bluuebunny/crossref_metadata_2025 huggingface dataset:
The future of British English in the European Union
Authors: Modiano Marko
Published: September 2022

In the three years and seven months between the referendum on 23 June 2016 and 31 January 2020, when the UK officially left the European Union, there was much speculation over what status English would have in the EU after the withdrawal of the UK. It is now apparent that English has continued to flourish. This is supported by statistics for Member States which chart the extent to which English is a school subject. Well over 95% of the children in the EU are taught English as a mandatory subject. Official EU figures also show that 38% of the population is proficient in English as a second language, three times more than both French and German (Special Eurobarometer 386: Europeans and their Languages, 2012). Moreover, although some, such as Danuta Hübner, EMP, wanted to question whether or not English could maintain its status as an official language in the EU, it is now apparent that it will not be possible to remove English in this respect (with changes requiring a unanimous vote in the Council, which Ireland has said it will not support [European Commission, 2016]), (The Guardian 27 December 2019). English has also retained its position as one of the three ‘procedural’ or ‘working languages’ alongside French and German. This has taken place despite the fact that without the UK, no Member State has English as its official EU language, and only approximately one percent of EU citizens have English as a mother tongue.
A scalable species-based genetic algorithm for reinforcement learning problems
Authors: Seth Anirudh , Nikou Alexandros , Daoutis Marios
Published: September 2022

Reinforcement Learning (RL) methods often rely on gradient estimates to learn an optimal policy for control problems. These expensive computations result in long training times, a poor rate of convergence, and sample inefficiency when applied to real-world problems with a large state and action space. Evolutionary Computation (EC)-based techniques offer a gradient-free apparatus to train a deep neural network for RL problems. In this work, we leverage the benefits of EC and propose a novel variant of genetic algorithm called SP-GA which utilizes a species-inspired weight initialization strategy and trains a population of deep neural networks, each estimating the Q-function for the RL problem. Efficient encoding of a neural network that utilizes less memory is also proposed which provides an intuitive mechanism to apply Gaussian mutations and single-point crossover. The results on Atari 2600 games outline comparable performance with gradient-based algorithms like Deep Q-Network (DQN), Asynchronous Advantage Actor Critic (A3C), and gradient-free algorithms like Evolution Strategy (ES) and simple Genetic Algorithm (GA) while requiring far fewer hyperparameters to train. The algorithm also improved certain Key Performance Indicators (KPIs) when applied to a Remote Electrical Tilt (RET) optimization task in the telecommunication domain.
The effects of powerlines on bustards: how best to mitigate, how best to monitor?
Authors: Silva João Paulo , Marques Ana Teresa , Bernardino Joana , Allinson Tris , Andryushchenko Yuri , Dutta Sutirtha , Kessler Mimi , Martins Ricardo C. , Moreira Francisco , Pallett John , Pretorius Mattheuns D. , Scott H. Ann , Shaw Jessica M. , Collar Nigel J.
Published: September 2022

Bustards comprise a highly threatened family of birds and, being relatively fast, heavy fliers with very limited frontal visual fields, are particularly susceptible to mortality at powerlines. These infrastructures can also displace them from immediately adjacent habitat and act as barriers, fragmenting their ranges. With geographically ever wider energy transmission and distribution grids, the powerline threat to bustards is constantly growing. Reviewing the published and unpublished literature up to January 2021, we found 2,774 records of bustard collision with powerlines, involving 14 species. Some studies associate powerline collisions with population declines. To avoid mortalities, the most effective solution is to bury the lines; otherwise they should be either routed away from bustard-frequented areas, or made redundant by local energy generation. When possible, new lines should run parallel to existing structures and wires should preferably be as low and thick as possible, with minimal conductor obstruction of vertical airspace, although it should be noted that these measures require additional testing. A review of studies finds limited evidence that ‘bird flight diverters’ (BFDs; devices fitted to wires to induce evasive action) achieve significant reductions in mortality for some bustard species. Nevertheless, dynamic BFDs are preferable to static ones as they are thought to perform more effectively. Rigorous evaluation of powerline mortalities, and effectiveness of mitigation measures, need systematic carcass surveys and bias corrections. Whenever feasible, assessments of displacement and barrier effects should be undertaken. Following best practice guidelines proposed with this review paper to monitor impacts and mitigation could help build a reliable body of evidence on best ways to prevent bustard mortality at powerlines. Research should focus on validating mitigation measures and quantifying, particularly for threatened bustards, the population effects of powerline grids at the national scale, to account for cumulative impacts on bustards and establish an equitable basis for compensation measures.
CASSEL, OHLIN, ÅKERMAN, AND THE WALL STREET CRASH OF 1929
Authors: Carlson Benny
Published: September 2022

The 1929 stock market crash on Wall Street is one of the most spectacular economic events of all times. In Sweden, leading economists got involved in a lively debate on the events on Wall Street before, during, and after the crash. Three of them were particularly active. Gustav Cassel and Bertil Ohlin were not overly worried since they regarded the stock market mania and the panic as phenomena more or less disconnected from the rest of the economy. Their theoretical argument was that booms and busts upon a stock market cannot create or destroy capital or purchasing power. Johan Åkerman, on the contrary, warned repeatedly that a serious stock market crash was in the making and, once it had happened, that it would in many ways affect the entire economy.
White Progress: Kant, Race and Teleology
Authors: Marwah Inder S.
Published: September 2022

This article examines how Kant’s conceptualizations of natural history and teleological judgement shape his understanding of human difference and race. I argue that the teleological framework encasing Kant’s racial theory implies constraints on the capacity of non-whites to make moral progress. While commentators tend to approach Kant’s racial theory in relation to his political theory, his late-life cosmopolitanism, and his treatments (or non-treatments) of colonialism, empire and slavery, the problem I focus on here is that race is itself only intelligible in relation to a teleological natural history limiting certain races’ capacities to engage in humanity’s moral vocation.
GROUPS ACTING ON TREES WITH PRESCRIBED LOCAL ACTION
Authors: TORNIER STEPHAN
Published: September 2022

We extend the Burger–Mozes theory of closed, nondiscrete, locally quasiprimitive automorphism groups of locally finite, connected graphs to the semiprimitive case, and develop a generalization of Burger–Mozes universal groups acting on the regular tree
$T_{d}$
of degree
$d\in \mathbb {N}_{\ge 3}$
. Three applications are given. First, we characterize the automorphism types that the quasicentre of a nondiscrete subgroup of
$\operatorname {\mathrm {Aut}}(T_{d})$
may feature in terms of the group’s local action. In doing so, we explicitly construct closed, nondiscrete, compactly generated subgroups of
$\operatorname {\mathrm {Aut}}(T_{d})$
with nontrivial quasicentre, and see that the Burger–Mozes theory does not extend further to the transitive case. We then characterize the
$(P_{k})$
-closures of locally transitive subgroups of
$\operatorname {\mathrm {Aut}}(T_{d})$
containing an involutive inversion, and thereby partially answer two questions by Banks et al. [‘Simple groups of automorphisms of trees determined by their actions on finite subtrees’, J. Group Theory18(2) (2015), 235–261]. Finally, we offer a new view on the Weiss conjecture.
Analysis of inequality in the distribution of general practitioners in China: evidence from 2012 to 2018
Authors: Yang Le , Cheng Jingmin
Published: September 2022

Aim:

This paper aims to analyze the inequalities in general practitioner (GP) distribution in China.

Background:

GPs-based primary health care (PHC) has been implemented from 2011 in China, aiming to improve the accessibility and quality of basic medical and healthcare services. GPs in China, as the gatekeeper of people’s health, mainly undertake integrated health services at the grass-roots level.

Methods:

The number of GPs and inequality in GPs distribution from 2012 to 2018 was analyzed by the Lorenz Curve/Gini coefficient and Theil L index. Data were extracted fromChina Health Statistical Yearbook 2013–2019.

Findings:

The demographic Gini coefficient of GPs changed from 2012 (0.234) to 2018 (0.167), showing high equality in China. In contrast, the Thiel L index from 2012 (0.372) to 2018 (0.345) showed less equality. The decomposition of Thiel L index implicated the inequalities within the divisions. The number of GPs in China shows a fast growth trend since the general practice system established, and the GPs distribution becomes more demographically equitable. However, the shortage of GPs and inequality in their distribution remains severe. More incentive and supportive policies need to be made to enhance the quantity, quality, and structure of GPs in China.
Predicting Commercial Pilot Training Performance
Authors: Martinussen Monica , Lang-Ree Ole Christian , Mjøen Håvard , Svendsen Bengt , Barone Adrian
Published: September 2022

Abstract. The main purpose of this study was to examine the predictive validity of the system used for ab initio selection of candidates to a bachelor program in aviation. The selection includes paper-and-pencil tests, computer-based tests, and an interview. A total of 188 candidates participated in the validation study. The total test score predicted the results of three exams in aviation theory ( r = .27–.38) and extra flying hours needed (−.22), but not mean university grade. The regression analyses indicated that all predictors (tests and interview ratings) explained 25% of the variance in aviation theory, 19% in extra flying hours needed, and 7% in mean university grade. The overall findings confirmed the predictive validity of selection tests, especially the computer-based tests.
A Framework for Mechanistic Flood Inundation Forecasting at the Metropolitan Scale
Authors: Schubert Jochen E. , Luke Adam , AghaKouchak Amir , Sanders Brett F.
Published: September 2022

Urban flooding from extreme precipitation and storm surge is a growing threat to cities, and detailed forecasts of urban inundation are needed for emergency response. We present a mechanistic framework to simulate flood inundation over metropolitan‐wide areas at fine resolution (3 m). A dual‐grid shallow‐water model is used to overcome computational bottlenecks, and an application to Hurricane Harvey focused on pluvial flooding provides a multi‐dimensional assessment of predictive skill. A hindcast model is shown to simulate peak stage across 41 stream gages with a mean absolute error (MAE) of 0.63 m, and hourly stage levels over a 5‐day period with a median MAE and Nash‐Sutcliffe Efficiency (NSE) of 0.74 m and 0.55, respectively. Peak flood level across 228 high water marks (HWMs) were captured with an MAE of 0.69 m. A forecast model forced by Quantitative Precipitation Forecast data is shown to be only marginally less accurate than the hindcast model. Peak stage is simulated with an MAE of 0.86 m, hourly stage is captured with a median MAE and NSE of 0.90 m and 0.41, respectively, and HWMs are captured with an MAE of 0.77 m. The forecast system also achieves hit rates of 90% and 73% predicting distress calls and FEMA damage claims, respectively, based on simulated flood depth. These results demonstrate the potential to operationally forecast pluvial flood inundation in the U.S. with the timeliness and accuracy needed for early warning, and we also highlight future research needs.
Radial and Local Time Variations in the Thickness of Jupiter's Magnetospheric Current Sheet
Authors: Khurana K. K. , Leinweber H. K. , Hospodarsky G. B. , Paranicas C. P.
Published: September 2022

The magnetic field observations from the Galileo, Ulysses, Voyager 1 and 2, and Pioneer 10 and 11 spacecraft are analyzed to understand the structures and thickness of the Jovian magnetospheric current sheet. Using a new technique that can determine the motion of the spacecraft relative to the current sheet, we have built the first global map of the thickness of the Jovian magnetospheric current sheet. We show that the current sheet thickness in Jupiter's magnetosphere is not equal everywhere but changes systematically with both radial distance and local time. The extremely thin dawnside current sheet appears to be linked to the stresses imposed by the solar wind on the open magnetic flux housed in the lobes of the magnetosphere in that sector. We also show evidence of a mostly closed magnetosphere in the dusk sector. We show that the current sheet thickness asymmetries likely arise from a field and plasma convection system set up by the reconnection of the interplanetary magnetic field with that of Jupiter.
Comparison of Energetic Electron Fluxes Measured by GPS and THEMIS Spacecraft in the Inner Magnetosphere
Authors: Curtis Reed , Artemyev Anton V. , Vainchtein Dmitri L. , Kellerman Adam , Morley Steven K. , Angelopoulos Vassilis
Published: September 2022

Key elements of space weather models are energetic electron fluxes in the inner magnetosphere and the outer radiation belt. Flux depletion is driven by various loss processes: scattering into atmosphere, magnetopause shadowing. Flux enhancement is driven by various acceleration processes: local wave‐particle interactions, radial transport, plasma sheet injections. Many of these processes operate on ∼ hour timescales. Such mesoscale flux variations are not well traced by equatorial spacecraft with much longer orbits. Energetic electron detectors onboard the Global Positioning System (GPS) constellation provide a unique opportunity for probing such ∼ hour‐scale flux variations. Measurements from up to 23 identically instrumented GPS satellites cover a wide energy and L‐shell range with a subhour time resolution. However, their orbits are inclined and thus all measurements at L‐shell >4.3 are off‐equatorial. In this report, we present a comparison of equatorial THEMIS and nonequatorial GPS measurements of omnidirectional ≤600 keV electron fluxes. Such a comparison allows us to derive coefficients for using off‐equatorial GPS fluxes to infer the equatorial values. These coefficients depend on particle energy and L‐shell. We demonstrate a new data set derived from GPS measurements and discuss how it can be used to investigate mesoscale dynamics of energetic electron fluxes in the inner magnetosphere.
Pressure‐Stimulated Rock Current as Loading Diorite to Failure: Particular Variation and Holistic Mechanisms
Authors: Mao Wenfei , Wu Lixin , Xu Youyou , Yao Rubing , Lu Jingchen , Sun Licheng , Qi Yuan
Published: September 2022

The variations in the electric property of loaded rocks are essential in understanding the rock dynamics and fracturing process. Decades of laboratory experiments have revealed different behaviors of stress‐stimulated electric current due to the effects of rock types, loading modes, and detection methods. These different behaviors result in difficulties in revealing the underlying physics of electric current in rock and adequately explaining the wide variety of electric precursors measured before rock failure or geohazards. In this study, cubic‐and conical‐shaped diorite specimens were specially designed and produced to experimentally investigate the characteristics of pressure‐stimulated rock current (PSRC) in the process of loading rock specimens to failure. We measured a particular phenomenon of diorite PSRC variation with pressure; that is, PSRC remained nearly stable until the applied stress reached 83%–98% of the failure strength. A remarkable step‐like increment in PSRC was uncovered, and drastic oscillations with maximum amplitudes of several hundreds of nA occurred 1 s prior to abrupt rock failure. A holistic mechanism that includes positive hole activation, field emission of electrons, crack charge separation, and moving charged dislocation was applied to interpret this particular phenomenon. We found that these mechanisms contribute comprehensively rather than individually to the evolution of PSRC. This study provides an improved understanding of the underlying physics of PSRC and the variation in rock electric properties, which is also helpful to understand the abnormal electromagnetic phenomena observed before earthquakes.
Contributions of Early‐ and Middle‐Winter Perturbations at Higher Altitudes to Late‐Winter Anomalously Strong Arctic Polar Vortex in the Lower Stratosphere
Authors: Qin Yusong , Gu Sheng‐Yang , Dou Xiankang , Teng Chen‐Ke‐Min , Yang Zhenlin
Published: September 2022

Based on the Modern‐Era Retrospective analysis for Research Applications Version 2 reanalysis, an upper stratosphere/lower mesosphere (USLM) disturbance in early January and a sudden stratospheric warming (SSW) in early February are both coincidentally captured preceding the anomalously strong polar vortex during the late boreal winters of 2010/2011 and 2019/2020. Our analysis indicates that planetary wave breaking during the USLM disturbance and SSW decelerates the westerly polar night jet (PNJ) in the upper stratosphere, which leads to a continuous downward and poleward propagation of the PNJ during the early and middle winter. As the peak height of the PNJ descends, the region with negative vertical wind shear and negative waveguides also extends downward and reaches an altitude of ∼40 km during the late winter, which significantly limits the upward propagation of planetary waves, inducing a stable polar vortex in the lower stratosphere. In addition, the transformed Eulerian mean diagnostic results based on the specified dynamics simulation of the Whole Atmosphere Community Climate Model eXtended version confirm that the planetary wave‐induced downwelling is the main cause of the stratospheric warming during the two perturbations. More importantly, the simulation results indicate that the strength of the two upper stratospheric perturbations is appropriate to maintain the reflective configuration during the late winter, which suggests that such a specific sequence of perturbations during the early and middle winter, namely a USLM disturbance followed by a minor SSW, is favorable for the development of a late‐winter unusually strong Arctic polar vortex in the lower stratosphere.
Micro 3D printing of a functional MEMS accelerometer
Authors: Pagliano Simone , Marschner David E. , Maillard Damien , Ehrmann Nils , Stemme Göran , Braun Stefan , Villanueva Luis Guillermo , Niklaus Frank
Published: September 2022

Microelectromechanical system (MEMS) devices, such as accelerometers, are widely used across industries, including the automotive, consumer electronics, and medical industries. MEMS are efficiently produced at very high volumes using large-scale semiconductor manufacturing techniques. However, these techniques are not viable for the cost-efficient manufacturing of specialized MEMS devices at low- and medium-scale volumes. Thus, applications that require custom-designed MEMS devices for markets with low- and medium-scale volumes of below 5000–10,000 components per year are extremely difficult to address efficiently. The 3D printing of MEMS devices could enable the efficient realization and production of MEMS devices at these low- and medium-scale volumes. However, current micro-3D printing technologies have limited capabilities for printing functional MEMS. Herein, we demonstrate a functional 3D-printed MEMS accelerometer using 3D printing by two-photon polymerization in combination with the deposition of a strain gauge transducer by metal evaporation. We characterized the responsivity, resonance frequency, and stability over time of the MEMS accelerometer. Our results demonstrate that the 3D printing of functional MEMS is a viable approach that could enable the efficient realization of a variety of custom-designed MEMS devices, addressing new application areas that are difficult or impossible to address using conventional MEMS manufacturing.
Therapeutic targets and biomarkers of tumor immunotherapy: response versus non-response
Authors: Wang Dong-Rui , Wu Xian-Lin , Sun Ying-Li
Published: September 2022

Cancers are highly complex diseases that are characterized by not only the overgrowth of malignant cells but also an altered immune response. The inhibition and reprogramming of the immune system play critical roles in tumor initiation and progression. Immunotherapy aims to reactivate antitumor immune cells and overcome the immune escape mechanisms of tumors. Represented by immune checkpoint blockade and adoptive cell transfer, tumor immunotherapy has seen tremendous success in the clinic, with the capability to induce long-term regression of some tumors that are refractory to all other treatments. Among them, immune checkpoint blocking therapy, represented by PD-1/PD-L1 inhibitors (nivolumab) and CTLA-4 inhibitors (ipilimumab), has shown encouraging therapeutic effects in the treatment of various malignant tumors, such as non-small cell lung cancer (NSCLC) and melanoma. In addition, with the advent of CAR-T, CAR-M and other novel immunotherapy methods, immunotherapy has entered a new era. At present, evidence indicates that the combination of multiple immunotherapy methods may be one way to improve the therapeutic effect. However, the overall clinical response rate of tumor immunotherapy still needs improvement, which warrants the development of novel therapeutic designs as well as the discovery of biomarkers that can guide the prescription of these agents. Learning from the past success and failure of both clinical and basic research is critical for the rational design of studies in the future. In this article, we describe the efforts to manipulate the immune system against cancer and discuss different targets and cell types that can be exploited to promote the antitumor immune response.
Sequential interspecies interactions affect production of antimicrobial secondary metabolites in Pseudomonas protegens DTU9.1
Authors: Hansen Morten Lindqvist , Wibowo Mario , Jarmusch Scott Alexander , Larsen Thomas Ostenfeld , Jelsbak Lars
Published: September 2022

Soil and rhizosphere microbiomes play important roles in suppression of plant pathogens through production of antagonistic secondary metabolites, yet mechanisms that determine the strength of pathogen control are not well understood. Many Pseudomonas species are associated with soil and rhizosphere microbiomes, and their ability to suppress pathogens is well documented. Here, we investigate how interactions within the Pseudomonas genus affect their production of antimicrobial metabolites. From a biosensor-based screen, we identify P. capeferrum species as capable of modulating secondary metabolite production in P. protegens. We show that P. capeferrum alters production of pyoluteorin and 2,4-diacetylphloroglucinol (DAPG) in P. protegens via two distinct and sequential mechanisms that depends on spatial proximity of the two species. Specifically, P. capeferrum secretes a diffusible signal that induce pyoluteorin production up to 100-fold in neighboring P. protegens colonies. In contrast, the interaction results in reduced DAPG production, but only within mixed-species colonies. Additionally, we found that increased pyoluteorin production and cell lysis of P. capeferrum is required for inhibition of DAPG production, suggesting that pyoluteorin-facilitated antibiosis of P. protegens on P. capeferrum leads to release of cell-associated metabolites and subsequent inhibition of DAPG production in P. protegens. As the interaction modulates in vitro bioactivity of the species, genus-specific interactions may assist in improving efficacy of biocontrol strains and consortia.
CAF-derived exosomal WEE2-AS1 facilitates colorectal cancer progression via promoting degradation of MOB1A to inhibit the Hippo pathway
Authors: Yang Peng , Zhang Dongsheng , Wang Tuo , Ji Jiangzhou , Jin Chi , Peng Chaofan , Tan Yuqian , Zhou Jiahui , Wang Lu , Feng Yifei , Sun Yueming
Published: September 2022

Cancer-associated fibroblasts (CAFs) are the most abundant stromal components in the tumor microenvironment (TME) and closely involved in tumor progression. However, the precise biological functions and molecular mechanisms of CAFs in the TME have yet to be understood. Here, we demonstrate that WEE2-AS1 is highly expressed in the CAF-derived small extracellular vesicles (sEVs). Moreover, WEE2-AS1 is markedly higher in plasma sEVs of CRC patients than in healthy subjects and its high level predicts advanced pathological staging and poor survival. Then, we conducted a series of in vitro and in vivo experiments. Elevated expression of WEE2-AS1 in sEVs increases CRC cell proliferation in vitro. Importantly, aberrant CAF-sEVsWEE2-AS1 leads to tumor formation and progression in BALB/c nude mice and promotes AOM/DSS-induced tumorigenesis. Mechanistically, WEE2-AS1 functions as a modular scaffold for the MOB1A and E3 ubiquitin-protein ligase praja2 complexes, leading to MOB1A degradation via the ubiquitin-proteasome pathway. The Hippo pathway is then inhibited and more YAP are transported into the nucleus, where they activate downstream gene transcription. Together, our data reveal that CAF-sEVsWEE2-AS1 interacts with MOB1A, promotes degradation of MOB1A, inhibits the Hippo pathway, and facilitates the growth of CRC cells. Hence, exosomal WEE2-AS1 may be a promising therapeutic target and circulating biomarker for CRC diagnosis and prognosis.
The therapeutic effect of KSP inhibitors in preclinical models of cholangiocarcinoma
Authors: Shi Yuanyuan , Cui Xiaowen , Jiang Tianyi , Pan Yufei , Lin Yunkai , Feng Xiaofan , Ding Zhiwen , Yang Chun , Tan Yexiong , Wang Hongyang , Dong Liwei
Published: September 2022

Cholangiocarcinoma (CCA) is an epithelial malignancy with a dismal prognosis owing to limited treatment options. Here, we identified several compound candidates against CCA using a high-throughput drug screen with approved or emerging oncology drugs, among which kinesin spindle protein (KSP) inhibitors showed potent cytotoxic effects on CCA cells. Treatment with KSP inhibitors SB743921 and ARRY520 caused significant tumor suppression in CCA xenograft models in vivo. Mechanistically, KSP inhibitors led to the formation of abnormal monopolar spindles, which further resulted in the mitotic arrest and cell death of CCA cells both in vivo and in vitro. KEGG pathway analysis of transcriptional data confirmed this finding. Moreover, our clinical data as well as the TCGA database showed KIF11 expression was abundant in most CCA tumor specimens and associated with poor outcomes of CCA patients. Our results demonstrate that the therapeutic regimen of KSP inhibitors could be a promising treatment strategy in CCA.
Mutated processes predict immune checkpoint inhibitor therapy benefit in metastatic melanoma
Authors: Patterson Andrew , Auslander Noam
Published: September 2022

Immune Checkpoint Inhibitor (ICI) therapy has revolutionized treatment for advanced melanoma; however, only a subset of patients benefit from this treatment. Despite considerable efforts, the Tumor Mutation Burden (TMB) is the only FDA-approved biomarker in melanoma. However, the mechanisms underlying TMB association with prolonged ICI survival are not entirely understood and may depend on numerous confounding factors. To identify more interpretable ICI response biomarkers based on tumor mutations, we train classifiers using mutations within distinct biological processes. We evaluate a variety of feature selection and classification methods and identify key mutated biological processes that provide improved predictive capability compared to the TMB. The top mutated processes we identify are leukocyte and T-cell proliferation regulation, which demonstrate stable predictive performance across different data cohorts of melanoma patients treated with ICI. This study provides biologically interpretable genomic predictors of ICI response with substantially improved predictive performance over the TMB.
The imprint of star formation on stellar pulsations
Authors: Steindl Thomas , Zwintz Konstanze , Vorobyov Eduard
Published: September 2022

In the earliest phases of their evolution, stars gain mass through the acquisition of matter from their birth clouds. The widely accepted classical concept of early stellar evolution neglects the details of this accretion phase and assumes the formation of stars with large initial radii that contract gravitationally. In this picture, the common idea is that once the stars begin their fusion processes, they have forgotten their past. By analysing stellar oscillations in recently born stars, we show that the accretion history leaves a potentially detectable imprint on the stars’ interior structures. Currently available data from space would allow discriminating between these more realistic accretion scenarios and the classical early stellar evolution models. This opens a window to investigate the interior structures of young pulsating stars that will also be of relevance for related fields, such as stellar oscillations in general and exoplanet studies.
Modeling human HSV infection via a vascularized immune-competent skin-on-chip platform
Authors: Sun Sijie , Jin Lei , Zheng Ying , Zhu Jia
Published: September 2022

Herpes simplex virus (HSV) naturally infects skin and mucosal surfaces, causing lifelong recurrent disease worldwide, with no cure or vaccine. Biomimetic human tissue and organ platforms provide attractive alternatives over animal models to recapitulate human diseases. Combining prevascularization and microfluidic approaches, we present a vascularized, three-dimensional skin-on-chip that mimics human skin architecture and is competent to immune-cell and drug perfusion. The endothelialized microvasculature embedded in a fibroblast-containing dermis responds to biological stimulation, while the cornified epidermis functions as a protective barrier. HSV infection of the skin-on-chip displays tissue-level key morphological and pathophysiological features typical of genital herpes infection in humans, including the production of proinflammatory cytokine IL-8, which triggers rapid neutrophil trans-endothelial extravasation and directional migration. Importantly, perfusion with the antiviral drug acyclovir inhibits HSV infection in a dose-dependent and time-sensitive manner. Thus, our vascularized skin-on-chip represents a promising platform for human HSV disease modeling and preclinical therapeutic evaluation.
Integrated stem cell signature and cytomolecular risk determination in pediatric acute myeloid leukemia
Authors: Huang Benjamin J. , Smith Jenny L. , Farrar Jason E. , Wang Yi-Cheng , Umeda Masayuki , Ries Rhonda E. , Leonti Amanda R. , Crowgey Erin , Furlan Scott N. , Tarlock Katherine , Armendariz Marcos , Liu Yanling , Shaw Timothy I. , Wei Lisa , Gerbing Robert B. , Cooper Todd M. , Gamis Alan S. , Aplenc Richard , Kolb E. Anders , Rubnitz Jeffrey , Ma Jing , Klco Jeffery M. , Ma Xiaotu , Alonzo Todd A. , Triche Timothy , Meshinchi Soheil
Published: September 2022

Relapsed or refractory pediatric acute myeloid leukemia (AML) is associated with poor outcomes and relapse risk prediction approaches have not changed significantly in decades. To build a robust transcriptional risk prediction model for pediatric AML, we perform RNA-sequencing on 1503 primary diagnostic samples. While a 17 gene leukemia stem cell signature (LSC17) is predictive in our aggregated pediatric study population, LSC17 is no longer predictive within established cytogenetic and molecular (cytomolecular) risk groups. Therefore, we identify distinct LSC signatures on the basis of AML cytomolecular subtypes (LSC47) that were more predictive than LSC17. Based on these findings, we build a robust relapse prediction model within a training cohort and then validate it within independent cohorts. Here, we show that LSC47 increases the predictive power of conventional risk stratification and that applying biomarkers in a manner that is informed by cytomolecular profiling outperforms a uniform biomarker approach.
Biosynthesis of plant hemostatic dencichine in Escherichia coli
Authors: Li Wenna , Zhou Zhao , Li Xianglai , Ma Lin , Guan Qingyuan , Zheng Guojun , Liang Hao , Yan Yajun , Shen Xiaolin , Wang Jia , Sun Xinxiao , Yuan Qipeng
Published: September 2022

Dencichine is a plant-derived nature product that has found various pharmacological applications. Currently, its natural biosynthetic pathway is still elusive, posing challenge to its heterologous biosynthesis. In this work, we design artificial pathways through retro-biosynthesis approaches and achieve de novo production of dencichine. First, biosynthesis of the two direct precursors L−2, 3-diaminopropionate and oxalyl-CoA is achieved by screening and integrating microbial enzymes. Second, the solubility of dencichine synthase, which is the last and only plant-derived pathway enzyme, is significantly improved by introducing 28 synonymous rare codons into the codon-optimized gene to slow down its translation rate. Last, the metabolic network is systematically engineered to direct the carbon flux to dencichine production, and the final titer reaches 1.29 g L−1 with a yield of 0.28 g g−1 glycerol. This work lays the foundation for sustainable production of dencichine and represents an example of how synthetic biology can be harnessed to generate unnatural pathways to produce a desired molecule.
MRI to assess response after neoadjuvant chemotherapy in breast cancer subtypes: a systematic review and meta-analysis
Authors: Janssen L. M. , den Dekker B. M. , Gilhuijs K. G. A. , van Diest P. J. , van der Wall E. , Elias S. G.
Published: September 2022

This meta-analysis aimed to estimate and compare sensitivity, specificity, positive- (PPV) and negative predictive value (NPV) of magnetic resonance imaging (MRI) for predicting pathological complete remission (pCR) after neoadjuvant chemotherapy (NAC) in patients with early-stage breast cancer. We stratified for molecular subtype by immunohistochemistry (IHC) and explored the impact of other factors. Two researchers systematically searched PUBMED and EMBASE to select relevant studies and extract data. For meta-analysis of sensitivity and specificity, we used bivariate random-effects models. Twenty-six included studies contained 4497 patients. There was a significant impact of IHC subtype on post-NAC MRI accuracy (p = 0.0082) for pCR. The pooled sensitivity was 0.67 [95% CI 0.58–0.74] for the HR−/HER2−, 0.65 [95% CI 0.56–0.73] for the HR−/HER2+, 0.55 [95% CI 0.45–0.64] for the HR+/HER2− and 0.60 [95% CI 0.50–0.70] for the HR+/HER2+ subtype. The pooled specificity was 0.85 [95% CI 0.81–0.88] for the HR−/HER2−, 0.81 [95% CI 0.74–0.86] for the HR−/HER2+, 0.88[95% CI 0.84–0.91] for the HR+/HER2− and 0.74 [95% CI 0.63–0.83] for the HR+/HER2+ subtype. The PPV was highest in the HR-/HER2- subtype and lowest in the HR+/HER2− subtype. MRI field strength of 3.0 T was associated with a higher sensitivity compared to 1.5 T (p = 0.00063). The accuracy of MRI for predicting pCR depends on molecular subtype, which should be taken into account in clinical practice. Higher MRI field strength positively impacts accuracy. When intervention trials based on MRI response evaluation are designed, the impact of IHC subtype and field strength on MR accuracy should be considered.
Adjuvant trastuzumab emtansine in HER2-positive breast cancer patients with HER2-negative residual invasive disease in KATHERINE
Authors: Loibl Sibylle , Huang Chiun-Sheng , Mano Max S. , Mamounas Eleftherios P. , Geyer Charles E. , Untch Michael , Thery Jean-Christophe , Schwaner Ingo , Limentani Steven , Loman Niklas , Lübbe Kristina , Chang Jenny C. , Hatschek Thomas , Tesarowski David , Song Chunyan , Lysbet de Haas Sanne , Boulet Thomas , Lambertini Chiara , Wolmark Norman
Published: September 2022

Following chemotherapy and human epidermal growth factor 2 (HER2)-targeted neoadjuvant therapy for HER2-positive early breast cancer, residual invasive breast cancer at surgery may be HER2-negative on retesting in some patients. We evaluated outcomes with T-DM1 and trastuzumab in patients randomized in the phase III KATHERINE trial based on HER2-positive central testing of the pre-treatment core biopsy with HER2-negative central testing on their corresponding surgical specimen after neoadjuvant treatment. In the 70/845 (8.3%) patients with HER2-negative residual disease on retesting at surgery, there were 11 IDFS events in the 42 trastuzumab-treated patients (26.2%) and none in the 28 T-DM1-treated patients, suggesting that T-DM1 should not be withheld in this patient population.
The evolutionary dynamics of extrachromosomal DNA in human cancers
Authors: Lange Joshua T. , Rose John C. , Chen Celine Y. , Pichugin Yuriy , Xie Liangqi , Tang Jun , Hung King L. , Yost Kathryn E. , Shi Quanming , Erb Marcella L. , Rajkumar Utkrisht , Wu Sihan , Taschner-Mandl Sabine , Bernkopf Marie , Swanton Charles , Liu Zhe , Huang Weini , Chang Howard Y. , Bafna Vineet , Henssen Anton G. , Werner Benjamin , Mischel Paul S.
Published: September 2022

Oncogene amplification on extrachromosomal DNA (ecDNA) is a common event, driving aggressive tumor growth, drug resistance and shorter survival. Currently, the impact of nonchromosomal oncogene inheritance—random identity by descent—is poorly understood. Also unclear is the impact of ecDNA on somatic variation and selection. Here integrating theoretical models of random segregation, unbiased image analysis, CRISPR-based ecDNA tagging with live-cell imaging and CRISPR-C, we demonstrate that random ecDNA inheritance results in extensive intratumoral ecDNA copy number heterogeneity and rapid adaptation to metabolic stress and targeted treatment. Observed ecDNAs benefit host cell survival or growth and can change within a single cell cycle. ecDNA inheritance can predict, a priori, some of the aggressive features of ecDNA-containing cancers. These properties are facilitated by the ability of ecDNA to rapidly adapt genomes in a way that is not possible through chromosomal oncogene amplification. These results show how the nonchromosomal random inheritance pattern of ecDNA contributes to poor outcomes for patients with cancer.
A prospective cohort study of the association between key family and individual factors and obesity status among youth
Authors: Wang Liang , Morelen Diana , Alamian Arsham
Published: September 2022

There remains a significant gap in our knowledge of the synergistic nature of family dynamics, child characteristics, and child-rearing features in the etiology of obesity from childhood through adolescence. We assessed the associations of family dynamics (poverty, family structure), child characteristics (child temperament), and child-rearing features (maternal depression, maternal sensitivity, and type of child care) with the development of childhood obesity. Children (n = 1240) whose weights and heights were measured at least once for ten time points (from 2 years through 15 years) from the NICHD Study of Early Child Care and Youth Development were included. Generalized estimating equation (GEE) was used to examine the associations of family and individual factors with the childhood obesity after adjusting for covariates. Adjusted GEE models showed that living below poverty level was associated with an increased odds of obesity (odds ratio = 1.62, 95% confidence interval 1.05, 2.53). Among these key family and individual factors, poverty status was observed to be the strongest predictor of obesity of offspring across time. Findings highlight the importance of systemic-level public health changes in obesity reduction efforts and suggest that poverty-reduction based prevention and intervention are likely more effective targets than more individual/family specific targets.
Utility of fatty acid profile and in vitro immune cell activation for chemical and biological standardization of Arthrospira/Limnospira
Authors: Huh Jungmoo , Zhang Jin , Hauerová Radka , Lee Joseph , Haider Saqlain , Wang Mei , Hauer Tomáš , Khan Ikhlas A. , Chittiboyina Amar G. , Pugh Nirmal D.
Published: September 2022

Commercially cultivated Limnospira (species formerly classified to genus Arthrospira) is a popular food/supplement consumed by millions of people worldwide for health benefits. The objective of the current research was to advance the standardization technology for Limnospira. Quantitative methods were established to detect fatty acids as potential chemical markers and immune-enhancing activity. Analysis of 20 different batches of biomass obtained from one commercial grower demonstrated that there was a statistically significant relationship between the sum of two fatty acids (linoleic and γ-linolenic) and Toll-like receptor (TLR)2/TLR1-dependent activation (R2 = 0.48, p = 0.0007). Investigation of 12 biomass samples sourced from growers in 10 different countries demonstrated that fatty acid content was again significantly correlated with biological activity (R2 = 0.72, p = 0.0005) and the content of fatty acids varied by twofold and activity by 12.5-fold. This large variation between different samples confirms the need to use the present standardization methods to ensure consistent and properly characterized biomass for consumers and for future scientific research.
Antibody dynamics post-Comirnaty and CoronaVac vaccination in Malaysia
Authors: Tan Cheng Siang , Noni Vaenessa , Melina Whilemena Upam Herman Ulok , Abdorahman Ummi Syafiqah , Bimbang Joseph Niler , Malik Natasya Marliana Abdul , Hossen Mohammad Esa , Rahman Md Mizanur , Su’ut Lela , Said Asri , Chen Claire , Sepop Bego , Samat Morni Abu , Chew John Chee Ming , Mamora Dewi , Tan Sian Kong
Published: September 2022

Several vaccines have been fast-tracked through clinical trials to mitigate the progression of the SARS‑CoV‑2 pandemic. We analyzed sequential blood samples from 314 recipients of Comirnaty and CoronaVac in East Malaysia for the spike-binding IgG (IgG-S), nucleocapsid-binding IgG (IgG-N), spike-binding IgM (IgM-S) and serum vitamin D (VitD). A subset of samples was analyzed for the neutralizing antibodies (Ig-RBD). Results showed that IgG-S due to Comirnaty was significantly higher than CoronaVac. IgM-S was detected in 80.0% Comirnaty and 69.5% CoronaVac recipients, while IgG-N was detected in 58.1% CoronaVac but not in Comirnaty recipients. All IgG-S-positive vaccines possessed detectable Ig-RBD after the second dose but with a weak to moderate correlation. The serum VitD levels did not influence the antibody magnitude in both vaccines. In essence, SARS-CoV-2 vaccination is an IgG-S-dominant event, Comirnaty was more effective than CoronaVac in mounting IgG-S and Ig-RBD responses, independent of the patient’s VitD level.
Combined experimental and TD-DFT/DMOl3 investigations, optical properties, and photoluminescence behavior of a thiazolopyrimidine derivative
Authors: Abozeed Amina A. , Younis Osama , Al-Hossainy Ahmed F. , El-Mawla Nada Abd , Sayed Mostafa , M. Kamal El-dean Adel , Tolba Mahmoud S.
Published: September 2022

We present here the FT-IR, DFT computation, XRD, optical, and photophysical characterization of a heterocyclic compound with thienopyrimidine and pyran moieties. TD-DFT/DMOl3 and TD-DFT/CASTEP computations were used to study the geometry of isolated and dimer molecules and their optical behavior. The indirect (3.93 eV) and direct (3.29 eV) optical energy bandgaps, HOMO–LUMO energy gap (3.02 eV), and wavelength of maximum absorption (353 nm) were determined in the gas phase with M062X/6-31+G (d, p). A thin film of the studied molecule was studied using XRD, FT-IR, and UV–Vis spectroscopy. The average crystallite size was found as 74.95 nm. Also, the photoluminescence spectroscopy revealed that the compound exhibited different emission bands at the visible range with different intensities depending on the degree of molecular aggregation. For instance, solutions with different concentrations emitted blue, cyan, and green light. On the other hand, the solid-state material produced a dual emission with comparable intensities at λmax = 455, 505, and 621 nm to cover the entire visible range and produce white emission from a single material with CIE coordinates of (0.34, 0.32) that are very similar to the ideal pure white light. Consequently, these findings could lead to the development of more attractive new luminous materials.
Field measurement of local wind environment on the approach deck of a suspension bridge in mountain terrain
Authors: Zhang Mingjin , Jiang Fanying , Zhang Jingyu , Qin Jingxi , Jiang Xulei , Li Yongle
Published: September 2022

The local wind environment above the bridge deck affects the aerodynamic characteristics of vehicles, thus affecting the driving safety of the bridge deck. Influenced by the mountain topography and the bridge deck's ancillary facilities, the local wind environment above the bridge deck is complex and changeable, and its impact on the bridge deck traffic can not be ignored. In order to accurately evaluate the local wind field parameters, a monitoring system of the local wind environment is developed. Utilizing the monitoring system, wind parameters above the approach deck of a long-span suspension bridge in a mountain area are measured. The relationship of wind characteristics between the incoming flow and the wind above the bridge deck is investigated. Results show the significant difference between the local wind environment above the bridge deck and the incoming flow's characteristics; the wind profile above the bridge deck does not follow the exponential distribution; the equivalent height of the wind load on the vehicle is higher than the vehicle's gravity centre. This study is relevant for studying the local wind environment, driving safety, and serviceability of long-span bridges in mountainous areas.
A proposed synergetic mechanism for metal fume fever involving ZnO and Fe3O4 nanoparticles
Authors: Suárez Guillaume , Niculita-Hirzel Hélène , Correia Daniela , Pralong Jacques A. , Vernez David
Published: September 2022

Metal fumes fever (MFF) is an inflammatory condition, whose mechanism is yet unclear, associated with the inhalation of metal fumes, particularly zinc. In this study we investigate experimentally the hypothesis of a two-step mechanism of MFF onset: (1) the photocatalytic production of airborne hydrogen peroxide (H2O2) via ZnO and (2) the production of hydroxyl radicals (HOׄ) through Fenton reaction via magnetite (Fe3O4) nanoparticles. Photocatalysis and Fenton reaction products were measured using a multiscattering-enhanced absorbance device and assessing the degradation of bromophenol blue with microplate photometry, respectively. We observed that in the presence of UV, ZnO produces 3 to 4-times more H2O2 than UV alone or that non-UV irradiated ZnO. In the presence of biologically-relevant ligands, we also measured a Fenton reaction at physiological pH with either Fe(II), Fe(III) or Fe3O4 nanoparticles. Our results support the hypothesis of a two-step mechanism of MFF onset, in which the prior presence of Fe in the lungs exacerbates the oxidative stress, triggered by the photocatalysis of ZnO, a situation that could occurs when welding galvanized steel. More broadly, this raises the question of the role of the Fenton mechanism in respiratory exposure to metal particles and its possible contribution to other lung diseases.