bluuebunny/crossref_metadata_2025 huggingface dataset:
Phenotypic clustering of dilated cardiomyopathy patients highlights important pathophysiological differences
Authors: Verdonschot Job A J , Merlo Marco , Dominguez Fernando , Wang Ping , Henkens Michiel T H M , Adriaens Michiel E , Hazebroek Mark R , Masè Marco , Escobar Luis E , Cobas-Paz Rafael , Derks Kasper W J , van den Wijngaard Arthur , Krapels Ingrid P C , Brunner Han G , Sinagra Gianfranco , Garcia-Pavia Pablo , Heymans Stephane R B
Published: September 2020

Aims

The dilated cardiomyopathy (DCM) phenotype is the result of combined genetic and acquired triggers. Until now, clinical decision-making in DCM has mainly been based on ejection fraction (EF) and NYHA classification, not considering the DCM heterogenicity. The present study aimed to identify patient subgroups by phenotypic clustering integrating aetiologies, comorbidities, and cardiac function along cardiac transcript levels, to unveil pathophysiological differences between DCM subgroups.

Methods and results

We included 795 consecutive DCM patients from the Maastricht Cardiomyopathy Registry who underwent in-depth phenotyping, comprising extensive clinical data on aetiology and comorbodities, imaging and endomyocardial biopsies. Four mutually exclusive and clinically distinct phenogroups (PG) were identified based upon unsupervised hierarchical clustering of principal components: [PG1] mild systolic dysfunction, [PG2] auto-immune, [PG3] genetic and arrhythmias, and [PG4] severe systolic dysfunction. RNA-sequencing of cardiac samples (n = 91) revealed a distinct underlying molecular profile per PG: pro-inflammatory (PG2, auto-immune), pro-fibrotic (PG3; arrhythmia), and metabolic (PG4, low EF) gene expression. Furthermore, event-free survival differed among the four phenogroups, also when corrected for well-known clinical predictors. Decision tree modelling identified four clinical parameters (auto-immune disease, EF, atrial fibrillation, and kidney function) by which every DCM patient from two independent DCM cohorts could be placed in one of the four phenogroups with corresponding outcome (n = 789; Spain, n = 352 and Italy, n = 437), showing a feasible applicability of the phenogrouping.

Conclusion

The present study identified four different DCM phenogroups associated with significant differences in clinical presentation, underlying molecular profiles and outcome, paving the way for a more personalized treatment approach.
An estimation of patients at potential risk for drug-induced sexual dysfunction using pharmacy dispensing data
Authors: Gordijn Rineke , Nicolai Melianthe P J , Elzevier Henk W , Guchelaar Henk-Jan , Teichert Martina
Published: September 2020

Background and Objectives

Adverse drug reactions on sexual functioning (sADRs) may seriously decrease a person’s quality of life. A multitude of diseases and drugs are known risk factors for sexual dysfunction. To inform patients better about these potential effects, more insight is needed on the estimated number of patients at high risk for sADRs and their characteristics.

Methods

This cross-sectional study estimated the number of patients in the Netherlands who were dispensed drugs with a potential very high risk (>10%) or high risk (1–10%) for sADRs as registered in the Summary of Product Characteristics, the official drug information text in Europe.

Results

In April 2019, 2.06% of the inhabitants of the Netherlands received drugs with >10% risk for sADRs and 7.76% with 1–10% risk. The majority of these patients had at least one additional risk factor for decreased sexual function such as high age or depression. Almost half of the patients were identified with two or more morbidities influencing sexual functioning. Paroxetine, sertraline and spironolactone were the most dispensed drugs with a potential >10% risk for sADRs. One-third of their first dispenses were not followed by a second dispense, with a higher risk of discontinuation for a decreasing number of morbidities.

Conclusion

About 1 in 11 inhabitants of the Netherlands was dispensed a drug with a potential high risk for sADRs, often with other risk factors for sexual complaints. Further research is needed whether these users actually experience sADRs, to understand its impact on multimorbid patients and to provide alternatives if needed.
Magnetic fabric and archaeomagnetic analyses of anthropogenic ash horizons in a cave sediment succession (Crvena Stijena site, Montenegro)
Authors: Bradák Balázs , Carrancho Ángel , Herrejón Lagunilla Ángela , Villalaín Juan J , Monnier Gilliane F , Tostevin Gilbert , Mallol Carolina , Pajović Goran , Baković Mile , Borovinić Nikola
Published: September 2020

An archaeomagnetic, rock magnetic and magnetic fabric study has been carried out on seven anthropogenic ash horizons in the Middle Palaeolithic sedimentary level XXIV at the rock shelter of Crvena Stijena (‘Red Rock’), Montenegro. The study has multiple goals, including the identification of iron bearing minerals formed during combustion, assessment of the suitability of these combustion features for recording the Earth´s magnetic field direction, revelation of the magnetic fabric and its significance in the characterization of cave (rock shelter) burnt facies, and identification of post-burning alteration processes. Magnetite has been identified as the main ferromagnetic component of the ash. The ash layers exhibit a high thermomagnetic reversibility in contrast to the irreversible behaviour of their subjacent burnt black layers which is related to the different temperatures attained. Seven mean archaeomagnetic directions were obtained with acceptable statistical values indicating that these features recorded the field direction at the time of burning. However, some of them are out of the expected range of secular variation for mid-latitude regions suggesting post-burning alterations. The magnetic fabric of the ash was characterized by anisotropy of low field magnetic susceptibility measurements. Statistical analysis (box and whisker plot) of the basic anisotropy parameters, such as foliation, lineation, degree of anisotropy and the shape parameter, along with the alignment of the principal susceptibilities on stereoplots, revealed variation among the ash units. The diverse, oblate to prolate, lineated or strongly foliated, quasi-horizontally and vertically oriented fabrics of the units may indicate different slope processes, such as orientation by gravity, solifluction, run-off water, quasi-vertical migration of groundwater and post-burning/post-depositional alteration of the fabric by rockfall impact. In sum, the magnetic characterization of the ash layers has shown the occurrence of different post-burning alteration processes previously not identified at the site. Alteration processes in prehistoric combustion features are often identified from macroscopic observations but our study demonstrates that multiple processes can affect them and are usually unnoted because they take place on a microscopic scale. Their identification is critical for a correct chronological and cultural interpretation of a site (e.g. collection of samples for dating, stratigraphic displacement of remains), especially if significant alterations are involved. Magnetic methods are therefore a powerful but underutilized tool in palaeolithic research for the identification and evaluation of taphonomic processes affecting prehistoric fires.
Propagation of waves with a wide range of frequencies in digital core samples and dynamic strain anomaly detection: carbonate rock as a case study
Authors: Matsushima Jun , Ali Mohammed Y , Bouchaala Fateh
Published: September 2020

Recent advancements in various types of seismic measurement methods, such as sonic logging, vertical seismic profiling (VSP) and surface seismic surveys, have allowed the high-quality measurement of seismic wave propagation over a broad frequency range. To elucidate the relationship between seismic wave propagation captured by various seismic methods at widely different frequencies and in highly heterogeneous zones (e.g. fractures, vuggy zones) developed in carbonate reservoirs, laboratory measurements have been conducted over a broad frequency range. However, existing laboratory methods measure the effective properties over an entire core sample. Furthermore, there are few laboratory measurements of individual fracture stiffnesses. We propose a method to indirectly estimate the local properties caused by local anomalies (e.g. fractures) in a core sample over a broad frequency range from the dynamic elastic properties of a dry core sample using synthetic seismic waveforms generated from a digital volume of the core sample. 3-D numerical simulations were conducted over a broad frequency range using a digital core model produced by X-ray computed tomography. The proposed method was applied to numerical models and two types (fractured and vuggy) of carbonate core plugs acquired in an Abu Dhabi oil field, with the frequency ranging from 200 Hz to 100 kHz in the tests. Local strain anomalies and their frequency dependencies were successfully detected in the fractured core plug. Such frequency-dependent local responses could be associated with the micromechanics of incomplete solid–solid contacts at fractures or the heterogeneity of core samples, and thus with the frequency-dependent fracture stiffness. It was also demonstrated that the heterogeneity-induced local strain in a vuggy core plug may affect the accuracy of existing low-frequency laboratory measurements.
Climate change accelerates range expansion of the invasive non-native species, the Pacific oyster,Crassostrea gigas
Authors: King Nathan G , Wilmes Sophie B , Smyth David , Tinker Jonathan , Robins Peter E , Thorpe Jamie , Jones Laurence , Malham Shelagh K
Published: September 2020

Invasive non-native species and global warming are two of the greatest components of global ecosystem change. The Pacific oyster, Crassostrea gigas, is the world most cultivated shellfish and was introduced throughout the Northwest European Shelf (NWES) under the premise it could not complete its life cycle. Recent warming trends have changed this and wild populations can be found as far north as Nordic Scandinavia. Under the RCP8.5 concentration pathway, we predict that the majority of NWES coastline will be within C. gigas’s thermal recruitment niche by 2100. Given the widespread occurrence of current naturalized C. gigas populations, its large larval dispersal potential and a lack of feasible management solutions, C. gigas will likely undergo a considerable range expansion this century. The time taken to reach maturity is predicted to decrease by up to 60 days, which may lead to precocious spawning events, facilitating expansion further. Crassostrea gigas can form extensive reefs completely transforming native systems. This may compromise native biodiversity, protected habitats, and commercial species. However, naturalization can also deliver a number of beneficial ecosystem goods and services to human society. Whether naturalization is deemed positive or negative will depend on biogeographic context, the perceptions of stakeholders, and the wider management priorities.
Multidecadal fluctuations of threespine stickleback in the White Sea and their correlation with temperature
Authors: Lajus Dmitry , Ivanova Tatiana , Rybkina Elena , Lajus Julia , Ivanov Mikhail
Published: September 2020

A major challenge of contemporary marine science is disentangling consequences of climate change from other impacts, and studying non-target species and using historical resources to see long-term trends can meet this need. However, such data can be fragmented, and here, we demonstrate the potential of leveraging across sources for insight. We assembled a variety of historical sources such as scientific and personal observations, anecdotal information, and archival fisheries data to create an abundance time series on threespine stickleback Gasterosteus aculeatus in the White Sea starting in the late 19th century—the longest time series for this species. Stickleback peaked during the warm period of the 1920–1940s and declined during the colder period of the 1950–1990s and now is the most numerous vertebrate in the sea. Analyses of historical and recent time series based on our own data (2007–2019) showed that stickleback abundance decreases during colder winters. It is not associated with zooplankton biomass, positively correlated with herring Clupea sp. catches and negatively with navaga Eleginus navaga catches. Large population size and food web interactions suggest that change in stickleback abundance has the potential to affect the entire White Sea ecosystem.
Weak and strong error analysis of recursive quantization: a general approach with an application to jump diffusions
Authors: Pagès Gilles , Sagna Abass
Published: September 2020

Observing that the recent developments of spatial discretization schemes based on recursive (product) quantization can be applied to a wide family of discrete time Markov chains, including all standard time discretization schemes of diffusion processes, we establish in this paper a generic strong error bound for such quantized schemes under a Lipschitz propagation assumption. We also establish a marginal weak error estimate that is entirely new to our best knowledge. As an illustration of their generality, we show how to recursively quantize the Euler scheme of a jump diffusion process, including details on the algorithmic aspects grid computation, transition weight computation, etc. Finally, we test the performances of the recursive quantization algorithm by pricing a European put option in a jump Merton model.
Postoperative Imaging Appearance of an Implantable Three-dimensional Bioabsorbable Tissue Marker After Breast Surgery: Initial Experience at a Single Institution
Authors: Chen Christine , Dodelzon Katerina , Ginter Paula S , Drotman Michele B , Arleo Elizabeth K
Published: September 2020

Objective

Three-dimensional bioabsorbable tissue marker (BTM) placement during breast surgery is performed for the purpose of improved surgical cavity delineation for radiotherapy and improved cosmetic outcome. The purpose of this study is to evaluate the postsurgical imaging findings of BTM.

Methods

This Institutional Review Board-approved retrospective review included all patients implanted with BTM at breast surgery from January 2017 to September 2018. Demographics, tumor characteristics, imaging, and histologic findings were evaluated. Medical records were reviewed during a three-year period to evaluate for tumor recurrence.

Results

Ninety-seven patients had BTM implanted, of which 76 patients had imaging follow-up of at least 1 year. Of the 76 patients who had mammographic follow-up, 3 (3.9%) developed suspicious microcalcifications requiring biopsy, yielding ductal carcinoma in-situ in 2 patients and benign calcifications in 1 patient. Of 61 patients who had sonographic follow-up, 44 (72.1%) patients had complex fluid collections containing avascular, heterogeneously hyperechoic solid components, which remained stable or decreased in size over time; no recurrent tumors were found in this group. One patient (1.6%) had a vascular solid mass, which yielded recurrent papilloma. Four (6.6%) patients developed irregular hypoechoic masses at the surgical site, one of which corresponded with a developing asymmetry mammographically; biopsy yielded fibromatosis. Tissue sampling of the remaining three cases yielded invasive ductal carcinoma, fat necrosis, and radiation changes, respectively.

Conclusion

Accurate identification of the expected postoperative imaging appearance of BTM may prevent unnecessary biopsy. Suspicious findings necessitating biopsy are pleomorphic calcifications, developing asymmetry and vascular and irregular hypoechoic masses.
A novel glycine-rich domain protein, GRDP1, functions as a critical feedback regulator for controlling cell death and disease resistance in rice
Authors: Zhao Xiaosheng , Qiu Tiancheng , Feng Huijing , Yin Changfa , Zheng Xunmei , Yang Jun , Peng You-Liang , Zhao Wensheng
Published: September 2020

Lesion mimic mutants constitute a valuable genetic resource for unraveling the signaling pathways and molecular mechanisms governing the programmed cell death and defense responses of plants. Here, we identified a lesion mimic mutant, spl-D, from T-DNA insertion rice lines. The mutant exhibited higher accumulation of H2O2, spontaneous cell death, decreased chlorophyll content, up-regulation of defense-related genes, and enhanced disease resistance. The causative gene, OsGRDP1, encodes a cytosol- and membrane-associated glycine-rich domain protein. OsGRDP1 was expressed constitutively in all of the organs of the wild-type plant, but was up-regulated throughout plant development in the spl-D mutant. Both the overexpression and knockdown (RNAi) of OsGRDP1 resulted in the lesion mimic phenotype. Moreover, the intact-protein level of OsGRDP1 was reduced in the spotted leaves from both overexpression and RNAi plants, suggesting that the disruption of intact OsGRDP1 is responsible for lesion formation. OsGRDP1 interacted with an aspartic proteinase, OsAP25. In the spl-D and overexpression plants, proteinase activity was elevated, and lesion formation was partially suppressed by an aspartic proteinase inhibitor. Taken together, our results reveal that OsGRDP1 is a critical feedback regulator, thus contributing to the elucidation of the mechanism underlying cell death and disease resistance.
Carbon, isotopic ratio 12C/13C, and nitrogen in solar twins: constraints for the chemical evolution of the local disc
Authors: Botelho R B , Milone A de C , Meléndez J , Alves-Brito A , Spina L , Bean J L
Published: September 2020

Abundances of light elements in dwarf stars of different ages are important constraints for stellar yields, Galactic chemical evolution and exoplanet chemical composition studies. We have measured C and N abundances and 12C/13C ratios for a sample of 63 solar twins spanning a wide range in age, based on spectral synthesis of a comprehensive list of CH A-X and CN B-X features using HARPS spectra. The analysis of 55 thin disc solar twins confirms the dependences of [C/Fe] and [N/Fe] on [Fe/H]. [N/Fe] is investigated as a function of [Fe/H] and age for the first time for these stars. Our derived correlation [C/Fe]–age agrees with works for solar-type stars and solar twins, but the [N/Fe]–age correlation does not. The relations [C,N/Fe]–[Fe/H] and [C,N/Fe]–age for the solar twins lay under solar. 12C/13C is found correlated with [Fe/H] and seems to have decreased along the evolution of the local thin disc. Predictions from chemical evolution models for the solar vicinity corroborate the relations [C,N/Fe]–[Fe/H], 12C/13C–age, and [N/O]–[O/H], but do not for the 12C/13C–[Fe/H] and [C/O]–[O/H] relations. The N/O ratio in the Sun is placed at the high end of the homogeneous distribution of solar twins, which suggests uniformity in the N–O budget for the formation of icy planetesimals, watery superearths, and giant planets. C and N had different nucleosynthetic origins along the thin disc evolution, as shown by the relations of [C/N], [C/O], and [N/O] against [O/H] and age. [C/N] and [C/O] are particularly observed increasing in time for solar twins younger than the Sun.
A time-dependent particle acceleration and emission model: understanding particle spectral evolution and blazar flares
Authors: Zheng Y G , Kang S J , Yang C Y , Bai J M
Published: September 2020

The jets of blazars are renowned for their multiwavelength flares and rapid extreme variability; however, there are still some important unanswered questions about the physical processes responsible for these spectral and temporal changes in emission properties. In this article, we develop a time-dependent particle evolution model for the time-varying emission spectrum of blazars. In the model, we introduce time-dependent electric and magnetic fields, which consistently include the variability of relevant physical quantities in the transport equation. The evolution of the electron distribution is solved numerically from a generalized transport equation that contains terms describing the electrostatic, first- and second-order Fermi acceleration, escape of particles due to both advection and spatial diffusion, and also energy losses due to synchrotron emission and inverse-Compton scattering of both synchrotron and external ambient photon fields. We find that the light-curve profiles of blazars are consistent with the particle spectral evolution resulting from time-dependent electric and magnetic fields, rather than the effects of acceleration or cooling processes. The proposed model is able to account simultaneously for the variability of both the energy spectrum and the light-curve profile of the BL Lac object Mrk 421, with reasonable assumptions about the physical parameters. The results indicate strongly that the magnetic field evolution in the dissipated region of a blazar jet can account for the variabilities.
The detection of solid phosphorus and fluorine in the dust from the coma of comet 67P/Churyumov–Gerasimenko
Authors: Gardner Esko , Lehto Harry J , Lehto Kirsi , Fray Nicolas , Bardyn Anaïs , Lönnberg Tuomas , Merouane Sihane , Isnard Robin , Cottin Hervé , Hilchenbach Martin ,   the COSIMA team
Published: September 2020

Here, we report the detection of phosphorus and fluorine in solid particles collected from the inner coma of comet 67P/Churyumov–Gerasimenko measured with the COmetary Secondary Ion Mass Analyser (COSIMA) instrument on-board the Rosetta spacecraft, only a few kilometers away from the comet nucleus. We have detected phosphorus-containing minerals from the presented COSIMA mass spectra, and can rule out e.g. apatite minerals as the source of phosphorus. This result completes the detection of life-necessary CHNOPS-elements in solid cometary matter, indicating cometary delivery as a potential source of these elements to the young Earth. Fluorine was also detected with CF+ secondary ions originating from the cometary dust.
Measuring interstellar delays of PSR J0613−0200 over 7 yr, using the Large European Array for Pulsars
Authors: Main R A , Sanidas S A , Antoniadis J , Bassa C , Chen S , Cognard I , Gaikwad M , Hu H , Janssen G H , Karuppusamy R , Kramer M , Lee K J , Liu K , Mall G , McKee J W , Mickaliger M B , Perrodin D , Stappers B W , Tiburzi C , Wucknitz O , Wang L , Zhu W W
Published: September 2020

Using data from the Large European Array for Pulsars, and the Effelsberg telescope, we study the scintillation parameters of the millisecond pulsar PSR J0613−0200 over a 7 yr timespan. The ‘secondary spectrum’ – the 2D power spectrum of scintillation – presents the scattered power as a function of time delay, and contains the relative velocities of the pulsar, observer, and scattering material. We detect a persistent parabolic scintillation arc, suggesting scattering is dominated by a thin, anisotropic region. The scattering is poorly described by a simple exponential tail, with excess power at high delays; we measure significant, detectable scattered power at times out to ${\sim}5 \, \mu {\rm s}$, and measure the bulk scattering delay to be between 50 to 200 ns with particularly strong scattering throughout 2013. These delays are too small to detect a change of the pulse profile shape, yet they would change the times of arrival as measured through pulsar timing. The arc curvature varies annually, and is well fitted by a one-dimensional scattering screen ${\sim}40{{\ \rm per\ cent}}$ of the way towards the pulsar, with a changing orientation during the increased scattering in 2013. Effects of uncorrected scattering will introduce time delays correlated over time in individual pulsars, and may need to be considered in gravitational wave analyses. Pulsar timing programmes would benefit from simultaneously recording in a way that scintillation can be resolved, in order to monitor the variable time delays caused by multipath propagation.
Reverberation of pulsar wind nebulae (I): impact of the medium properties and other parameters upon the extent of the compression
Authors: Bandiera R , Bucciantini N , Martín J , Olmi B , Torres D F
Published: September 2020

The standard approach to the long-term evolution of pulsar wind nebulae (PWNe) is based on one-zone models treating the nebula as a uniform system. In particular for the late phase of evolved systems, many of the generally used prescriptions are based on educated guesses for which a proper assessment lacks. Using an advanced radiative code, we evaluate the systematic impact of various parameters, like the properties of the supernova ejecta, of the inner pulsar, as well of the ambient medium, upon the extent of the reverberation phase of PWNe. We investigate how different prescriptions shift the starting time of the reverberation phase, how this affects the amount of the compression, and how much of this can be ascribable to the radiation processes. Some critical aspects are the description of the reverse shock evolution, the efficiency by which at later times material from the ejecta accretes on to the swept-up shell around the PWN, and finally the density, velocity, and pressure profiles in the surrounding supernova remnant. We have explicitly treated the cases of the Crab Nebula, and of J1834.9−0846, taken to be representatives of the more and the less energetic pulsars, respectively. Especially for the latter object, the prediction of large compression factors is confirmed, even larger in the presence of radiative losses, also confirming our former prediction of periods of superefficiency during the reverberation phase of some PWNe.
Multiwavelength study of different flaring and low-activity states of blazar 4C+21.35
Authors: Bhattacharya Debbijoy , Mohana A Krishna , Bhattacharyya Subir , Bhatt Nilay , Stalin C S
Published: September 2020

Blazars, a class of active galactic nuclei, emit over the entire accessible electromagnetic spectrum and modelling of their broad-band spectral energy distribution (SED) is the key to constrain the underlying emission mechanisms. Here we report the results on the one-zone leptonic emission modelling carried out on the blazar 4C+21.35 using multiwavelength data spanning over the period 2008–2018. Broad-band SED modelling using γ-ray data from Fermi-Large Area Telescope, X-ray data from Swift-XRT and AstroSat, and UV–optical data from Swift-UVOT, AstroSat, and Catalina Real-Time Transient Survey was carried out at seven different epochs, including three γ-ray flaring episodes and four quiescent periods (three long-term averaged ones and one during AstroSat observing period). Our SED modelling suggests that two compact emission regions originating at a different time outside the broad-line region and moving away from the core with variation primarily in the jet electron spectra can explain the emission from the high-, moderate-, and low-activity periods. The emissions from high- and first low-activity states are likely to have originated in the first region. The moderate- and second low-activity states are likely due to the second emission region with fresh particle acceleration/injection at a later time.
Resolved star formation in the metal-poor star-forming region Magellanic Bridge C
Authors: Kalari Venu M , Rubio Monica , Saldaño Hugo P , Bolatto Alberto D
Published: September 2020

Magellanic Bridge C (MB-C) is a metal-poor (∼1/5 Z⊙) low-density star-forming region located 59 kpc away in the Magellanic Bridge, offering a resolved view of the star formation process in conditions different to the Galaxy. From Atacama Large Millimetre Array CO (1–0) observations, we detect molecular clumps associated with candidate young stellar objects (YSOs), pre-main sequence (PMS) stars, and filamentary structure identified in far-infrared imaging. YSOs and PMS stars form in molecular gas having densities between 17 and 200 M⊙ pc−2, and have ages between ≲0.1 and 3 Myr. YSO candidates in MB -C have lower extinction than their Galactic counterparts. Otherwise, our results suggest that the properties and morphologies of molecular clumps, YSOs, and PMS stars in MB -C present no patent differences with respect to their Galactic counterparts, tentatively alluding that the bottleneck to forming stars in regions similar to MB-C is the conversion of atomic gas to molecular.
Tracing the 107 K warm–hot intergalactic medium with UV absorption lines
Authors: Fresco A Y , Péroux C , Merloni A , Hamanowicz A , Szakacs R
Published: September 2020

Today, the majority of the cosmic baryons in the Universe are not observed directly, leading to an issue of ‘missing baryons’ at low redshift. Cosmological hydrodynamical simulations have indicated that a significant portion of them will be converted into the so-called warm–hot intergalactic medium (WHIM), with gas temperature ranging between 105 and 107 K. While the cooler phase of this gas has been observed using O vi and Ne viii absorbers at ultraviolet (UV) wavelengths, the hotter fraction detection relies mostly on observations of O vii and O viii at X-ray wavelengths. Here, we target the forbidden line of [Fe xxi] λ 1354 Å which traces 107 K gas at UV wavelengths, using more than 100 high-spectral resolution ($R\sim 49\, 000$) and high signal to noise VLT/UVES quasar spectra, corresponding to over 600 h of VLT time observations. A stack of these at the position of known Ly α absorbers lead to a 5σ limit of $\log [N\mathrm{([Fe\,{\small XXI}])]\lt }$17.4 (EWrest < 22 mÅ), three orders of magnitude higher than the expected column density of the WHIM $\log [N\mathrm{([Fe\,{\small XXI}])]\lt }$14.5. This work proposes an alternative to X-ray detected 107 K WHIM tracers, by targeting faint lines at UV wavelengths from the ground benefiting from higher instrumental throughput, enhanced spectral resolution, longer exposure times, and increased number of targets. The number of quasar spectra required to reach this theoretical column density with future facilities including 4MOST, ELT/HIRES, MSE, and the Spectroscopic Telescope appears challenging at present. Probing the missing baryons is essential to constrain the accretion and feedback processes that are fundamental to galaxy formation.
Ejection of supermassive black holes and implications for merger rates in fuzzy dark matter haloes
Authors: El-Zant Amr A , Roupas Zacharias , Silk Joseph
Published: September 2020

Fuzzy dark matter (FDM) consisting of ultralight axions has been invoked to alleviate galactic-scale problems in the cold dark matter scenario. FDM fluctuations, created via the superposition of waves, can impact the motion of a central supermassive black hole (SMBH) immersed in an FDM halo. The SMBH will undergo a random walk, induced by FDM fluctuations, that can result in its ejection from the central region. This effect is strongest in dwarf galaxies, accounting for wandering SMBHs and the low detection rate of active galactic nuclei in dwarf spheroidal galaxies. In addition, a lower bound on the allowed axion masses is inferred both for Sagitarius A* and heavier SMBH; to avoid ejection from the galactic centres, axion masses of the order of 10−22 eV or lighter are excluded. Stronger limits are inferred for merging galaxies. We find that the event rate of SMBH mergers in FDM haloes and the associated SMBH growth rates can be reduced by at least an order of magnitude.
NGTS-12b: A sub-Saturn mass transiting exoplanet in a 7.53 day orbit
Authors: Bryant Edward M , Bayliss Daniel , Nielsen Louise D , Veras Dimitri , Acton Jack S , Anderson David R , Armstrong David J , Bouchy François , Briegal Joshua T , Burleigh Matthew R , Cabrera Juan , Casewell Sarah L , Chaushev Alexander , Cooke Benjamin F , Csizmadia Szilárd , Eigmüller Philipp , Erikson Anders , Gill Samuel , Gillen Edward , Goad Michael R , Grieves Nolan , Günther Maximilian N , Henderson Beth , Hogan Aleisha , Jenkins James S , Lendl Monika , McCormac James , Moyano Maximiliano , Queloz Didier , Rauer Heike , Raynard Liam , Smith Alexis M S , Tilbrook Rosanna H , Udry Stéphane , Vines Jose I , Watson Christopher A , West Richard G , Wheatley Peter J
Published: September 2020

We report the discovery of the transiting exoplanet NGTS-12b by the Next Generation Transit Survey (NGTS). The host star, NGTS-12, is a V = 12.38 mag star with an effective temperature of Teff = 5690 ± 130 K. NGTS-12b orbits with a period of P = 7.53 d, making it the longest period planet discovered to date by the main NGTS survey. We verify the NGTS transit signal with data extracted from the Transiting Exoplanet Survey Satellite (TESS) full-frame images, and combining the photometry with radial velocity measurements from HARPS and FEROS we determine NGTS-12b to have a mass of 0.208 ± 0.022 MJ and a radius of 1.048 ± 0.032 RJ. NGTS-12b sits on the edge of the Neptunian desert when we take the stellar properties into account, highlighting the importance of considering both the planet and star when studying the desert. The long period of NGTS-12b combined with its low density of just 0.223 ± 0.029 g cm−3 make it an attractive target for atmospheric characterization through transmission spectroscopy with a Transmission Spectroscopy Metric of 89.4.
Seed magnetic fields in turbulent small-scale dynamos
Authors: Seta Amit , Federrath Christoph
Published: September 2020

Magnetic fields in galaxies and galaxy clusters are amplified from a very weak seed value to the observed $\mu$G strengths by the turbulent dynamo. The seed magnetic field can be of primordial or astrophysical origin. The strength and structure of the seed field, on the galaxy or galaxy cluster scale, can be very different, depending on the seed-field generation mechanism. The seed field first encounters the small-scale dynamo, thus we investigate the effects of the strength and structure of the seed field on the small-scale dynamo action. Using numerical simulations of driven turbulence and considering three different seed-field configurations: (1) uniform field, (2) random field with a power-law spectrum, and (3) random field with a parabolic spectrum, we show that the strength and statistical properties of the dynamo-generated magnetic fields are independent of the details of the seed field. We demonstrate that, even when the small-scale dynamo is not active, small-scale magnetic fields can be generated and amplified linearly due to the tangling of the large-scale field. In the presence of the small-scale dynamo action, we find that any memory of the seed field for the non-linear small-scale dynamo generated magnetic fields is lost and thus, it is not possible to trace back seed-field information from the evolved magnetic fields in a turbulent medium.
Systematic use of synthetic 5′-UTR RNA structures to tune protein translation improves yield and quality of complex proteins in mammalian cell factories
Authors: Eisenhut Peter , Mebrahtu Aman , Moradi Barzadd Mona , Thalén Niklas , Klanert Gerald , Weinguny Marcus , Sandegren Anna , Su Chao , Hatton Diane , Borth Nicole , Rockberg Johan
Published: September 2020

Predictably regulating protein expression levels to improve recombinant protein production has become an important tool, but is still rarely applied to engineer mammalian cells. We therefore sought to set-up an easy-to-implement toolbox to facilitate fast and reliable regulation of protein expression in mammalian cells by introducing defined RNA hairpins, termed ‘regulation elements (RgE)’, in the 5′-untranslated region (UTR) to impact translation efficiency. RgEs varying in thermodynamic stability, GC-content and position were added to the 5′-UTR of a fluorescent reporter gene. Predictable translation dosage over two orders of magnitude in mammalian cell lines of hamster and human origin was confirmed by flow cytometry. Tuning heavy chain expression of an IgG with the RgEs to various levels eventually resulted in up to 3.5-fold increased titers and fewer IgG aggregates and fragments in CHO cells. Co-expression of a therapeutic Arylsulfatase-A with RgE-tuned levels of the required helper factor SUMF1 demonstrated that the maximum specific sulfatase activity was already attained at lower SUMF1 expression levels, while specific production rates steadily decreased with increasing helper expression. In summary, we show that defined 5′-UTR RNA-structures represent a valid tool to systematically tune protein expression levels in mammalian cells and eventually help to optimize recombinant protein expression.
Inhibition ofPlasmodium falciparumLysyl-tRNA synthetase via an anaplastic lymphoma kinase inhibitor
Authors: Zhou Jintong , Huang Zhenghui , Zheng Li , Hei Zhoufei , Wang Zhiyong , Yu Biao , Jiang Lubin , Wang Jing , Fang Pengfei
Published: September 2020

Aminoacyl-tRNA synthetases are attractive targets for the development of antibacterial, antifungal, antiparasitic agents and for the treatment of other human diseases. Lysyl-tRNA synthetase (LysRS) from this family has been validated as a promising target for the development of antimalarial drugs. Here, we developed a high-throughput compatible assay and screened 1215 bioactive compounds to identify Plasmodium falciparum cytoplasmic LysRS (PfLysRS) inhibitor. ASP3026, an anaplastic lymphoma kinase inhibitor that was used in clinical trials for the treatment of B-cell lymphoma and solid tumors, was identified as a novel PfLysRS inhibitor. ASP3026 suppresses the enzymatic activity of PfLysRS at nanomolar potency, which is >380-fold more effective than inhibition of the human counterpart. In addition, the compound suppressed blood-stage P. falciparum growth. To understand the molecular mechanism of inhibition by ASP3026, we further solved the cocrystal structure of PfLysRS-ASP3026 at a resolution of 2.49 Å, providing clues for further optimization of the compound. Finally, primary structure-activity relationship analyses indicated that the inhibition of PfLysRS by ASP3026 is highly structure specific. This work not only provides a new chemical scaffold with good druggability for antimalarial development but also highlights the potential for repurposing kinase-inhibiting drugs to tRNA synthetase inhibitors to treat human diseases.
Structural analysis of SARS-CoV-2 genome and predictions of the human interactome
Authors: Vandelli Andrea , Monti Michele , Milanetti Edoardo , Armaos Alexandros , Rupert Jakob , Zacco Elsa , Bechara Elias , Delli Ponti Riccardo , Tartaglia Gian Gaetano
Published: September 2020

Specific elements of viral genomes regulate interactions within host cells. Here, we calculated the secondary structure content of >2000 coronaviruses and computed >100 000 human protein interactions with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The genomic regions display different degrees of conservation. SARS-CoV-2 domain encompassing nucleotides 22 500–23 000 is conserved both at the sequence and structural level. The regions upstream and downstream, however, vary significantly. This part of the viral sequence codes for the Spike S protein that interacts with the human receptor angiotensin-converting enzyme 2 (ACE2). Thus, variability of Spike S is connected to different levels of viral entry in human cells within the population. Our predictions indicate that the 5′ end of SARS-CoV-2 is highly structured and interacts with several human proteins. The binding proteins are involved in viral RNA processing, include double-stranded RNA specific editases and ATP-dependent RNA-helicases and have strong propensity to form stress granules and phase-separated assemblies. We propose that these proteins, also implicated in viral infections such as HIV, are selectively recruited by SARS-CoV-2 genome to alter transcriptional and post-transcriptional regulation of host cells and to promote viral replication.
CovalentInDB: a comprehensive database facilitating the discovery of covalent inhibitors
Authors: Du Hongyan , Gao Junbo , Weng Gaoqi , Ding Junjie , Chai Xin , Pang Jinping , Kang Yu , Li Dan , Cao Dongsheng , Hou Tingjun
Published: September 2020

Inhibitors that form covalent bonds with their targets have traditionally been considered highly adventurous due to their potential off-target effects and toxicity concerns. However, with the clinical validation and approval of many covalent inhibitors during the past decade, design and discovery of novel covalent inhibitors have attracted increasing attention. A large amount of scattered experimental data for covalent inhibitors have been reported, but a resource by integrating the experimental information for covalent inhibitor discovery is still lacking. In this study, we presented Covalent Inhibitor Database (CovalentInDB), the largest online database that provides the structural information and experimental data for covalent inhibitors. CovalentInDB contains 4511 covalent inhibitors (including 68 approved drugs) with 57 different reactive warheads for 280 protein targets. The crystal structures of some of the proteins bound with a covalent inhibitor are provided to visualize the protein–ligand interactions around the binding site. Each covalent inhibitor is annotated with the structure, warhead, experimental bioactivity, physicochemical properties, etc. Moreover, CovalentInDB provides the covalent reaction mechanism and the corresponding experimental verification methods for each inhibitor towards its target. High-quality datasets are downloadable for users to evaluate and develop computational methods for covalent drug design. CovalentInDB is freely accessible at http://cadd.zju.edu.cn/cidb/.
Regulation and pharmacological targeting of RAD51 in cancer
Authors: Grundy McKenzie K , Buckanovich Ronald J , Bernstein Kara A
Published: September 2020

Regulation of homologous recombination (HR) is central for cancer prevention. However, too little HR can increase cancer incidence, whereas too much HR can drive cancer resistance to therapy. Importantly, therapeutics targeting HR deficiency have demonstrated a profound efficacy in the clinic improving patient outcomes, particularly for breast and ovarian cancer. RAD51 is central to DNA damage repair in the HR pathway. As such, understanding the function and regulation of RAD51 is essential for cancer biology. This review will focus on the role of RAD51 in cancer and beyond and how modulation of its function can be exploited as a cancer therapeutic.
DDX5 resolves R-loops at DNA double-strand breaks to promote DNA repair and avoid chromosomal deletions
Authors: Yu Zhenbao , Mersaoui Sofiane Y , Guitton-Sert Laure , Coulombe Yan , Song Jingwen , Masson Jean-Yves , Richard Stéphane
Published: September 2020

R-loops are three-stranded structures consisting of a DNA/RNA hybrid and a displaced DNA strand. The regulatory factors required to process this fundamental genetic structure near double-strand DNA breaks (DSBs) are not well understood. We previously reported that cellular depletion of the ATP-dependent DEAD box RNA helicase DDX5 increases R-loops genome-wide causing genomic instability. In this study, we define a pivotal role for DDX5 in clearing R-loops at or near DSBs enabling proper DNA repair to avoid aberrations such as chromosomal deletions. Remarkably, using the non-homologous end joining reporter gene (EJ5-GFP), we show that DDX5-deficient U2OS cells exhibited asymmetric end deletions on the side of the DSBs where there is overlap with a transcribed gene. Cross-linking and immunoprecipitation showed that DDX5 bound RNA transcripts near DSBs and required its helicase domain and the presence of DDX5 near DSBs was also shown by chromatin immunoprecipitation. DDX5 was excluded from DSBs in a transcription- and ATM activation-dependent manner. Using DNA/RNA immunoprecipitation, we show DDX5-deficient cells had increased R-loops near DSBs. Finally, DDX5 deficiency led to delayed exonuclease 1 and replication protein A recruitment to laser irradiation-induced DNA damage sites, resulting in homologous recombination repair defects. Our findings define a role for DDX5 in facilitating the clearance of RNA transcripts overlapping DSBs to ensure proper DNA repair.
Influence of a low-dose tacrolimus protocol on the appearance of de novo donor-specific antibodies during 7 years of follow-up after renal transplantation
Authors: Unagami Kohei , Ishida Hideki , Furusawa Miyuki , Kitajima Kumiko , Hirai Toshihito , Kakuta Yoichi , Toki Daisuke , Shimizu Tomokazu , Omoto Kazuya , Okumi Masayoshi , Nitta Kosaku , Tanabe Kazunari
Published: September 2020

Background

Tacrolimus (TAC) is a key immunosuppressant drug for kidney transplantation (KTx). However, the optimal serum trough level of TAC for good long-term outcomes remains unclear. This study aimed to investigate the relationship between the maintenance TAC trough level and the appearance of de novo donor-specific anti-human leukocyte antigen (HLA) antibodies (dnDSAs).

Methods

A total of 584 KTx recipients were enrolled in this study, of whom 164 developed dnDSAs during the follow-up period and 420 did not.

Results

We found no significant relationship between TAC trough level during the follow-up period and dnDSA incidence. Patients who developed dnDSAs had a significantly greater number of HLA-A/B/DR mismatches (3.4 ± 1.3 versus 2.8 ± 1.5; P < 0.001), were more likely to have preformed DSAs (48.2% versus 27.1%; P < 0.001) and showed poor allograft outcome.

Conclusions

There was no clear relationship between TAC trough level and dnDSA incidence for KTx recipients whose TAC trough levels were kept within the narrow range of 4–6 ng/mL during the immunosuppression maintenance period.
Brain tumors and COVID-19: the patient and caregiver experience*
Authors: Voisin Mathew R , Oliver Kathy , Farrimond Stuart , Chee Tess , Arzbaecher Jean , Kruchko Carol , Maher Mary Ellen , Tse Chris , Cashman Rosemary , Daniels Maureen , Mungoshi Christine , Lamb Sharon , Granero Anita , Lovely Mary , Baker Jenifer , Payne Sally , Zadeh Gelareh
Published: September 2020

Background

Since the COVID-19 pandemic began, thousands of medical procedures and appointments have been canceled or delayed. The long-term effects of these drastic measures on brain tumor patients and caregivers are unknown. The purpose of this study is to better understand how COVID-19 has affected this vulnerable population on a global scale.

Methods

An online 79-question survey was developed by the International Brain Tumour Alliance, in conjunction with the SNO COVID-19 Task Force. The survey was sent to more than 120 brain tumor charities and not-for-profits worldwide and disseminated to pediatric and adult brain tumor patients and caregivers. Responses were collected from April to May 2020 and subdivided by patient versus caregiver and by geographical region.

Results

In total, 1989 participants completed the survey from 33 countries, including 1459 patients and 530 caregivers. There were no significant differences in COVID-19 testing rates (P = .662) or positive cases for brain tumor patients between regions (P = .1068). Caregivers were significantly more anxious than patients (P ≤ .0001). Patients from the Americas were most likely to have lost their jobs due to the pandemic, practiced self-isolation, and received telehealth services (P ≤ .0001). Patients from Europe experienced the most treatment delays (P = .0031). Healthcare providers, brain tumor charities, and not-for-profits were ranked as the most trusted sources of information.

Conclusions

As a result of COVID-19, brain tumor patients and caregivers have experienced significant stress and anxiety. We must continue to provide accessible high-quality care, information, and support in the age of COVID-19.