bluuebunny/crossref_metadata_2025 huggingface dataset:
שינויים במפת המקומות הקדושים היהודיים בירושלים: תהליך התקדשותם של קברי צדיקים בשלושה מבתי הקברות של העיר, 1967–2017
Authors: דורון בר
Published: April 2021

בשנים האחרונות מתמלאים מדי שבוע לוחות המודעות בירושלים במודעות המעודדות את ציבור המאמינים לקחת חלק בהתכנסויות, הילולות, ועליות לרגל. מודעות אלו מכריזות על כנסים דתיים שנערכים ליד קברי רבנים וצדיקים מקומיים ועל תפילות המעניקות למשתטחים סגולות שונות.
Developing students’ linguistic and digital literacy skills through the use of multimedia presentations
Authors: Yu Baohua , Zadorozhnyy Artem
Published: April 2021

With the immense presence of English language video content in the online digital environment and students’ everyday exposure to multimedia content, this project aims to explore how to replace traditional in-class presentation with video presentation within an autonomous learning environment, examine the impact of doing so on the development of English language and digital literacy skills, and develop assessment rubrics at both individual and group levels. The project was conducted as part of an English language course for undergraduate students majoring in English in the context of a higher education institution in Hong Kong. Data were collected through multiple methods: survey questionnaires, open-ended questions, and face-to-face interviews. The results showed that the video production mode of presentation could not only replace traditional in-class presentation but also improve students’ learning autonomy, and language, collaborative, and digital literacy skills. The analysis of videos elucidated how the video production (VPR) group of students use multimodal semiotic resources to design their relationships with viewers while simultaneously adapting their discoursal identities. In addition, the comparison between VPR- and non-VPR-group presentations demonstrates that constructing audio-visual resources in a collaborative environment contributes to a variety of aspects to a higher extent. Implications for foreign language curriculum and instructional design, as well as recommendations for future studies of digitalization of students’ oral assessment tasks, are discussed.
BMI and risk of all-cause mortality in normotensive and hypertensive adults: the rural Chinese cohort study
Authors: Zhou Qionggui , Liu Xuejiao , Zhao Yang , Qin Pei , Ren Yongcheng , Liu Dechen , Liu Leilei , Chen Xu , Liu Feiyan , Cheng Cheng , Guo Chunmei , Li Quanman , Tian Gang , Wu Xiaoyan , Qie Ranran , Han Minghui , Huang Shengbing , Xu Lidan , Zhang Ming , Hu Dongsheng
Published: April 2021

Objective:

The impact of baseline hypertension status on the BMI–mortality association is still unclear. We aimed to examine the moderation effect of hypertension on the BMI–mortality association using a rural Chinese cohort.

Design:

In this cohort study, we investigated the incident of mortality according to different BMI categories by hypertension status.

Setting:

Longitudinal population-based cohort.

Participants:

17 262 adults ≥18 years were recruited from July to August of 2013 and July to August of 2014 from a rural area in China.

Results:

During a median 6-year follow-up, we recorded 1109 deaths (610 with and 499 without hypertension). In adjusted models, as compared with BMI 22–24 kg/m2, with BMI ≤ 18, 18–20, 20–22, 24–26, 26–28, 28–30 and >30 kg/m2, the hazard ratios for mortality in normotensive participants were 1·92 (95% CI 1·23, 3·00), 1·44 (95% CI 1·01, 2·05), 1·14 (95% CI 0·82, 1·58), 0·96 (95% CI 0·70, 1·31), 0·96 (95% CI 0·65, 1·43), 1·32 (95% CI 0·81, 2·14) and 1·32 (95% CI 0·74, 2·35), respectively, and in hypertensive participants were 1·85 (95% CI 1·08, 3·17), 1·67 (95% CI 1·17, 2·39), 1·29 (95% CI 0·95, 1·75), 1·20 (95% CI 0·91, 1·58), 1·10 (95% CI 0·83, 1·46), 1·10 (95% CI 0·80, 1·52) and 0·61 (95% CI 0·40, 0·94), respectively. The risk of mortality was lower in individuals with hypertension with overweight or obesity v. normal weight, especially in older hypertensives (≥60 years old). Sensitivity analyses gave consistent results for both normotensive and hypertensive participants.

Conclusions:

Low BMI was significantly associated with increased risk of all-cause mortality regardless of hypertension status in rural Chinese adults, but high BMI decreased the mortality risk among individuals with hypertension, especially in older hypertensives.
Micro-Structural Stability of Micropropagated Plants ofVitex negundoL.
Authors: Manokari M. , Priyadharshini S. , Shekhawat Mahipal S.
Published: April 2021

Micropropagation techniques allow producing large numbers of clones of genetically identical plants. However, there is evidence of disorders in internal structures due to sophisticatedin vitroconditions. Such variations are responsible for the mortality of plantlets in the field and cause huge loss to the tissue culture industry. Anatomical evaluation at different growth conditions allows for understanding structural repair ofin vitroraised plantlets. Therefore, the present study was aimed to identify the structural changes that occurred in micropropagated plants ofVitex negundounder heterotrophic, photomixotrophic, and photoautotrophic conditions. To achieve this, structural variations were analyzed in the plantlets obtained fromin vitro, greenhouse and field transferred stages using light microscopy. Underdeveloped dermal tissues, palisade cells, intercellular spaces, mechanical tissues, vascular bundles, and ground tissues were observed with the plants growing underin vitroconditions. The self-repairing of structural disorders and transitions in vegetative anatomy was observed during hardening under the greenhouse environment. Field transferred plantlets were characterized by well-developed internal anatomy. These findings showed that the micropropagated plantlets ofV. negundowere well-adapted through a series of self-repairing thein vitroinduced structural abnormalities at the subsequent stages of plant development.
ON MENTAL ILLNESS AND BROKEN BRAINS
Authors: Jefferson Anneli
Published: April 2021

We often hear that certain mental disorders are disorders of the brain, but it is not clear what this claim amounts to. Does it mean that they are like classic brain diseases such as brain cancer? I argue that this is not the case for most mental disorders. Neither does the claim that all mental disorders are brain disorders follow from a materialist world-view. The only plausible way of understanding mental disorders as brain disorders is a fairly modest one, where we label brain differences we find in mental illness as pathological based on their link to mental dysfunction. How many mental disorders will turn out to be brain disorders on this understanding is an empirical question.
RIPM: A Retrospective Index to Music Periodicals (1760–1966)
Authors: Joubert Estelle
Published: April 2021

RIPM (Le Répertoire International de la Presse Musicale) is widely regarded as the most comprehensive resource offering electronic access to music periodicals from the early Romantic era to the twentieth century. Founded in 1980 by H. Robert Cohen, RIPM is the youngest of the so-called ‘4 R's of International Music Research’; its partner initiatives include RISM (Répertoire International des Sources Musicales), RILM (Répertoire International de Littérature Musicale), and RIdIM (Répertoire International d'Iconographie Musicale). Cohen's ambitious project was notably visionary in its use of technology: not only did it use computing from the start (beginning with DOS-based indexing systems), but it was also the first of the 4 R's to explore full text searching. RIPM seeks to address ‘two main problems that have prevented these [historic music] journals from being systematically collected and examined: (1) the limited number of libraries possessing the journals, and (2) the difficulty encountered when one attempts to locate specific information within an available source’. The project has thus focused on collection building, curation, indexing and accessibility. This international cooperative's accomplishments are impressive: as of July 2020, the database contains 527 music periodicals, 430 available in full text complete runs, totalling 996,000 annotated records and 1.47 million full-text pages of music periodicals.
Zircon and Melt Extraction From a Long‐Lived and Vertically Extensive Magma System Underneath Ilopango Caldera (El Salvador)
Authors: Cisneros de León A. , Schmitt A. K. , Kutterolf S. , Schindlbeck‐Belo J. C. , Hernández W. , Sims K. W. W. , Garrison J. , Kant L. B. , Weber B. , Wang K.‐L. , Lee H.‐Y. , Trumbull R. B.
Published: April 2021

The Tierra Blanca (TB) eruptive suite comprises the last four major eruptions of Ilopango caldera in El Salvador (≤45 ka), including the youngest Tierra Blanca Joven eruption (TBJ; ∼106 km3): the most voluminous event during the Holocene in Central America. Despite the protracted and productive history of explosive silicic eruptions at Ilopango caldera, many aspects regarding the longevity and the prevailing physicochemical conditions of the underlying magmatic system remain unknown. Zircon 238U‐230Th geochronology of the TB suite (TBJ, TB2, TB3, and TB4) reveals a continuous and overlapping crystallization history among individual eruptions, suggesting persistent melt presence in thermally and compositionally distinct magma reservoirs over the last ca. 80 kyr. The longevity of zircon is in contrast to previously determined crystallization timescales of <10 kyr for major mineral phases in TBJ. This dichotomy is explained by a process of rhyolitic melt segregation from a crystal‐rich refractory residue that incorporates zircon, whereas a new generation of major mineral phases crystallized shortly before eruption. Ti‐in‐zircon temperatures and amphibole geothermobarometry suggest that rhyolitic melt was extracted from different storage zones of the magma reservoir as indicated by distinct but synchronous thermochemical zircon histories among the TB suite eruptions. Zircon from TBJ and TB2 suggests magma differentiation within deeper and hotter parts of the reservoir, whereas zircon from TB3 and TB4 instead hints at crystallization in comparatively shallower and cooler domains. The assembly of the voluminous TBJ magma reservoir was also likely enhanced by cannibalization of hydrothermally altered components as suggested by low‐δ18O values in zircon (+4.5 ± 0.3‰).
Influence of Europa’s Time‐Varying Electromagnetic Environment on Magnetospheric Ion Precipitation and Surface Weathering
Authors: Addison Peter , Liuzzo Lucas , Arnold Hannes , Simon Sven
Published: April 2021

We combine the electromagnetic fields from a hybrid model with a particle‐tracing code to calculate the time‐varying spatial distribution of magnetospheric ion flux onto the surface of Jupiter’s moon Europa. The electromagnetic fields at Europa are perturbed by the sub‐alfvénic interaction of the moon’s ionosphere and induced dipole with the magnetospheric plasma. These perturbations substantially modify magnetospheric ion trajectories at all energies. We calculate spatially resolved surface flux maps of thermal and energetic ions for various distances between Europa and the center of Jupiter’s magnetospheric plasma sheet. The upstream ion distributions are constrained through in‐situ particle data from the Galileo and Juno spacecraft. These maps are then combined to obtain the average distribution of magnetospheric ion surface flux over a full synodic rotation. Our results show that the draping and pileup of the magnetic field reduce ion flux onto Europa’s trailing hemisphere by several orders of magnitude, while a significant number of the incident ions are deflected onto the leading hemisphere. Taking into account the deflection of energetic ions in the draped electromagnetic fields shifts the region of minimum energetic ion surface flux from Europa’s wakeside equator to its ramside equator. This generates an “inverted bullseye” pattern of energetic ion flux centered at the trailing apex. Despite drastic changes to the morphology of the ion surface flux when the alfvénic plasma interaction is included, we still find a strong correlation between variations of sulfuric acid concentration observed across Europa’s surface by Galileo and our modeled sulfur influx pattern.
Large Mesoscale Eddies in the Western Arctic Ocean From Satellite Altimetry Measurements
Authors: Kubryakov A. A. , Kozlov I. E. , Manucharyan G. E.
Published: April 2021

Eddies in the Western Arctic play an important role in transporting heat, salt, and biogeochemical tracers across the continental shelf and within the deep basins. However, comprehensive observations of the regional and temporal variability of the eddy field characteristics are difficult to obtain remotely due to the presence of sea ice, and the available in situ observations remain relatively sparse. Nonetheless, with continuing global warming, increasingly large areas of the Arctic Ocean become seasonally ice‐free and can be observed with remote sensing. Here, we use satellite altimetry data acquired between 1993 and 2018 over the seasonally ice‐free Western Arctic Ocean to detect the signatures and hot spots of large mesoscale eddies, validating their detection method using independent optical and infrared satellite observations. The altimetry measurements were most frequent from July to October, revealing signatures of over 2000 individual eddies that were roughly equally partitioned between cyclones and anticyclones, with radii between 20 and 60 km and characteristic orbital velocities of about 0.05–0.4 m/s. A maximum number of eddies were detected in October in the Beaufort Sea and in November in the Chukchi Sea. The interannual variability of eddies in the Beaufort Sea is correlated with variations of intensity and freshwater content in the Beaufort Gyre. Using the regional eddy statistics, we discuss the potential eddy formation mechanisms over the key regions of their observations in the Amundsen Gulf, the area adjacent to the Mackenzie River mouth, the western part of the Beaufort Sea, and the Chukchi Sea.
Estimation of Bottom Friction Coefficient in Multi‐Constituent Tidal Models Using the Adjoint Method: Temporal Variations and Spatial Distributions
Authors: Wang Daosheng , Zhang Jicai , Wang Ya Ping
Published: April 2021

The bottom friction coefficient (BFC) is critical for precisely determining hydrodynamic conditions and sediment transport rates, which are important for scientific research and coastal ocean engineering. The BFC varies spatially and temporally, as indicated by in situ observations, but it is difficult to accurately set this parameter in tidal models. In this study, based on a two‐dimensional multi‐constituent tidal model and its adjoint model, the harmonic constants of four principal tidal constituents (M2, S2, K1, and O1) obtained from TOPEX/Poseidon altimeter data were assimilated to estimate spatially and temporally varying BFCs using the adjoint method in the Bohai, Yellow, and East China Seas. The model performance was significantly improved after data assimilation, which was independently tested by harmonic constants at coastal tidal gauge stations. Through several sensitivity experiments, the spatial distributions of the temporally averaged BFCs were verified to be robust and not affected by model settings, while the temporal variations of the spatially averaged BFCs were also robust but related to the tidal constituents. The variations in the estimated BFCs with the current speed and water depth were nearly consistent with those in the observations. Overall, the temporal and spatial variations in the estimated BFCs are significantly correlated with the current speed and water depth, which is attributed to the erosion‐deposition of sediment on the seabed and the changes in seabed roughness under different current speeds. The results can be beneficial for determining reasonable parameters for the bottom stress and setting the BFC in multi‐constituent tidal models.
Physical Controls on the Macrofaunal Benthic Biomass in Barrow Canyon, Chukchi Sea
Authors: Pickart Robert S. , Spall Michael A. , Lin Peigen , Bahr Frank , McRaven Leah T. , Arrigo Kevin R. , Grebmeier Jacqueline M.
Published: April 2021

A region of exceptionally high macrofaunal benthic biomass exists in Barrow Canyon, implying a carbon export process that is locally concentrated. Here we offer an explanation for this benthic “hotspot” using shipboard data together with a set of dynamical equations. Repeat occupations of the Distributed Biological Observatory transect in Barrow Canyon reveal that when the northward flow is strong and the density front in the canyon is sharp, plumes of fluorescence and oxygen extend from the pycnocline to the seafloor in the vicinity of the hotspot. By solving the quasi‐geostrophic omega equation with an analytical flow field fashioned after the observations, we diagnose the vertical velocity in the canyon. This reveals that, as the along stream flow converges into the canyon, it drives a secondary circulation cell with strong downwelling on the cyclonic side of the northward flow. The downwelling quickly advects material from the pycnocline to the seafloor in a vertical plume analogous to those seen in the observations. The plume occurs only when the phytoplankton reside in the pycnocline, since the near‐surface vertical velocity is weak, also consistent with the observations. Using a wind‐based proxy to represent the strength of the northward flow and hence the pumping, in conjunction with a satellite‐derived phytoplankton source function, we construct a time series of carbon supply to the bottom of Barrow Canyon.
Seasonality and Source Apportionment of Nonmethane Volatile Organic Compounds at Boulder Reservoir, Colorado, Between 2017 and 2019
Authors: Pollack Ilana B. , Helmig Detlev , O'Dell Katelyn , Fischer Emily V.
Published: April 2021

Multiyear observations of 13 nonmethane volatile organic compounds (NMVOCs) were collected at the Boulder Reservoir in the Colorado Northern Front Range Metropolitan Area (NFRMA). We separate abundances of NMVOCs in the 2017–2019 data into source contributions using two approaches that have been applied to prior NFRMA datasets. Positive matrix factorization analysis identifies five NMVOC factors in winter, spring, and fall that correspond to long‐lived and short‐lived NMVOCs from regional oil and natural gas (O&NG) production, traffic, local shorter‐lived alkenes, and regional anthropogenic background. In summer, there is an additional biogenic NMVOC factor dominated by isoprene. The PMF model indicates that 79 ± 1% of C2‐C5 alkanes in winter and 84 ± 20% in summer are attributed to O&NG activities. Ethyne is largely from traffic with contributions ranging from 45 ± 6% in winter to 87 ± 32% in summer. Ethene and propene are associated with a potentially separate source of shorter‐lived alkenes that we cannot identify. The largest contributing sectors to the observed hazardous air pollutants (HAPs) differ substantially by species and season. Benzene is attributed to O&NG production, traffic and other industrial activities. Toluene is predominantly attributed to regional anthropogenic activities in all seasons. Of the HAPs quantified in this dataset, hexane stands out as largely attributed to O&NG production. Consistent with prior analyses, this work shows that the NFRMA is more strongly influenced by O&NG sources than many other U.S. urban regions.
Controls on the Global Distribution of Martian Landslides
Authors: Roback Kevin P. , Ehlmann Bethany L.
Published: April 2021

Recent acquisition of high‐resolution satellite imagery of the Martian surface has permitted landslides to be studied on a global scale on Mars for the first time. We apply the Scoops3D software package to compute slope stability for select regions of the Martian surface, combining calculations of slope stability with number of observed landslides (Crosta, Frattini, et al., 2018; Crosta, De Blasio, et al., 2018), as reported in a recently published inventory of Martian landslides, to understand controls on the global distribution of landslides on Mars. We find that the distribution of landslides does not simply follow the distribution of unstable slopes. In particular, there is an abundance of landslides around Tharsis, and especially in Valles Marineris and Noctis Labyrinthus, which is not explained by an abundance of unstable topography alone. We analyzed for but did not find a clear large‐scale lithologic or stratigraphic control on landslide occurrence from subsurface heterogeneities. Other possibilities to explain the increased occurrence of landslides in Tharsis include (1) thin weak unit(s) that is regionally widespread and at multiple stratigraphic levels, such as from interbedded ashes; (2) seismic activity related to the Tharsis's geological activity, and (3) possible groundwater near Valles Marineris into the Amazonian. Given the apparently young ages of many landslide deposits in Valles Marineris (Quantin et al., 2004), continued modern day analysis of lithologies in Valles Marineris and observations of Martian seismicity may act to strengthen or rebut the first two hypotheses.
Global phosphoproteomics reveals DYRK1A regulates CDK1 activity in glioblastoma cells
Authors: Recasens Ariadna , Humphrey Sean J. , Ellis Michael , Hoque Monira , Abbassi Ramzi H. , Chen Brianna , Longworth Mitchell , Needham Elise J. , James David E. , Johns Terrance G. , Day Bryan W. , Kassiou Michael , Yang Pengyi , Munoz Lenka
Published: April 2021

Both tumour suppressive and oncogenic functions have been reported for dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). Herein, we performed a detailed investigation to delineate the role of DYRK1A in glioblastoma. Our phosphoproteomic and mechanistic studies show that DYRK1A induces degradation of cyclin B by phosphorylating CDC23, which is necessary for the function of the anaphase-promoting complex, a ubiquitin ligase that degrades mitotic proteins. DYRK1A inhibition leads to the accumulation of cyclin B and activation of CDK1. Importantly, we established that the phenotypic response of glioblastoma cells to DYRK1A inhibition depends on both retinoblastoma (RB) expression and the degree of residual DYRK1A activity. Moderate DYRK1A inhibition leads to moderate cyclin B accumulation, CDK1 activation and increased proliferation in RB-deficient cells. In RB-proficient cells, cyclin B/CDK1 activation in response to DYRK1A inhibition is neutralized by the RB pathway, resulting in an unchanged proliferation rate. In contrast, complete DYRK1A inhibition with high doses of inhibitors results in massive cyclin B accumulation, saturation of CDK1 activity and cell cycle arrest, regardless of RB status. These findings provide new insights into the complexity of context-dependent DYRK1A signalling in cancer cells.
Design of multi-scale protein complexes by hierarchical building block fusion
Authors: Hsia Yang , Mout Rubul , Sheffler William , Edman Natasha I. , Vulovic Ivan , Park Young-Jun , Redler Rachel L. , Bick Matthew J. , Bera Asim K. , Courbet Alexis , Kang Alex , Brunette T. J. , Nattermann Una , Tsai Evelyn , Saleem Ayesha , Chow Cameron M. , Ekiert Damian , Bhabha Gira , Veesler David , Baker David
Published: April 2021

A systematic and robust approach to generating complex protein nanomaterials would have broad utility. We develop a hierarchical approach to designing multi-component protein assemblies from two classes of modular building blocks: designed helical repeat proteins (DHRs) and helical bundle oligomers (HBs). We first rigidly fuse DHRs to HBs to generate a large library of oligomeric building blocks. We then generate assemblies with cyclic, dihedral, and point group symmetries from these building blocks using architecture guided rigid helical fusion with new software named WORMS. X-ray crystallography and cryo-electron microscopy characterization show that the hierarchical design approach can accurately generate a wide range of assemblies, including a 43 nm diameter icosahedral nanocage. The computational methods and building block sets described here provide a very general route to de novo designed protein nanomaterials.
Defective viral genomes as therapeutic interfering particles against flavivirus infection in mammalian and mosquito hosts
Authors: Rezelj Veronica V. , Carrau Lucía , Merwaiss Fernando , Levi Laura I. , Erazo Diana , Tran Quang Dinh , Henrion-Lacritick Annabelle , Gausson Valérie , Suzuki Yasutsugu , Shengjuler Djoshkun , Meyer Bjoern , Vallet Thomas , Weger-Lucarelli James , Bernhauerová Veronika , Titievsky Avi , Sharov Vadim , Pietropaoli Stefano , Diaz-Salinas Marco A. , Legros Vincent , Pardigon Nathalie , Barba-Spaeth Giovanna , Brodsky Leonid , Saleh Maria-Carla , Vignuzzi Marco
Published: April 2021

Arthropod-borne viruses pose a major threat to global public health. Thus, innovative strategies for their control and prevention are urgently needed. Here, we exploit the natural capacity of viruses to generate defective viral genomes (DVGs) to their detriment. While DVGs have been described for most viruses, identifying which, if any, can be used as therapeutic agents remains a challenge. We present a combined experimental evolution and computational approach to triage DVG sequence space and pinpoint the fittest deletions, using Zika virus as an arbovirus model. This approach identifies fit DVGs that optimally interfere with wild-type virus infection. We show that the most fit DVGs conserve the open reading frame to maintain the translation of the remaining non-structural proteins, a characteristic that is fundamental across the flavivirus genus. Finally, we demonstrate that the high fitness DVG is antiviral in vivo both in the mammalian host and the mosquito vector, reducing transmission in the latter by up to 90%. Our approach establishes the method to interrogate the DVG fitness landscape, and enables the systematic identification of DVGs that show promise as human therapeutics and vector control strategies to mitigate arbovirus transmission and disease.
Interleukin-11-expressing fibroblasts have a unique gene signature correlated with poor prognosis of colorectal cancer
Authors: Nishina Takashi , Deguchi Yutaka , Ohshima Daisuke , Takeda Wakami , Ohtsuka Masato , Shichino Shigeyuki , Ueha Satoshi , Yamazaki Soh , Kawauchi Mika , Nakamura Eri , Nishiyama Chiharu , Kojima Yuko , Adachi-Akahane Satomi , Hasegawa Mizuho , Nakayama Mizuho , Oshima Masanobu , Yagita Hideo , Shibuya Kazutoshi , Mikami Tetuo , Inohara Naohiro , Matsushima Kouji , Tada Norihiro , Nakano Hiroyasu
Published: April 2021

Interleukin (IL)-11 is a member of the IL-6 family of cytokines and is involved in multiple cellular responses, including tumor development. However, the origin and functions of IL-11-producing (IL-11+) cells are not fully understood. To characterize IL-11+cells in vivo, we generateIl11reporter mice. IL-11+cells appear in the colon in murine tumor and acute colitis models.Il11ra1orIl11deletion attenuates the development of colitis-associated colorectal cancer. IL-11+cells express fibroblast markers and genes associated with cell proliferation and tissue repair. IL-11 induces the activation of colonic fibroblasts and epithelial cells through phosphorylation of STAT3. Human cancer database analysis reveals that the expression of genes enriched in IL-11+fibroblasts is elevated in human colorectal cancer and correlated with reduced recurrence-free survival. IL-11+fibroblasts activate both tumor cells and fibroblasts via secretion of IL-11, thereby constituting a feed-forward loop between tumor cells and fibroblasts in the tumor microenvironment.
Genetic perturbation of PU.1 binding and chromatin looping at neutrophil enhancers associates with autoimmune disease
Authors: Watt Stephen , Vasquez Louella , Walter Klaudia , Mann Alice L. , Kundu Kousik , Chen Lu , Sims Ying , Ecker Simone , Burden Frances , Farrow Samantha , Farr Ben , Iotchkova Valentina , Elding Heather , Mead Daniel , Tardaguila Manuel , Ponstingl Hannes , Richardson David , Datta Avik , Flicek Paul , Clarke Laura , Downes Kate , Pastinen Tomi , Fraser Peter , Frontini Mattia , Javierre Biola-Maria , Spivakov Mikhail , Soranzo Nicole
Published: April 2021

Neutrophils play fundamental roles in innate immune response, shape adaptive immunity, and are a potentially causal cell type underpinning genetic associations with immune system traits and diseases. Here, we profile the binding of myeloid master regulator PU.1 in primary neutrophils across nearly a hundred volunteers. We show that variants associated with differential PU.1 binding underlie genetically-driven differences in cell count and susceptibility to autoimmune and inflammatory diseases. We integrate these results with other multi-individual genomic readouts, revealing coordinated effects of PU.1 binding variants on the local chromatin state, enhancer-promoter contacts and downstream gene expression, and providing a functional interpretation for 27 genes underlying immune traits. Collectively, these results demonstrate the functional role of PU.1 and its target enhancers in neutrophil transcriptional control and immune disease susceptibility.
Conserved long-range base pairings are associated with pre-mRNA processing of human genes
Authors: Kalmykova Svetlana , Kalinina Marina , Denisov Stepan , Mironov Alexey , Skvortsov Dmitry , Guigó Roderic , Pervouchine Dmitri
Published: April 2021

The ability of nucleic acids to form double-stranded structures is essential for all living systems on Earth. Current knowledge on functional RNA structures is focused on locally-occurring base pairs. However, crosslinking and proximity ligation experiments demonstrated that long-range RNA structures are highly abundant. Here, we present the most complete to-date catalog of conserved complementary regions (PCCRs) in human protein-coding genes. PCCRs tend to occur within introns, suppress intervening exons, and obstruct cryptic and inactive splice sites. Double-stranded structure of PCCRs is supported by decreased icSHAPE nucleotide accessibility, high abundance of RNA editing sites, and frequent occurrence of forked eCLIP peaks. Introns with PCCRs show a distinct splicing pattern in response to RNAPII slowdown suggesting that splicing is widely affected by co-transcriptional RNA folding. The enrichment of 3’-ends within PCCRs raises the intriguing hypothesis that coupling between RNA folding and splicing could mediate co-transcriptional suppression of premature pre-mRNA cleavage and polyadenylation.
Spin texture induced by non-magnetic doping and spin dynamics in 2D triangular lattice antiferromagnet h-Y(Mn,Al)O3
Authors: Park Pyeongjae , Park Kisoo , Oh Joosung , Lee Ki Hoon , Leiner Jonathan C. , Sim Hasung , Kim Taehun , Jeong Jaehong , Rule Kirrily C. , Kamazawa Kazuya , Iida Kazuki , Perring T. G. , Woo Hyungje , Cheong S.-W. , Zhitomirsky M. E. , Chernyshev A. L. , Park Je-Geun
Published: April 2021

Novel effects induced by nonmagnetic impurities in frustrated magnets and quantum spin liquid represent a highly nontrivial and interesting problem. A theoretical proposal of extended modulated spin structures induced by doping of such magnets, distinct from the well-known skyrmions has attracted significant interest. Here, we demonstrate that nonmagnetic impurities can produce such extended spin structures in h-YMnO3, a triangular antiferromagnet with noncollinear magnetic order. Using inelastic neutron scattering (INS), we measured the full dynamical structure factor in Al-doped h-YMnO3 and confirmed the presence of magnon damping with a clear momentum dependence. Our theoretical calculations can reproduce the key features of the INS data, supporting the formation of the proposed spin textures. As such, our study provides the first experimental confirmation of the impurity-induced spin textures. It offers new insights and understanding of the impurity effects in a broad class of noncollinear magnetic systems.
Orally delivered MK-4482 inhibits SARS-CoV-2 replication in the Syrian hamster model
Authors: Rosenke Kyle , Hansen Frederick , Schwarz Benjamin , Feldmann Friederike , Haddock Elaine , Rosenke Rebecca , Barbian Kent , Meade-White Kimberly , Okumura Atsushi , Leventhal Shanna , Hawman David W. , Ricotta Emily , Bosio Catharine M. , Martens Craig , Saturday Greg , Feldmann Heinz , Jarvis Michael A.
Published: April 2021

The COVID-19 pandemic progresses unabated in many regions of the world. An effective antiviral against SARS-CoV-2 that could be administered orally for use following high-risk exposure would be of substantial benefit in controlling the COVID-19 pandemic. Herein, we show that MK-4482, an orally administered nucleoside analog, inhibits SARS-CoV-2 replication in the Syrian hamster model. The inhibitory effect of MK-4482 on SARS-CoV-2 replication is observed in animals when the drug is administered either beginning 12 h before or 12 h following infection in a high-risk exposure model. These data support the potential utility of MK-4482 to control SARS-CoV-2 infection in humans following high-risk exposure as well as for treatment of COVID-19 patients.
Classical MHC expression by DP thymocytes impairs the selection of non-classical MHC restricted innate-like T cells
Authors: Georgiev Hristo , Peng Changwei , Huggins Matthew A. , Jameson Stephen C. , Hogquist Kristin A.
Published: April 2021

Conventional T cells are selected by peptide-MHC expressed by cortical epithelial cells in the thymus, and not by cortical thymocytes themselves that do not express MHC I or MHC II. Instead, cortical thymocytes express non-peptide presenting MHC molecules like CD1d and MR1, and promote the selection of PLZF+iNKT and MAIT cells, respectively. Here, we report an inducible class-I transactivator mouse that enables the expression of peptide presenting MHC I molecules in different cell types. We show that MHC I expression in DP thymocytes leads to expansion of peptide specific PLZF+innate-like (PIL) T cells. Akin to iNKT cells, PIL T cells differentiate into three functional effector subsets in the thymus, and are dependent on SAP signaling. We demonstrate that PIL and NKT cells compete for a narrow niche, suggesting that the absence of peptide-MHC on DP thymocytes facilitates selection of non-peptide specific lymphocytes.
Ultraviolet irradiation-responsive dynamic ultralong organic phosphorescence in polymeric systems
Authors: Zhang Yongfeng , Gao Liang , Zheng Xian , Wang Zhonghao , Yang Chaolong , Tang Hailong , Qu Lunjun , Li Youbing , Zhao Yanli
Published: April 2021

Room temperature phosphorescence (RTP) has drawn extensive attention in recent years. Efficient stimulus-responsive phosphorescent organic materials are attractive, but are extremely rare because of unclear design principles and intrinsically spin-forbidden intersystem crossing. Herein, we present a feasible and facile strategy to achieve ultraviolet irradiation-responsive ultralong RTP (IRRTP) of some simple organic phosphors by doping into amorphous poly(vinyl alcohol) matrix. In addition to the observed green and yellow afterglow emission with distinct irradiation-enhanced phosphorescence, the phosphorescence lifetime can be tuned by varying the irradiation period of 254 nm light. Significantly, the dynamic phosphorescence lifetime could be increased 14.3 folds from 58.03 ms to 828.81 ms in one of the obtained hybrid films after irradiation for 45 min under ambient conditions. As such, the application in polychromatic screen printing and multilevel information encryption is demonstrated. The extraordinary IRRTP in the amorphous state endows these systems with a highly promising potential for smart flexible luminescent materials and sensors with dynamically controlled phosphorescence.
DNase II mediates a parthanatos-like developmental cell death pathway in Drosophila primordial germ cells
Authors: Tarayrah-Ibraheim Lama , Maurice Elital Chass , Hadary Guy , Ben-Hur Sharon , Kolpakova Alina , Braun Tslil , Peleg Yoav , Yacobi-Sharon Keren , Arama Eli
Published: April 2021

During Drosophila embryonic development, cell death eliminates 30% of the primordial germ cells (PGCs). Inhibiting apoptosis does not prevent PGC death, suggesting a divergence from the conventional apoptotic program. Here, we demonstrate that PGCs normally activate an intrinsic alternative cell death (ACD) pathway mediated by DNase II release from lysosomes, leading to nuclear translocation and subsequent DNA double-strand breaks (DSBs). DSBs activate the DNA damage-sensing enzyme, Poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) and the ATR/Chk1 branch of the DNA damage response. PARP-1 and DNase II engage in a positive feedback amplification loop mediated by the release of PAR polymers from the nucleus and the nuclear accumulation of DNase II in an AIF- and CypA-dependent manner, ultimately resulting in PGC death. Given the anatomical and molecular similarities with an ACD pathway called parthanatos, these findings reveal a parthanatos-like cell death pathway active during Drosophila development.
Hypothalamic Rax+ tanycytes contribute to tissue repair and tumorigenesis upon oncogene activation in mice
Authors: Mu Wenhui , Li Si , Xu Jingkai , Guo Xize , Wu Haoda , Chen Zhenhua , Qiao Lianyong , Helfer Gisela , Lu Falong , Liu Chong , Wu Qing-Feng
Published: April 2021

Hypothalamic tanycytes in median eminence (ME) are emerging as a crucial cell population that regulates endocrine output, energy balance and the diffusion of blood-born molecules. Tanycytes have recently been considered as potential somatic stem cells in the adult mammalian brain, but their regenerative and tumorigenic capacities are largely unknown. Here we found that Rax+ tanycytes in ME of mice are largely quiescent but quickly enter the cell cycle upon neural injury for self-renewal and regeneration. Mechanistically, Igf1r signaling in tanycytes is required for tissue repair under injury conditions. Furthermore, Braf oncogenic activation is sufficient to transform Rax+ tanycytes into actively dividing tumor cells that eventually develop into a papillary craniopharyngioma-like tumor. Together, these findings uncover the regenerative and tumorigenic potential of tanycytes. Our study offers insights into the properties of tanycytes, which may help to manipulate tanycyte biology for regulating hypothalamic function and investigate the pathogenesis of clinically relevant tumors.
Structural insight into the molecular mechanism of p53-mediated mitochondrial apoptosis
Authors: Wei Hudie , Qu Lingzhi , Dai Shuyan , Li Yun , Wang Haolan , Feng Yilu , Chen Xiaojuan , Jiang Longying , Guo Ming , Li Jun , Chen Zhuchu , Chen Lin , Zhang Ye , Chen Yongheng
Published: April 2021

The tumor suppressor p53 is mutated in approximately half of all human cancers. p53 can induce apoptosis through mitochondrial membrane permeabilization by interacting with and antagonizing the anti-apoptotic proteins BCL-xL and BCL-2. However, the mechanisms by which p53 induces mitochondrial apoptosis remain elusive. Here, we report a 2.5 Å crystal structure of human p53/BCL-xL complex. In this structure, two p53 molecules interact as a homodimer, and bind one BCL-xL molecule to form a ternary complex with a 2:1 stoichiometry. Mutations at the p53 dimer interface or p53/BCL-xL interface disrupt p53/BCL-xL interaction and p53-mediated apoptosis. Overall, our current findings of the bona fide structure of p53/BCL-xL complex reveal the molecular basis of the interaction between p53 and BCL-xL, and provide insight into p53-mediated mitochondrial apoptosis.
Dynamic contrast-enhanced breast MRI features correlate with invasive breast cancer angiogenesis
Authors: Xiao Jennifer , Rahbar Habib , Hippe Daniel S. , Rendi Mara H. , Parker Elizabeth U. , Shekar Neal , Hirano Michael , Cheung Kevin J. , Partridge Savannah C.
Published: April 2021

Angiogenesis is a critical component of breast cancer development, and identification of imaging-based angiogenesis assays has prognostic and treatment implications. We evaluated the association of semi-quantitative kinetic and radiomic breast cancer features on dynamic contrast-enhanced (DCE)-MRI with microvessel density (MVD), a marker for angiogenesis. Invasive breast cancer kinetic features (initial peak percent enhancement [PE], signal enhancement ratio [SER], functional tumor volume [FTV], and washout fraction [WF]), radiomics features (108 total features reflecting tumor morphology, signal intensity, and texture), and MVD (by histologic CD31 immunostaining) were measured in 27 patients (1/2016–7/2017). Lesions with high MVD levels demonstrated higher peak SER than lesions with low MVD (mean: 1.94 vs. 1.61, area under the receiver operating characteristic curve [AUC] = 0.79, p = 0.009) and higher WF (mean: 50.6% vs. 22.5%, AUC = 0.87, p = 0.001). Several radiomics texture features were also promising for predicting increased MVD (maximum AUC = 0.84, p = 0.002). Our study suggests DCE-MRI can non-invasively assess breast cancer angiogenesis, which could stratify biology and optimize treatments.
Suppression of nuclear spin fluctuations in an InGaAs quantum dot ensemble by GHz-pulsed optical excitation
Authors: Evers E. , Kopteva N. E. , Yugova I. A. , Yakovlev D. R. , Reuter D. , Wieck A. D. , Bayer M. , Greilich A.
Published: April 2021

The coherent electron spin dynamics of an ensemble of singly charged (In,Ga)As/GaAs quantum dots in a transverse magnetic field is driven by periodic optical excitation at 1 GHz repetition frequency. Despite the strong inhomogeneity of the electron g factor, the spectral spread of optical transitions, and the broad distribution of nuclear spin fluctuations, we are able to push the whole ensemble of excited spins into a single Larmor precession mode that is commensurate with the laser repetition frequency. Furthermore, we demonstrate that an optical detuning of the pump pulses from the probed optical transitions induces a directed dynamic nuclear polarization and leads to a discretization of the total magnetic field acting on the electron ensemble. Finally, we show that the highly periodic optical excitation can be used as universal tool for strongly reducing the nuclear spin fluctuations and preparation of a robust nuclear environment for subsequent manipulation of the electron spins, also at varying operation frequencies.
Fisetin inhibits lipopolysaccharide-induced inflammatory response by activating β-catenin, leading to a decrease in endotoxic shock
Authors: Molagoda Ilandarage Menu Neelaka , Jayasingha Jayasingha Arachchige Chathuranga C , Choi Yung Hyun , Jayasooriya Rajapaksha Gedara Prasad Tharanga , Kang Chang-Hee , Kim Gi-Young
Published: April 2021

Fisetin is a naturally occurring flavonoid that possesses several pharmacological benefits including anti-inflammatory activity. However, its precise anti-inflammatory mechanism is not clear. In the present study, we found that fisetin significantly inhibited the expression of proinflammatory mediators, such as nitric oxide (NO) and prostaglandin E2 (PGE2), and cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Additionally, fisetin attenuated LPS-induced mortality and abnormalities in zebrafish larvae and normalized the heart rate. Fisetin decreased the recruitment of macrophages and neutrophils to the LPS-microinjected inflammatory site in zebrafish larvae, concomitant with a significant downregulation of proinflammatory genes, such as inducible NO synthase (iNOS), cyclooxygenase-2a (COX-2a), IL-6, and TNF-α. Fisetin inhibited the nuclear localization of nuclear factor-kappa B (NF-κB), which reduced the expression of pro-inflammatory genes. Further, fisetin inactivated glycogen synthase kinase 3β (GSK-3β) via phosphorylation at Ser9, and inhibited the degradation of β-catenin, which consequently promoted the localization of β-catenin into the nucleus. The pharmacological inhibition of β-catenin with FH535 reversed the fisetin-induced anti-inflammatory activity and restored NF-κB activity, which indicated that fisetin-mediated activation of β-catenin results in the inhibition of LPS-induced NF-κB activity. In LPS-microinjected zebrafish larvae, FH535 promoted the migration of macrophages to the yolk sac and decreased resident neutrophil counts in the posterior blood island and induced high expression of iNOS and COX-2a, which was accompanied by the inhibition of fisetin-induced anti-inflammatory activity. Altogether, the current study confirmed that the dietary flavonoid, fisetin, inhibited LPS-induced inflammation and endotoxic shock through crosstalk between GSK-3β/β-catenin and the NF-κB signaling pathways.
The influence of wisdom tooth impaction and occlusal support on mandibular angle and condyle fractures
Authors: Mohammed Al-Sharani Hesham , Bin Zhang , Ahmed Mashrah Mubarak , Galvão Endi Lanza , Ahmed Al-Moraissi Essam , Ali Al-Aroomi Maged , Ahmed Sakran Karim , Gabriel Moreira Falci Saulo
Published: April 2021

This study aimed to analyze the relationship of the occlusal support together with the lower third molars to the mandibular fractures of the angle and condyle among patients in our medical institutions. This was a retrospective study that reviewed the medical records and radiographs of all patients treated for mandibular fractures from 2015 to 2019. The data collected by using picture archiving and communicating system. Only records with mandibular angle or condyle fractures were included. The dependent variable was the presence of the fractures of the mandibular angle or condyle. The independent variables were epidemiological data, third molar characteristics, existence or absence of occlusal support. The data was analyzed through Univariate logistic regression and multivariate logistic regression. From a total of 187 mandibular fractures, 44 presented mandibular angle fracture and 29 shown condyle fractures. The average age was 40.34 ± 13.47 years. The absence of occlusal support increased the chance of condyle fractures by 5.1 times (95% CI 1.61–17.29). The lack of occlusal support is more associated with condyle fractures than the presence of occlusal support, regardless of third molar presence and characteristics and other variables evaluated.
Resonance frequency is not always stable over time and could be related to the inter-beat interval
Authors: Capdevila Lluis , Parrado Eva , Ramos-Castro Juan , Zapata-Lamana Rafael , Lalanza Jaume F.
Published: April 2021

Heart Rate Variability Biofeedback (HRVB) is based on breathing at an optimal rate (or resonance frequency, RF) corresponding to the respiratory sinus arrhythmia (RSA). Our aim is to check whether the RF is a stable factor and analyse the HRV parameters individually per each breathing rate, comparing it with free slow breathing. A sample of 21 participants were trained in a test–retest HRVB protocol. The results indicated that RF changed between Test and Retest sessions in 66.7% of participants. This instability could be related to the average of interbeat interval (IBI). HRV time domain parameters (SDNN and RMSSD) were significantly higher for RF than for other breathing rates, including 6 breath/min and free slow breathing. Free slow breathing showed a lower heart rate averages than RF and other slow breathing rates. Overall, our study suggests the relevance of assessing RF individually and before each HRVB session, because the maximum cardiovascular benefits in terms of increasing HRV were found only at RF. Thus, breathing at the individualized and momentary frequency of resonance increases cardiac variability.