bluuebunny/crossref_metadata_2025 huggingface dataset:
Health-related quality of life and overall survival: a prospective study in patients with head and neck cancer treated with radiotherapy
Authors: van Nieuwenhuizen A. J. , Buffart L. M. , Langendijk J. A. , Vergeer M. R. , Voortman J. , Leemans C. R. , Verdonck-de Leeuw I. M.
Published: December 2020

Purpose

We aimed to examine whether pre-treatment, post-treatment and change in health-related quality of Life (HRQoL) is associated with survival, in patients with head and neck cancer (HNC).

Methods

We included 948 newly diagnosed HNC patients treated with primary or adjuvant (chemo)radiotherapy with curative intent. The EORTC QLQ-C30 questionnaire was assessed pre-treatment and at 6 weeks, 6 months and 12 months post-treatment. Multivariable Cox regression analyses were performed to examine whether HRQoL at all time points and changes in HRQoL over time were associated with survival, after adjusting for demographic, clinical and lifestyle-related variables.

Results

Higher HRQoL scores were significantly associated with improved 5-year overall survival at all time points, except for the subscale global QoL at 6 weeks. Changes in HRQoL at 6 weeks post-treatment compared to pre-treatment were not significantly associated with survival. Changes in physical (HR: 0.88 95% CI: 0.82–0.96) and emotional functioning (HR: 0.90 95% CI: 0.85–0.96) from pre-treatment to 6 months post-treatment and changes in global QOL, and physical, emotional, and social functioning from pre-treatment to 12 months post-treatment were significantly associated with survival.

Conclusion

Higher HRQoL reported pre-treatment and post-treatment (6 weeks, 6 months and 12 months) are significantly associated with improved survival, as well as changes in HRQoL at 6 and 12 months compared to pre-treatment. Our results highlight the value of monitoring HRQoL and to identify those patients that report decreased or deteriorated HRQOL. This may help to further improve cancer care in a timely and efficient manner.
FLUKA Simulations of Pion Decay Gamma-Radiation from Energetic Flare Ions
Authors: MacKinnon Alexander , Szpigel Sergio , Gimenez de Castro Guillermo , Tuneu Jordi
Published: December 2020

Gamma-ray continuum at $> 10 $
>
10
MeV photon energy yields information on $\gtrsim 0.2 $
≳
0.2
 – 0.3 GeV/nucleon ions at the Sun. We use the general-purpose Monte Carlo code FLUktuierenden KAskade (FLUKA) to model the transport of ions injected into thick and thin target sources, the nuclear processes that give rise to pions and other secondaries and the escape of the resulting photons from the atmosphere. We give examples of photon spectra calculated with a range of different assumptions about the primary ion velocity distribution and the source region. We show that FLUKA gives results for pion decay photon emissivity in agreement with previous treatments. Through the directionality of secondary products, as well as Compton scattering and pair production of photons prior to escaping the Sun, the predicted spectrum depends significantly on the viewing angle. Details of the photon spectrum in the $\approx 100$
≈
100
MeV range may constrain the angular distribution of primary ions and the depths at which they interact. We display a set of thick-target spectra produced making various assumptions about the incident ion energy and angular distribution and the viewing angle. If ions are very strongly beamed downward, or ion energies do not extend much above 1 GeV/nucleon, the photon spectrum is highly insensitive to details of the ion distribution. Under the simplest assumptions, flares observed near disc centre should not display significant radiation above 1 GeV photon energy. We give an example application to Fermi Large Area Telescope data from the flare of 12 June 2010.
Comments on the Theory of Fluid Flow Between Solids with Anisotropic Roughness
Authors: Persson B. N. J.
Published: December 2020

I consider fluid flow at the interface between solids with random roughness. For anisotropic roughness, obtained by stretching isotropic roughness in the x-direction by a factor of $$\gamma ^{1/2}$$

γ

1
/
2

and in the y-direction with a factor of $$\gamma ^{-1/2}$$

γ

-
1
/
2

, I give an argument for why the flow conductivity in the critical junction theory should be proportional to $$\gamma $$
γ
in the x-direction and proportional to $$1/\gamma $$

1
/
γ

in the y-direction.
Mathematikleistungen von Schülerinnen und Schülern der gymnasialen Oberstufe in Deutschland: Ein Review und eine Sekundäranalyse der Schulleistungsstudien seit 1995
Authors: Rolfes Tobias , Lindmeier Anke , Heinze Aiso
Published: December 2020

Die Mathematikleistungen von Schülerinnen und Schülern der gymnasialen Oberstufe sind in den letzten zehn Jahren in Deutschland verstärkt in den Fokus der Bildungsforschung, der Hochschullehre und der Bildungspolitik gerückt. Der vorliegende Artikel hat das Ziel, die vorhandene empirische Befundlage genauer in den Blick zu nehmen und so zu einer Bestandsaufnahme beizutragen. Dazu wird im ersten Teil des Artikels ein systematisches Review über die seit 1995 durchgeführten Schulleistungsuntersuchungen zu Mathematikleistungen in der Oberstufe berichtet. Dabei wurde analysiert, welche Facetten mathematischer Fähigkeiten in diesen Schulleistungsstudien erfasst, welche Aspekte der übergreifenden Bildungsziele vertiefte Allgemeinbildung, Wissenschaftspropädeutik und Studierfähigkeit in den Schulleistungsstudien abgebildet und welche Niveaustufenmodelle zur kriterialen Einordnung der Schülerleistungen entwickelt wurden. Es zeigte sich, dass die verwendeten Instrumente jeweils nur einen besonderen Ausschnitt der mathematischen Fähigkeiten abbildeten und wichtige Aspekte (z. B. prozedural-technische Fertigkeiten) nahezu unberücksichtigt ließen. Auch wurde deutlich, dass ein kriterialer Vergleich der Ergebnisse aus den unterschiedlichen Schulleistungsstudien bisher kaum erfolgte. Deshalb wurden im zweiten Teil des Artikels die Daten und Ergebnisse der Schulleistungsuntersuchungen einer Sekundäranalyse unterzogen. Die Schülerleistungen wurden auf vergleichbare Skalen transformiert und anhand vorhandener Niveaustufenmodelle verglichen. Es zeigte sich, dass der größte Teil der Schülerschaft im Bereich der Allgemeinbildung lebensweltliche Problemstellungen auf der Basis der mathematischen Begriffe und Verfahren der Sekundarstufe I bewältigen konnte. Bezüglich der Wissenschaftspropädeutik und der Studierfähigkeit zeigte die Mehrheit deutliche Defizite, da sie mit fachspezifischen Lerninhalten der Oberstufe (z. B. Analysis, Analytische Geometrie) nur eingeschränkt umgehen konnte. Implikationen für die mathematikdidaktische Forschung zum Mathematikunterricht in der gymnasialen Oberstufe und seinen Bildungszielen werden diskutiert.
Peridynamic Formulation for Higher-Order Plate Theory
Authors: Yang Zhenghao , Oterkus Erkan , Oterkus Selda
Published: December 2020

In this study, a new peridynamic model is presented for higher-order plate theory. The formulation is derived by using Euler-Lagrange equation and Taylor’s expansion. The formulation is verified by considering two benchmark problems including simply supported and clamped plates subjected to transverse loading. Moreover, mixed (simply supported-clamped) boundary conditions are also considered to investigate the capability of the current formulation for mixed boundary conditions. Peridynamic results are compared with finite element analysis results and a very good agreement was obtained between the two approaches.
Chitin- and cellulose-based sustainable barrier materials: a review
Authors: Yu Zeyang , Ji Yue , Bourg Violette , Bilgen Mustafa , Meredith J. Carson
Published: December 2020

The accumulation of synthetic plastics used in packaging applications in landfills and the environment is a serious problem. This challenge is driving research efforts to develop biodegradable, compostable, or recyclable barrier materials derived from renewable sources. Cellulose, chitin/chitosan, and their combinations are versatile biobased packaging materials because of their diverse biological properties (biocompatibility, biodegradability, antimicrobial properties, antioxidant activity, non-toxicity, and less immunogenic compared to protein), superior physical properties (high surface area, good barrier properties, and mechanical properties), and they can be assembled into different forms and shapes (powders, fibers, films, beads, sponges, gels, and solutions). They can be either assembled into packaging films or used as fillers to improve the properties of other biobased polymers. Methods such as preparation of composites, multilayer coating, and alignment control are used to further improve their barrier, mechanical properties, and ameliorate their moisture sensitivity. With the growing application of cellulose and chitin-based packaging materials, their biodegradability and recyclability are also discussed in this review paper. The future trends of these biobased materials in packaging applications and the possibility of gradually replacing petroleum-based plastics are analyzed in the “Conclusions” section.
Movement tracing and analysis of benthic sting ray (Dasyatis akajei) and electric ray (Narke japonica) toward seabed exploration
Authors: Funano Shun-ichi , Tanaka Nobuyuki , Amaya Satoshi , Hamano Akira , Sasakura Toyoki , Tanaka Yo
Published: December 2020

Creation of a seabed map is a significant task for various activities including safe navigation of vessels, commercial fishing and securing sea-mined resources. Conventionally, search machines including autonomous underwater vehicles or sonar systems have been used for this purpose. Here, we propose a completely different approach to improve the seabed map by using benthic (sting and electric) rays as agents which may explore the seabed by their autonomous behavior without precise control and possibly add extra information such as biota. For the first step to realize this concept, the detail behavior of the benthic rays must be analyzed. In this study, we used a system with a large water tank (10 m × 5 m × 6 m height) to measure the movement patterns of the benthic rays. We confirmed that it was feasible to optically trace the 2D and 3D movement of a sting and an electric ray and that the speed of the rays indicated whether they were skimming slowly over the bottom surface or swimming. Then, we investigated feasibility for measuring the sea bottom features using two electric rays equipped with small pingers (acoustic transmitters) and receivers on a boat. We confirmed tracing of the movements of the rays over the sea bottom for more than 90 min at 1 s time resolution. Since we can know whether rays are skimming slowly over the bottom surface or swimming in water from the speed, this would be applicable to mapping the sea bottom depth. This is the first step to investigate the feasibility of mapping the seabed using a benthic creature.
Predation of invasive raccoon (Procyon lotor) on hibernating bats in the Nietoperek reserve in Poland
Authors: Cichocki Jan , Ważna Agnieszka , Bator-Kocoł Anna , Lesiński Grzegorz , Grochowalska Renata , Bojarski Jacek
Published: December 2020

The raccoon Procyon lotor is an invasive species inhabiting Europe and its impact on local populations, particularly on endangered species, is not well known. The aim of the study was to determine whether raccoons pose a threat to bats wintering in the Nietoperek nature reserve, one of the largest hibernation sites in Central Europe. In the winter of 2016–2017, 67 raccoon scats were collected in one of the main underground corridors in the reserve. It was confirmed, with the use of molecular methods, that the scats belonged to raccoons. Raccoon prey was identified based on the features of skulls, jaws or hair found in the scats. Analysis of the determinable remains indicates that bats (including Daubenton’s bat/Natterer’s bat/Brandt’s bat M. daubentonii/nattereri/brandtii, Natterer’s bat Myotis nattereri, greater mouse-eared bat Myotis myotis, brown long-eared bat Plecotus auritus) made up the largest percentage of raccoon diet (96%). Remains of other mammal species, lizards Lacerta spp., plant materials and anthropogenic food were also identified in raccoon scats. The results of the research indicate that predation by raccoons can constitute a significant factor in the increasing mortality of bats wintering in Nietoperek.
Fire seal is designed for use on aircraft with engines that operate at high temperatures
Authors: Atkinson Simon
Published: December 2020

Trelleborg Sealing Solutions has developed a high-temperature fire seal for the aerospace industry. The company says that the structure and design of the Ultra High Temp Seal will help aircraft manufacturers to develop engines that run more efficiently and – by achieving lower fuel consumption – more sustainably.
Our Strange Body
Authors: Slatman Jenny
Published: December 2020

The ever increasing ability of medical technology to reshape the human body in fundamental ways - from organ and tissue transplants to reconstructive surgery and prosthetics - is something now largely taken for granted. But for a philosopher, such interventions raise fundamental and fascinating questions about our sense of individual identity and its relationship to the physical body. Drawing on and engaging with philosophers from across the centuries, Jenny Slatman here develops a novel argument: that our own body always entails a strange dimension, a strangeness that enables us to incorporate radical physical changes.
Alles nur Nebenwirkungen von Capecitabin? Fallbericht aus der onkologischen und neurologischen Sprechstunde
Authors: Schmutz-Kober Katrin , Kappeler Liliane
Published: December 2020

Zusammenfassung. Berichtet wird über einen Fall aus der onkologischen und neurologischen Praxis. Ein Patient entwickelte unter der neoadjuvanten Radiochemotherapie mit Capecitabin bei Rektumkarzinom eine sensible Polyneuropathie sowie eine leichte motorische Schwäche der linken Extremiäten, einhergehend mit ipsilateraler Hyperreflexie und paresebedingter Gangstörung. Als ursächlich für die Polyneuropathie wird eine Toxizität durch Capecitabin angenommen. Die Hemiparese resultierte retrospektiv betrachtet jedoch eher aus einer akuten Varizella-Zoster-Virus-Myelitis, einer seltenen Komplikation eines Herpes-Zoster-Infekts, die aufgrund der Immunsuppression durch die Chemotherapie und auch durch die Tumorerkrankung selbst begünstigt wurde.
CME-EKG 67: Arrhythmie bei Belastung
Authors: Molitor Nadine , Brunckhorst Corinna B.
Published: December 2020

Zusammenfassung. Ventrikuläre Tachykardien sind potenziell lebensbedrohliche Herzrhythmusstörungen mit einer Herzfrequenz >100 Schläge/min und einem Ursprungsort der Arrhythmie unterhalb des Hisbündels im spezifischen Reizleitungssystem oder im ventrikulären Myokard. Die Morphologie im Oberflächen-EKG kann bereits Hinweise auf den zugrundeliegenden Mechanismus und die damit assoziierte Grunderkrankung liefern. Der jeweilige Pathomechanismus ist entscheidend für die weiterführende Therapie. Dieser Artikel soll einen Einblick in die verschiedenen Ursachen und Therapieoptionen sowie die Differenzialdiagnose der ventrikulären Tachykardien geben.
Acoustic and In‐Situ Observations of Deep Seafloor Hydrothermal Discharge: An OOI Cabled Array ASHES Vent Field Case Study
Authors: Xu Guangyu , Bemis Karen , Jackson Darrell , Ivakin Anatoliy
Published: December 2020

The Cabled Observatory Vent Imaging Sonar (COVIS) was installed on the Ocean Observatories Initiative's Regional Cabled Array observatory at ASHES hydrothermal vent field on Axial Seamount in July 2018. The acoustic backscatter data recorded by COVIS in August–September 2018, in conjunction with in situ temperature measurements, are used to showcase and verify the use of COVIS for long‐term, quantitative monitoring of hydrothermal discharge. Specifically, sonar data processing generates three‐dimensional backscatter images of the buoyant plumes above major sulfide structures and two‐dimensional maps of diffuse flows within COVIS's field‐of‐view. The backscatter images show substantial changes of plume appearance and orientation that mostly reflect plume bending in the presence of ambient currents and potentially the variations of outflow fluxes. The intensity of acoustic backscatter decreases significantly for highly bent plumes as compared to nearly vertical plumes, reflecting enhanced mixing of plume fluids with seawater driven by ambient currents. A forward model of acoustic backscatter from a buoyancy‐driven plume developed in this study yields a reasonable match with the observation, which paves the way for inversely estimating the source heat flux of a hydrothermal plume from acoustic backscatter measurements. The acoustic observations of diffuse flows show large temporal variations on time scales of hours to days, especially at tidal frequencies, but no apparent long‐term trend. These findings demonstrate COVIS's ability to quantitatively monitor hydrothermal discharge from both focused and diffuse sources to provide the research community with key observational data for studying the linkage of hydrothermal activity with oceanic and geological processes.
Rock Water as a Key Resource for Patchy Ecosystems on Shallow Soils: Digging Deep Tree Clumps Subsidize Surrounding Surficial Grass
Authors: Montaldo Nicola , Corona Roberto , Curreli Matteo , Sirigu Serena , Piroddi Luca , Oren Ram
Published: December 2020

Mediterranean mountainous areas of shallow soil often display a mosaic of tree clumps surrounded by grass. The combined role and dynamics of water extracted from the underlying rock, and the competition between adjacent patches of trees and grass, has not been investigated. We quantified the role rock water plays in the seasonal dynamics of evapotranspiration (ET), over a patchy landscape in the context of current and past seasonal climate changes, and land‐cover change strategies. Soil water budget suggests deep water uptake by roots of trees (0.8–0.9 mm/d), penetrating into the fractured basalt, subsidized grass transpiration in spring through hydraulic redistribution. However, in summer trees used all the rock water absorbed (0.79 mm/d). A 15‐year data set shows that, with increasing seasonal drought‐severity (potential ET/precipitation) to >1.04, the vertical water flux through the bottom of the thin soil layer transitions from drainage to uptake in support of ET. A hypothetical grass‐covered landscape, with no access to deep water, would require 0.68–0.85 mm/d more than is available, forcing shortened growing season and/or reduced leaf area. Long‐term decreasing winter precipitation and increasing spring potential ET suggest drying climate, so far with stable vegetation mosaic but progressively earlier peak of grass leaf area. Intervention policies to increase water yield by reducing tree cover will curtail grass access to rock moisture, while attempting to increase tree‐related products (including carbon sequestration) by increasing forest cover will limit water availability per tree leaf area. Both changes may further reduce ecosystem stability.
Lyme Disease and the Dangers of the Forest Edge
Authors: Thomasy Hannah
Published: December 2020

Living near a forest edge may be an important risk factor for Lyme disease; these liminal spaces provide the perfect habitat for one of the black-legged tick’s favorite hosts.
On the Influence of the Current Feedback to the Atmosphere on the Western Mediterranean Sea Dynamics
Authors: Renault L. , Arsouze T. , Ballabrera‐Poy J.
Published: December 2020

The ocean Current FeedBack to the atmosphere (CFB) has been shown to be an unambiguous physical process to achieve proper equilibrium in the Ocean. However, its effects on the Western Mediterranean Sea (WMS) are not known. In this study, eddy‐rich coupled ocean‐atmosphere simulations are carried out for the WMS to assess the extent to which CFB alters the WMS circulation and to characterize the low‐level wind and surface stress responses to CFB. By generating conduits of energy from oceanic currents to the atmosphere, CFB slows the mean circulation by about 10% and acts as an oceanic eddy killer, reducing the mesoscale activity by 25% and attenuating the intensity of their intermittency. It also alters the mean barotropic vorticity balance of the WMS Gyre, reducing the role of wind stress curl, nonlinear torque, and bottom pressure torque. By reducing the eddy‐mean flow interaction, CFB has a large influence on the properties of the Algerian Current, reducing the presence of standing eddies near Sardinia and improving the realism of the circulation. It also modifies the Alboran Gyres formation and the Northern Current retroflection. Finally, coupling coefficients from the coupled simulations are estimated and are consistent with those for other regions. The CFB coupling coefficients can be used to parameterize the CFB in a forced ocean model. Overall, our results show that, as for other regions, the CFB is another physical mechanism to be considered for the representation of the WMS circulation.
Spatiotemporal Characteristics and Associated Synoptic Patterns of Extremely Persistent Heavy Rainfall in Southern China
Authors: Zhang Chi , Huang Xiaogang , Fei Jianfang , Luo Xia , Zhou Yan
Published: December 2020

Persistent heavy rainfall has a longer duration than short‐duration heavy rainfall (SHR), with few studies on its extreme duration. Hourly gridded precipitation data from April to September during 2008–2019 were used to define and study extremely persistent heavy rainfall (EPHR) in southern China. It was found that the EPHR process was asymmetric, with growing time about 1 h shorter than fading time on average. On average, EPHR accounts for less than 40% of duration but nearly 3/4 of precipitation in events. There was a tendency for EPHR to occur near land‐sea boundaries and mountainous areas. It was more frequent in the early morning, differing from the “afternoon peak” observed for SHR. There were five EPHR high‐incidence areas (HIAs). EPHR with longest duration occurred in coastal areas, and the largest precipitation was recorded near the Yunkai Mountains. Influenced by local characteristics, the peaking time of monthly and diurnal variations differed in HIAs. The low in Beibu Gulf was closely related to the occurrence of EPHR, but the relative positions of the low and HIAs varied in different synoptic pattern types. The trough at 500 hPa and the low vortex or shear line at 850 hPa interacted with the surface convergence mechanism to produce strong upward motion. There was also a warm and wet tongue at 850 hPa above the HIAs, combined with the vertically integrated moisture flux convergence. Additionally, the marine boundary‐layer jet and isentropic ascent in lower troposphere possibly supported the coastal EPHR.
Two‐Phase Fluid Flow Properties of Rough Fractures With Heterogeneous Wettability: Analysis With Lattice Boltzmann Simulations
Authors: Guiltinan Eric J. , Santos J. E. , Cardenas M. Bayani , Espinoza D. Nicolas , Kang Qinjun
Published: December 2020

Fractures are conduits for fluid flow in low‐permeability geological formations. Multiphase flow properties of fractures are important in natural processes and in engineering applications such as the evaluation of the sealing capacity of caprocks and productivity of hydrocarbon‐bearing tight rocks. Investigations of flow and transport through fractures typically focus on the effects of fracture geometric and mechanical factors such as aperture, roughness, and compressibility. The wettability of the fracture surfaces and its influence on microscale interfacial phenomena and macroscale effective transport properties are seldom studied. Here, we investigated the effect of heterogeneous wetting properties on the displacement of water by supercritical CO2 through a series of lattice Boltzmann method simulations. The results show the evolution of the CO2 plume within a fracture is controlled by both the roughness of the aperture field and the wetting distribution. We combined these factors into a capillary pressure map that can be related to the macroscopic flow behavior of the fracture. We observed that heterogeneous wetting distributions promote the residual trapping of water where lower capillary pressures allowed for isolated water pockets in higher capillary pressure zones. Analysis of fracture unsteady relative permeability shows the effect of wetting on permeability evolution and provides support for the viscous‐coupling relative permeability model. Finally, analysis of the steady‐state relative permeability and saturation demonstrates a strong correlation between permeability and the standard deviation of the capillary pressure field. Thus, characterizing the distribution of wetting properties of fractures is crucial to understanding multiphase fracture flow and transport properties.
Disentangling the Impact of Catchment Heterogeneity on Nitrate Export Dynamics From Event to Long‐Term Time Scales
Authors: Winter Carolin , Lutz Stefanie R. , Musolff Andreas , Kumar Rohini , Weber Michael , Fleckenstein Jan H.
Published: December 2020

Defining effective measures to reduce nitrate pollution in heterogeneous mesoscale catchments remains challenging when based on concentration measurements at the outlet only. One reason for this is our limited understanding of the subcatchment contributions to nitrate export and their importance at different time scales. While upstream subcatchments often disproportionally contribute to runoff generation and in turn to nutrient export, agricultural areas (which are typically found in downstream lowlands) are known to be a major source of nitrate pollution. To examine the interplay of different subcatchments, we analyzed seasonal long‐term trends and event dynamics of nitrate concentrations, loads, and the concentration–discharge relationship in three nested catchments within the Selke catchment (456 km2), Germany. The upstream subcatchments (40.4% of total catchment area, 34.5% of N input) had short transit times and dynamic concentration–discharge relationships with elevated nitrate concentrations during wet seasons and events. Consequently, the upstream subcatchments dominated nitrate export during high flow and disproportionally contributed to overall annual nitrate loads at the outlet (64.2%). The downstream subcatchment was characterized by higher N input, longer transit times, and relatively constant nitrate concentrations between seasons, dominating nitrate export during low‐flow periods. Neglecting the disproportional role of upstream subcatchments for temporally elevated nitrate concentrations and net annual loads can lead to an overestimation of the role of agricultural lowlands. Nonetheless, constantly high concentrations from nitrate legacies pose a long‐term threat to water quality in agricultural lowlands. This knowledge is crucial for an effective and site‐specific water quality management.
The current treatment landscape in the UK for stage III NSCLC
Authors:   on behalf of AstraZeneca UK Limited, Evison Matthew
Published: December 2020

For stage III non-small cell lung cancer (NSCLC), approximately a third of patients survive up to 5 years, with decreasing 5-year survival rates for stage IIIB and stage IIIC disease. Although curable, stage III NSCLC encompasses a diverse range of disease presentation, with an equally complex range of multi-modal treatment options, including systemic and local therapies for distant and local disease control, respectively. This complexity results in a number of challenges for the multi-disciplinary team (MDT) in achieving optimal treatment outcomes for patients. As multi-modality treatment is the preferred treatment strategy for all stage III disease, the focus of this article is the key surgical, chemotherapy and radiotherapy clinical trials as well as guidelines that currently outline radical therapy options for patients with both potentially resectable and unresectable stage III NSCLC.
Global immune characterization of HBV/HCV-related hepatocellular carcinoma identifies macrophage and T-cell subsets associated with disease progression
Authors: Song Guohe , Shi Yang , Zhang Meiying , Goswami Shyamal , Afridi Saifullah , Meng Lu , Ma Jiaqiang , Chen Yi , Lin Youpei , Zhang Juan , Liu Yuming , Jin Zijie , Yang Shuaixi , Rao Dongning , Zhang Shu , Ke Aiwu , Wang Xiaoying , Cao Ya , Zhou Jian , Fan Jia , Zhang Xiaoming , Xi Ruibin , Gao Qiang
Published: December 2020

Diverse immune cells in the tumor microenvironment form a complex ecosystem, but our knowledge of their heterogeneity and dynamics within hepatocellular carcinoma (HCC) still remains limited. To assess the plasticity and phenotypes of immune cells within HBV/HCV-related HCC microenvironment at single-cell level, we performed single-cell RNA sequencing on 41,698 immune cells from seven pairs of HBV/HCV-related HCC tumors and non-tumor liver tissues. We combined bio-informatic analyses, flow cytometry, and multiplex immunohistochemistry to assess the heterogeneity of different immune cell subsets in functional characteristics, transcriptional regulation, phenotypic switching, and interactions. We identified 29 immune cell subsets of myeloid cells, NK cells, and lymphocytes with unique transcriptomic profiles in HCC. A highly complex immunological network was shaped by diverse immune cell subsets that can transit among different states and mutually interact. Notably, we identified a subset of M2 macrophage with high expression of CCL18 and transcription factor CREM that was enriched in advanced HCC patients, and potentially participated in tumor progression. We also detected a new subset of activated CD8+ T cells highly expressing XCL1 that correlated with better patient survival rates. Meanwhile, distinct transcriptomic signatures, cytotoxic phenotypes, and evolution trajectory of effector CD8+ T cells from early-stage to advanced HCC were also identified. Our study provides insight into the immune microenvironment in HBV/HCV-related HCC and highlights novel macrophage and T-cell subsets that could be further exploited in future immunotherapy.
Faster chiral versus collinear magnetic order recovery after optical excitation revealed by femtosecond XUV scattering
Authors: Kerber Nico , Ksenzov Dmitriy , Freimuth Frank , Capotondi Flavio , Pedersoli Emanuele , Lopez-Quintas Ignacio , Seng Boris , Cramer Joel , Litzius Kai , Lacour Daniel , Zabel Hartmut , Mokrousov Yuriy , Kläui Mathias , Gutt Christian
Published: December 2020

While chiral spin structures stabilized by Dzyaloshinskii-Moriya interaction (DMI) are candidates as novel information carriers, their dynamics on the fs-ps timescale is little known. Since with the bulk Heisenberg exchange and the interfacial DMI two distinct exchange mechanisms are at play, the ultrafast dynamics of the chiral order needs to be ascertained and compared to the dynamics of the conventional collinear order. Using an XUV free-electron laser we determine the fs-ps temporal evolution of the chiral order in domain walls in a magnetic thin film sample by an IR pump - X-ray magnetic scattering probe experiment. Upon demagnetization we observe that the dichroic (CL-CR) signal connected with the chiral order correlator mzmx in the domain walls recovers significantly faster than the (CL + CR) sum signal representing the average collinear domain magnetization mz2 + mx2. We explore possible explanations based on spin structure dynamics and reduced transversal magnetization fluctuations inside the domain walls and find that the latter can explain the experimental data leading to different dynamics for collinear magnetic order and chiral magnetic order.
RNA structure-wide discovery of functional interactions with multiplexed RNA motif library
Authors: Komatsu Kaoru R. , Taya Toshiki , Matsumoto Sora , Miyashita Emi , Kashida Shunnichi , Saito Hirohide
Published: December 2020

Biochemical assays and computational analyses have discovered RNA structures throughout various transcripts. However, the roles of these structures are mostly unknown. Here we develop folded RNA element profiling with structure library (FOREST), a multiplexed affinity assay system to identify functional interactions from transcriptome-wide RNA structure datasets. We generate an RNA structure library by extracting validated or predicted RNA motifs from gene-annotated RNA regions. The RNA structure library with an affinity enrichment assay allows for the comprehensive identification of target-binding RNA sequences and structures in a high-throughput manner. As a proof-of-concept, FOREST discovers multiple RNA-protein interaction networks with quantitative scores, including translational regulatory elements that function in living cells. Moreover, FOREST reveals different binding landscapes of RNA G-quadruplex (rG4) structures-binding proteins and discovers rG4 structures in the terminal loops of precursor microRNAs. Overall, FOREST serves as a versatile platform to investigate RNA structure-function relationships on a large scale.
Engineering rules that minimize germline silencing of transgenes in simple extrachromosomal arrays in C. elegans
Authors: Aljohani Mohammed D. , El Mouridi Sonia , Priyadarshini Monika , Vargas-Velazquez Amhed M. , Frøkjær-Jensen Christian
Published: December 2020

Transgenes are prone to progressive silencing due to their structure, copy number, and genomic location. In C. elegans, repressive mechanisms are particularly strong in the germline with almost fully penetrant transgene silencing in simple extrachromosomal arrays and frequent silencing of single-copy transgene insertions. A class of non-coding DNA, Periodic An/Tn Clusters (PATCs) can prevent transgene-silencing in repressive chromatin or from small interfering RNAs (piRNAs). Here, we describe design rules (codon-optimization, intron and PATC inclusion, elevated temperature (25 °C), and vector backbone removal) for efficient germline expression from arrays in wildtype animals. We generate web-based tools to analyze PATCs and reagents for the convenient assembly of PATC-rich transgenes. An extensive collection of silencing resistant fluorescent proteins (e.g., gfp, mCherry, and tagBFP) can be used for dissecting germline regulatory elements and a set of enhanced enzymes (Mos1 transposase, Cas9, Cre, and Flp recombinases) enable efficient genetic engineering in C. elegans.
Hybrid guided space-time optical modes in unpatterned films
Authors: Shiri Abbas , Yessenov Murat , Webster Scott , Schepler Kenneth L. , Abouraddy Ayman F.
Published: December 2020

Light is confined transversely and delivered axially in a waveguide. However, waveguides are lossy static structures whose modal characteristics are fundamentally determined by their boundary conditions. Here we show that unpatterned planar waveguides can provide low-loss two-dimensional waveguiding by using space-time wave packets, which are unique one-dimensional propagation-invariant pulsed optical beams. We observe hybrid guided space-time modes that are index-guided in one transverse dimension and localized along the unbounded dimension. We confirm that these fields enable overriding the boundary conditions by varying post-fabrication the group index of the fundamental mode in a 2-μm-thick, 25-mm-long silica film, achieved by modifying the field’s spatio-temporal structure. Tunability of the group index over an unprecedented range from 1.26 to 1.77 is verified while maintaining a spectrally flat zero-dispersion profile. Our work paves the way to utilizing space-time wave packets in on-chip platforms, and enable phase-matching strategies that circumvent restrictions due to intrinsic material properties.
Plant-based and cell-based approaches to meat production
Authors: Rubio Natalie R. , Xiang Ning , Kaplan David L.
Published: December 2020

Advances in farming technology and intensification of animal agriculture increase the cost-efficiency and production volume of meat. Thus, in developed nations, meat is relatively inexpensive and accessible. While beneficial for consumer satisfaction, intensive meat production inflicts negative externalities on public health, the environment and animal welfare. In response, groups within academia and industry are working to improve the sensory characteristics of plant-based meat and pursuing nascent approaches through cellular agriculture methodology (i.e., cell-based meat). Here we detail the benefits and challenges of plant-based and cell-based meat alternatives with regard to production efficiency, product characteristics and impact categories.
Design of efficacious somatic cell genome editing strategies for recessive and polygenic diseases
Authors: Carlson-Stevermer Jared , Das Amritava , Abdeen Amr A. , Fiflis David , Grindel Benjamin I , Saxena Shivani , Akcan Tugce , Alam Tausif , Kletzien Heidi , Kohlenberg Lucille , Goedland Madelyn , Dombroe Micah J. , Saha Krishanu
Published: December 2020

Compound heterozygous recessive or polygenic diseases could be addressed through gene correction of multiple alleles. However, targeting of multiple alleles using genome editors could lead to mixed genotypes and adverse events that amplify during tissue morphogenesis. Here we demonstrate that Cas9-ribonucleoprotein-based genome editors can correct two distinct mutant alleles within a single human cell precisely. Gene-corrected cells in an induced pluripotent stem cell model of Pompe disease expressed the corrected transcript from both corrected alleles, leading to enzymatic cross-correction of diseased cells. Using a quantitative in silico model for the in vivo delivery of genome editors into the developing human infant liver, we identify progenitor targeting, delivery efficiencies, and suppression of imprecise editing outcomes at the on-target site as key design parameters that control the efficacy of various therapeutic strategies. This work establishes that precise gene editing to correct multiple distinct gene variants could be highly efficacious if designed appropriately.
Macrophage ATP citrate lyase deficiency stabilizes atherosclerotic plaques
Authors: Baardman Jeroen , Verberk Sanne G. S. , van der Velden Saskia , Gijbels Marion J. J. , van Roomen Cindy P. P. A. , Sluimer Judith C. , Broos Jelle Y. , Griffith Guillermo R. , Prange Koen H. M. , van Weeghel Michel , Lakbir Soufyan , Molenaar Douwe , Meinster Elisa , Neele Annette E. , Kooij Gijs , de Vries Helga E. , Lutgens Esther , Wellen Kathryn E. , de Winther Menno P. J. , Van den Bossche Jan
Published: December 2020

Macrophages represent a major immune cell population in atherosclerotic plaques and play central role in the progression of this lipid-driven chronic inflammatory disease. Targeting immunometabolism is proposed as a strategy to revert aberrant macrophage activation to improve disease outcome. Here, we show ATP citrate lyase (Acly) to be activated in inflammatory macrophages and human atherosclerotic plaques. We demonstrate that myeloid Acly deficiency induces a stable plaque phenotype characterized by increased collagen deposition and fibrous cap thickness, along with a smaller necrotic core. In-depth functional, lipidomic, and transcriptional characterization indicate deregulated fatty acid and cholesterol biosynthesis and reduced liver X receptor activation within the macrophages in vitro. This results in macrophages that are more prone to undergo apoptosis, whilst maintaining their capacity to phagocytose apoptotic cells. Together, our results indicate that targeting macrophage metabolism improves atherosclerosis outcome and we reveal Acly as a promising therapeutic target to stabilize atherosclerotic plaques.
HIF1A signaling selectively supports proliferation of breast cancer in the brain
Authors: Ebright Richard Y. , Zachariah Marcus A. , Micalizzi Douglas S. , Wittner Ben S. , Niederhoffer Kira L. , Nieman Linda T. , Chirn Brian , Wiley Devon F. , Wesley Benjamin , Shaw Brian , Nieblas-Bedolla Edwin , Atlas Lian , Szabolcs Annamaria , Iafrate Anthony J. , Toner Mehmet , Ting David T. , Brastianos Priscilla K. , Haber Daniel A. , Maheswaran Shyamala
Published: December 2020

Blood-borne metastasis to the brain is a major complication of breast cancer, but cellular pathways that enable cancer cells to selectively grow in the brain microenvironment are poorly understood. We find that cultured circulating tumor cells (CTCs), derived from blood samples of women with advanced breast cancer and directly inoculated into the mouse frontal lobe, exhibit striking differences in proliferative potential in the brain. Derivative cell lines generated by serial intracranial injections acquire selectively increased proliferative competency in the brain, with reduced orthotopic tumor growth. Increased Hypoxia Inducible Factor 1A (HIF1A)-associated signaling correlates with enhanced proliferation in the brain, and shRNA-mediated suppression of HIF1A or drug inhibition of HIF-associated glycolytic pathways selectively impairs brain tumor growth while minimally impacting mammary tumor growth. In clinical specimens, brain metastases have elevated HIF1A protein expression, compared with matched primary breast tumors, and in patients with brain metastases, hypoxic signaling within CTCs predicts decreased overall survival. The selective activation of hypoxic signaling by metastatic breast cancer in the brain may have therapeutic implications.
Heme biosynthesis depends on previously unrecognized acquisition of iron-sulfur cofactors in human amino-levulinic acid dehydratase
Authors: Liu Gang , Sil Debangsu , Maio Nunziata , Tong Wing-Hang , Bollinger J. Martin , Krebs Carsten , Rouault Tracey Ann
Published: December 2020

Heme biosynthesis and iron-sulfur cluster (ISC) biogenesis are two major mammalian metabolic pathways that require iron. It has long been known that these two pathways interconnect, but the previously described interactions do not fully explain why heme biosynthesis depends on intact ISC biogenesis. Herein we identify a previously unrecognized connection between these two pathways through our discovery that human aminolevulinic acid dehydratase (ALAD), which catalyzes the second step of heme biosynthesis, is an Fe-S protein. We find that several highly conserved cysteines and an Ala306-Phe307-Arg308 motif of human ALAD are important for [Fe4S4] cluster acquisition and coordination. The enzymatic activity of human ALAD is greatly reduced upon loss of its Fe-S cluster, which results in reduced heme biosynthesis in human cells. As ALAD provides an early Fe-S-dependent checkpoint in the heme biosynthetic pathway, our findings help explain why heme biosynthesis depends on intact ISC biogenesis.
The CloudUPDRS smartphone software in Parkinson’s study: cross-validation against blinded human raters
Authors: Jha Ashwani , Menozzi Elisa , Oyekan Rebecca , Latorre Anna , Mulroy Eoin , Schreglmann Sebastian R. , Stamate Cosmin , Daskalopoulos Ioannis , Kueppers Stefan , Luchini Marco , Rothwell John C. , Roussos George , Bhatia Kailash P.
Published: December 2020

Digital assessments of motor severity could improve the sensitivity of clinical trials and personalise treatment in Parkinson’s disease (PD) but have yet to be widely adopted. Their ability to capture individual change across the heterogeneous motor presentations typical of PD remains inadequately tested against current clinical reference standards. We conducted a prospective, dual-site, crossover-randomised study to determine the ability of a 16-item smartphone-based assessment (the index test) to predict subitems from the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale part III (MDS-UPDRS III) as assessed by three blinded clinical raters (the reference-standard). We analysed data from 60 subjects (990 smartphone tests, 2628 blinded video MDS-UPDRS III subitem ratings). Subject-level predictive performance was quantified as the leave-one-subject-out cross-validation (LOSO-CV) accuracy. A pre-specified analysis classified 70.3% (SEM 5.9%) of subjects into a similar category to any of three blinded clinical raters and was better than random (36.7%; SEM 4.3%) classification. Post hoc optimisation of classifier and feature selection improved performance further (78.7%, SEM 5.1%), although individual subtests were variable (range 53.2–97.0%). Smartphone-based measures of motor severity have predictive value at the subject level. Future studies should similarly mitigate against subjective and feature selection biases and assess performance across a range of motor features as part of a broader strategy to avoid overly optimistic performance estimates.
Data-driven computational prediction and experimental realization of exotic perovskite-related polar magnets
Authors: Han Yifeng , Wu Meixia , Gui Churen , Zhu Chuanhui , Sun Zhongxiong , Zhao Mei-Huan , Savina Aleksandra A. , Abakumov Artem M. , Wang Biao , Huang Feng , He LunHua , Chen Jie , Huang Qingzhen , Croft Mark , Ehrlich Steven , Khalid Syed , Deng Zheng , Jin Changqing , Grams Christoph P. , Hemberger Joachim , Wang Xueyun , Hong Jiawang , Adem Umut , Ye Meng , Dong Shuai , Li Man-Rong
Published: December 2020

Rational design of technologically important exotic perovskites is hampered by the insufficient geometrical descriptors and costly and extremely high-pressure synthesis, while the big-data driven compositional identification and precise prediction entangles full understanding of the possible polymorphs and complicated multidimensional calculations of the chemical and thermodynamic parameter space. Here we present a rapid systematic data-mining-driven approach to design exotic perovskites in a high-throughput and discovery speed of the A2BB’O6 family as exemplified in A3TeO6. The magnetoelectric polar magnet Co3TeO6, which is theoretically recognized and experimentally realized at 5 GPa from the six possible polymorphs, undergoes two magnetic transitions at 24 and 58 K and exhibits helical spin structure accompanied by magnetoelastic and magnetoelectric coupling. We expect the applied approach will accelerate the systematic and rapid discovery of new exotic perovskites in a high-throughput manner and can be extended to arbitrary applications in other families.
EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood
Authors: Weller Michael , van den Bent Martin , Preusser Matthias , Le Rhun Emilie , Tonn Jörg C. , Minniti Giuseppe , Bendszus Martin , Balana Carmen , Chinot Olivier , Dirven Linda , French Pim , Hegi Monika E. , Jakola Asgeir S. , Platten Michael , Roth Patrick , Rudà Roberta , Short Susan , Smits Marion , Taphoorn Martin J. B. , von Deimling Andreas , Westphal Manfred , Soffietti Riccardo , Reifenberger Guido , Wick Wolfgang
Published: December 2020

In response to major changes in diagnostic algorithms and the publication of mature results from various large clinical trials, the European Association of Neuro-Oncology (EANO) recognized the need to provide updated guidelines for the diagnosis and management of adult patients with diffuse gliomas. Through these evidence-based guidelines, a task force of EANO provides recommendations for the diagnosis, treatment and follow-up of adult patients with diffuse gliomas. The diagnostic component is based on the 2016 update of the WHO Classification of Tumors of the Central Nervous System and the subsequent recommendations of the Consortium to Inform Molecular and Practical Approaches to CNS Tumour Taxonomy — Not Officially WHO (cIMPACT-NOW). With regard to therapy, we formulated recommendations based on the results from the latest practice-changing clinical trials and also provide guidance for neuropathological and neuroradiological assessment. In these guidelines, we define the role of the major treatment modalities of surgery, radiotherapy and systemic pharmacotherapy, covering current advances and cognizant that unnecessary interventions and expenses should be avoided. This document is intended to be a source of reference for professionals involved in the management of adult patients with diffuse gliomas, for patients and caregivers, and for health-care providers.