNA modifications such as oxidized forms of 5mC.
Statistical analysis of comparative tumor growth repeated measures experiments in the ovarian cancer patient derived xenograft (PDX) setting
Authors: Oberg Ann L. , Heinzen Ethan P. , Hou Xiaonan , Al Hilli Mariam M. , Hurley Rachel M. , Wahner Hendrickson Andrea E. , Goergen Krista M. , Larson Melissa C. , Becker Marc A. , Eckel-Passow Jeanette E. , Maurer Matthew J. , Kaufmann Scott H. , Haluska Paul , Weroha S. John
Published: April 2021

Repeated measures studies are frequently performed in patient-derived xenograft (PDX) models to evaluate drug activity or compare effectiveness of cancer treatment regimens. Linear mixed effects regression models were used to perform statistical modeling of tumor growth data. Biologically plausible structures for the covariation between repeated tumor burden measurements are explained. Graphical, tabular, and information criteria tools useful for choosing the mean model functional form and covariation structure are demonstrated in a Case Study of five PDX models comparing cancer treatments. Power calculations were performed via simulation. Linear mixed effects regression models applied to the natural log scale were shown to describe the observed data well. A straight growth function fit well for two PDX models. Three PDX models required quadratic or cubic polynomial (time squared or cubed) terms to describe delayed tumor regression or initial tumor growth followed by regression. Spatial(power), spatial(power) + RE, and RE covariance structures were found to be reasonable. Statistical power is shown as a function of sample size for different levels of variation. Linear mixed effects regression models provide a unified and flexible framework for analysis of PDX repeated measures data, use all available data, and allow estimation of tumor doubling time.
Differences in survival and phenotypic traits of curly birch preserved by heterovegetative propagation: a case study from Central-East Europe
Authors: Sarvašová Ivana , Sedmák Róbert , Sedmáková Denisa , Lukáčik Ivan
Published: April 2021

Curly birch (Betula pendula Roth. var. carelica [Merklin] Hämet-Ahti) is a disappearing representative of the Betula genus facing a regeneration failure in a large part of its natural distribution in Europe. The unique long-term study of clonal replications originating in heterogeneous environments enabled the evaluation of long-term survival and phenotypic stability of progenies in seed orchard to assess the conservation and commercial potential of heterovegetative propagation. Seventy-eight geographic sources (95 clone origins) representing the south distribution edge in East-Central Europe were analysed for species variation in survival, growth form, bark colour, and stem quality of parent trees and their vegetative progeny, and the effects of four parental site origin characteristics. The survival rate was 73% after 28–33 years of growth. Retention of curly-grained wood was high, the curly-grained wood structure is heritable and thus clonally efficiently achievable (only 3.5% of grafted individuals showed no occurrence of figured wood structure). The phenotypic expression of curliness manifested on the trunks as bulges, stem growth forms (tree/shrub) and stem technical quality showed a lower degree of stability (coincidence) between the parent trees and heterovegatively propagated progenies. Despite this, the conservation potential of seed orchard is very high, especially when stabilization of the stem growth forms affecting the survival and commercial value of progenies can be probably achieved by a more careful selection of scions. Overall, heterovegetative orchards seem to be a very promising method for the long-term conservation of curly birch populations, which, in addition to their great biological and ecological value, have considerable commercial potential.
A neoclerodane orthoester and other new neoclerodane diterpenoids from Teucrium yemense chemistry and effect on secretion of insulin
Authors: Nur-e-Alam Mohammad , Parveen Ifat , Wilkinson Barrie , Ahmed Sarfaraz , Hafizur Rahman M. , Bari Ahmed , Woodman Timothy J. , Threadgill Michael D. , Al-Rehaily Adnan J.
Published: April 2021

Teucrium yemense, a medicinal plant commonly grown in Saudi Arabia and Yemen, is traditionally used to treat infections, kidney diseases, rheumatism, and diabetes. Extraction of the dried aerial parts of the plant with methanol, followed by further extraction with butanol and chromatography, gave twenty novel neoclerodanes. Their structures, relative configurations and some conformations were determined by MS and 1-D and 2-D NMR techniques. Most were fairly conventional but one contained an unusual stable orthoester, one had its (C-16)–(C-13)–(C-14)–(C-15) (tetrahydro)furan unit present as a succinic anhydride and one had a rearranged carbon skeleton resulting from ring-contraction to give a central octahydroindene bicyclic core, rather than the usual decalin. Mechanisms are proposed for the biosynthetic formation of the orthoester and for the ring-contraction. Four novel neoclerodanes increased the glucose-triggered release of insulin from isolated murine pancreatic islets by more than the standard drug tolbutamide, showing that they are potential leads for the development of new anti-diabetic drugs.
Salmon bias effect as hypothesis of the lower mortality rates among immigrants in Italy
Authors: Di Napoli Anteo , Rossi Alessandra , Alicandro Gianfranco , Ventura Martina , Frova Luisa , Petrelli Alessio
Published: April 2021

Compared with natives, immigrants have lower all-cause mortality rates, despite their lower socioeconomic status, an epidemiological paradox generally explained by the healthy migrant effect. Another hypothesis is the so-called salmon bias effect: “statistically immortal” subjects return to their country of origin when they expect to die shortly, but their deaths are not registered in the statistics of the country of residence. This underestimation of deaths determines an artificially low immigrant mortality rate. We aimed to estimate the potential salmon bias effect on differences in mortality rates between Italians and immigrants. We used a national cohort of all Italians registered in the 2011 census and followed up for mortality from 2012 to 2016. Mortality data were retrieved from the Causes of Death Register, which included all deaths occurring in the country and the Resident Population Register, which collects also the deaths occurring abroad. We assumed as a possible salmon bias event the death of an immigrant resident in Italy that died in his/her country of origin. Considering the deaths occurring in the country of origin, we observed an 18.1% increase in the overall mortality rates for immigrants and an increase of 23.7% in the age-standardized mortality rate. Mortality rates of immigrants resident in Italy, calculated without taking into account the deaths occurring in the country of origin, are certainly underestimated. However, the salmon bias only partly explains the difference in mortality rates between immigrants and Italians.
Magnetic, electrical and mechanical properties of Fe40Mn40Co10Cr10 high entropy alloy
Authors: Egilmez M. , Abuzaid W.
Published: April 2021

A prototypical, single-phase, and non-equiatomic high entropy alloy Fe40Mn40Co10Cr10 has been mechanically deformed at room and cryogenic temperatures. Plastic deformation was accommodated via crystallographic slip at room temperature while transformation induced plasticity (TRIP) has been observed in samples deformed at 77 K. The stress-induced martensitic transformation occurred from face-centered cubic (FCC) to hexagonal close-packed (HCP) structures. A detailed electron backscatter diffraction analysis was utilized to detect phase change and evaluate the evolution of the HCP phase volume fraction as a function of plastic strain. Physical properties of undeformed and deformed samples were measured to elucidate the effect of deformation-induced phase transitions on the magnetic and electrical properties of Fe40Mn40Co10Cr10 alloy. Relatively small magnetic moments along with non-saturating magnetic field dependencies suggest that the ground state in the considered material is ferrimagnetic ordering with coexisting antiferromagnetic phase. The temperature evolution of the coercive fields has been revealed for all samples. The magnitudes of the coercive fields place the considered system into the semi-hard magnetic alloys category. The temperature dependence of the zero-field cooled (ZFC) and field cooled (FC) magnetization was measured for all samples in the low field regime and the origin of irreversibility in ZFC/FC curves was discussed. Besides, the temperature dependence of the resistivity in all samples was measured and the possible conduction mechanisms were discussed.
Characterization of combined linagliptin and Y2R agonist treatment in diet-induced obese mice
Authors: Hansen Henrik H. , Grønlund Rikke V. , Baader-Pagler Tamara , Haebel Peter , Tammen Harald , Larsen Leif Kongskov , Jelsing Jacob , Vrang Niels , Klein Thomas
Published: April 2021

Dipeptidyl peptidase IV (DPP-IV) inhibitors improve glycemic control by prolonging the action of glucagon-like peptide-1 (GLP-1). In contrast to GLP-1 analogues, DPP-IV inhibitors are weight-neutral. DPP-IV cleavage of PYY and NPY gives rise to PYY3-36 and NPY3-36 which exert potent anorectic action by stimulating Y2 receptor (Y2R) function. This invites the possibility that DPP-IV inhibitors could be weight-neutral by preventing conversion of PYY/NPY to Y2R-selective peptide agonists. We therefore investigated whether co-administration of an Y2R-selective agonist could unmask potential weight lowering effects of the DDP-IV inhibitor linagliptin. Male diet-induced obese (DIO) mice received once daily subcutaneous treatment with linagliptin (3 mg/kg), a Y2R-selective PYY3-36 analogue (3 or 30 nmol/kg) or combination therapy for 14 days. While linagliptin promoted marginal weight loss without influencing food intake, the PYY3-36 analogue induced significant weight loss and transient suppression of food intake. Both compounds significantly improved oral glucose tolerance. Because combination treatment did not further improve weight loss and glucose tolerance in DIO mice, this suggests that potential negative modulatory effects of DPP-IV inhibitors on endogenous Y2R peptide agonist activity is likely insufficient to influence weight homeostasis. Weight-neutrality of DPP-IV inhibitors may therefore not be explained by counter-regulatory effects on PYY/NPY responses.
Identification of novel autophagy-related lncRNAs associated with a poor prognosis of colon adenocarcinoma through bioinformatics analysis
Authors: Wu Dejun , Yin Zhenhua , Ji Yisheng , Li Lin , Li Yunxin , Meng Fanqiang , Ren Xiaohan , Xu Ming
Published: April 2021

LncRNAs play a pivotal role in tumorigenesis and development. However, the potential involvement of lncRNAs in colon adenocarcinoma (COAD) needs to be further explored. All the data used in this study were obtained from The Cancer Genome Atlas database, and all analyses were conducted using R software. Basing on the seven prognosis-related lncRNAs finally selected, we developed a prognosis-predicting model with powerful effectiveness (training cohort, 1 year: AUC = 0.70, 95% Cl = 0.57–0.78; 3 years: AUC = 0.71, 95% Cl = 0.6–0.8; 5 years: AUC = 0.76, 95% Cl = 0.66–0.87; validation cohort, 1 year: AUC = 0.70, 95% Cl = 0.58–0.8; 3 years: AUC = 0.73, 95% Cl = 0.63–0.82; 5 years: AUC = 0.68, 95% Cl = 0.5–0.85). The VEGF and Notch pathway were analyzed through GSEA analysis, and low immune and stromal scores were found in high-risk patients (immune score, cor =  − 0.15, P < 0.001; stromal score, cor =  − 0.18, P < 0.001) , which may partially explain the poor prognosis of patients in the high-risk group. We screened lncRNAs that are significantly associated with the survival of patients with COAD and possibly participate in autophagy regulation. This study may provide direction for future research.
The mathematics of multiple lockdowns
Authors: Scala Antonio
Published: April 2021

While vaccination is the optimal response to an epidemic, recent events have obliged us to explore new strategies for containing worldwide epidemics, like lockdown strategies, where the contacts among the population are strongly reduced in order to slow down the propagation of the infection. By analyzing a classical epidemic model, we explore the impact of lockdown strategies on the evolution of an epidemic. We show that repeated lockdowns have a beneficial effect, reducing the final size of the infection, and that they represent a possible support strategy to vaccination policies.
Predictive factors of continuous negative extrathoracic pressure management failure in children with moderate to severe respiratory syncytial virus infection
Authors: Ishimori Shingo , Okizuka Yo , Onishi Satoshi , Shinomoto Tadashi , Minami Hirotaka
Published: April 2021

Continuous negative extrathoracic pressure (CNEP) might be beneficial for children with severe respiratory tract infections. However, there are no available data on the predictors of its failure among individuals with respiratory syncytial virus (RSV) infections. Here, we conducted a retrospective cohort study between October 1, 2015 and October 31, 2018 in hospitalized children with moderate to severe symptoms of respiratory syncytial virus (RSV) infections. We divided 45 children requiring CNEP ventilation with a non-fluctuating negative pressure of − 12 cm H2O into two groups. They were classified based on improvement or deterioration of their respiratory disorder under CNEP ventilation (responder group: n = 27, failure group: n = 18). Based on the univariate analysis, the responder and failure groups significantly differed in terms of median age, days elapsed from RSV onset to the initiation of CNEP, white blood cell count (WBC), titer of venous pCO2, body temperature at admission, and modified Wood-Downes Score (mWDS) 6 h after initiating CNEP. Based on a logistic regression analysis adjusted for age < 1 year upon admission, less than 5 days elapsed from RSV onset to the initiation of CNEP, not high value of WBC and body temperature at admission, and high values of mWDS 6 h after initiating CNEP were found to be significant independent risk factors for CNEP ventilation failure. The former two variables were associated with less failure (odds ratio was approximately 5), and the latter two variables are associated with more failure (odds ratio was approximately 8–9). Thus, CNEP could be a valid option for children with moderate to severe RSV infections, especially in those who were aged > 1 year, and specific clinical and laboratory findings.